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2011N130296_01 CONFIDENTIALGlaxoSmithKline group of companies MTF116086

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TITLE PAGE

Division: Worldwide Development Information Type: Protocol Amendment

Title: A pharmacy based open study to evaluate whether pack size affects compliance for subjects diagnosed with diabetes type II who are established on metformin treatment

Compound Number: [GR90570]

Development Phase IV

Effective Date: [2013-JAN-28]

Protocol Amendment Number: 01

Description: MTF116086 is an open-label, randomised, parallel-design study to demonstrate non-inferiority of the metformin small pack to a large monthly pack of metformin in adult subjects aged 18 years or older with type II diabetes. The aim is to test the hypothesis that the introduction of a metformin small pack does not adversely affect subjects’ treatment compliance or behaviour when compared against a large monthly pack when the factor of cost has been removed. All subjects will enter an initial 8-week observational study phase during which usual purchase behaviour and compliance with metformin use will be observed and recorded. At the end of the observational phase, subjects will be randomised between two treatment arms for a treatment period of 20 weeks, one arm using the small pack and the other the large pack. Subjects will be provided with medication free of charge so that the effect of pack size can be studied when the effect of cost has been removed. Subjects will be randomised between two arms: metformin small pack arm or large, monthly metformin pack arm. The primary endpoint will be the mean change from baseline (Week 8) to end of treatment (Week 28) in haemoglobin A1c (HbA1c). Other assessments will include tablet compliance and subject pack preference. Throughout the duration of the study, subjects will remain on their recommended metformin dosing regimens, unless a change of metformin dose is prescribed by their physician. The only factors modified during the interventional phase will be the pack size, the metformin brand for those randomised to small pack arm, and the provision of medication by GSK.

Subject: Medication compliance, Metformin, Socioeconomic

Author(s):

1PPD Inc.; 2Emerging Markets R&D; 3Clinical Statistics; 4Cardiovascular/Metabolic MPC; 5Worldwide Epidemiology, R&D; 6Safety Evaluation & Risk Management

Copyright 2013 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

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2011N130296_01 CONFIDENTIAL GlaxoSmithKline group of companies MTF116086

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Revision Chronology:

2011N130296_00 2012-JUL-25 Original

2011N130296_01 2013-JAN-28 Amendment No. 01:

Updated age restriction in protocol summary

Updated sponsor signature page

Updated contacts for medical monitor and pharmacovigilance. Added details of pharmacy follow-up for subjects lost to follow-up

Added description for QR code on small packs

Updated treatment management for poorly controlled diabetes cases

Updated reporting for SAEs to include PPD

Modified informed consent form aide from audio to video

Removed Cohort A

Removed inclusion criteria pertaining to income level status and part or full purchase of metformin

Revision of maximum daily dose permitted and action to be taken

Removal of HCP visit other than the recommendation to consult the physician treating the subject

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2011N130296_01 CONFIDENTIAL MTF116086

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SPONSOR INFORMATION PAGE

Clinical Study Identifier: MTF116086

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK

Telephone:

Sponsor Contact Address

GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK

Telephone:

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission.

Primary Medical Monitor Contact Information:

Dr MD

Medical Director, PPD Maipu 1300, piso 15 C1006ACT, Buenos Aires Argentina Telephone: /

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GSK Medical Monitor Contact Information

Dr MRCP, DCPSA, FFPM

Emerging Markets R&D GlaxoSmithKline R&D 980 Great West Road Brentford, TW8 9GS United Kingdom e-mail: Telephone (cell phone):

Sponsor Serious Adverse Events (SAEs) Contact Information:

PPD Pharmacovigilance

Maipu 1300, piso 15 C1006ACT, Buenos Aires Argentina Telephone: Fax: Toll free #s: Telefónica: Telecom: Alternative number (paid)

Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP)

GlaxoSmithKline Research Triangle Park, North Carolina, USA Email: Fax:

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

For protocol number MTF116086

• I confirm agreement to conduct the study in compliance with the protocol.

• I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.

• I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name: _____________________________

Investigator Signature Date

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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS ............................................................................................... 9

PROTOCOL SUMMARY ................................................................................................. 10

1. INTRODUCTION ..................................................................................................... 12 1.1. Background .................................................................................................. 12 1.2. Rationale ...................................................................................................... 13

2. OBJECTIVE(S) ........................................................................................................ 14

3. INVESTIGATIONAL PLAN ...................................................................................... 14 3.1. Study Design ................................................................................................ 14 3.2. Discussion of Design .................................................................................... 16

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 16 4.1. Number of Subjects ...................................................................................... 16 4.2. Inclusion Criteria .......................................................................................... 16 4.3. Exclusion Criteria ......................................................................................... 17 4.4. Withdrawal Criteria ....................................................................................... 17 4.5. Screen Failures ............................................................................................ 17

5. STUDY TREATMENTS ........................................................................................... 17 5.1. Investigational Product and Other Study Treatment .................................... 17 5.2. Treatment Assignment ................................................................................. 18 5.3. Blinding ........................................................................................................ 19 5.4. Product Accountability .................................................................................. 19 5.5. Treatment Compliance ................................................................................. 19 5.6. Concomitant Medications and Non-Drug Therapies .................................... 19

5.6.1. Permitted Medications and Non-Drug Therapies .......................... 19 5.7. Treatment after the End of the Study ........................................................... 20 5.8. Treatment of Study Treatment Overdose ..................................................... 20

6. STUDY ASSESSMENTS AND PROCEDURES ...................................................... 21 6.1. Study Assessments ...................................................................................... 22 6.2. Efficacy ......................................................................................................... 23 6.3. Safety ........................................................................................................... 23

6.3.1. Adverse Events ............................................................................. 23 6.3.1.1. Definition of an AE ....................................................... 23 6.3.1.2. Definition of a SAE ...................................................... 24

6.3.2. Pregnancy ..................................................................................... 25 6.3.3. Medical Devices ............................................................................ 26 6.3.4. Time Period and Frequency of Detecting AEs and SAEs ............. 26 6.3.5. Prompt Reporting of SAEs and Other Events to GSK .................. 26

6.3.5.1. Regulatory Reporting Requirements for SAEs ............ 27

7. DATA MANAGEMENT ............................................................................................. 27

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 28

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8.1. Hypotheses .................................................................................................. 28 8.2. Study Design Considerations ....................................................................... 28

8.2.1. Sample Size Assumptions ............................................................ 28 8.2.2. Sample Size Re-estimation ........................................................... 29

8.3. Data Analysis Considerations ...................................................................... 29 8.3.1. Analysis Populations ..................................................................... 29 8.3.2. Analysis Data Sets ........................................................................ 29 8.3.3. Treatment Comparisons ............................................................... 29

8.3.3.1. Primary Comparisons of Interest ................................. 29 8.3.3.2. Other Comparisons of Interest .................................... 30

8.3.4. Interim Analysis ............................................................................. 30 8.3.5. Key Elements of Analysis Plan ..................................................... 30

8.3.5.1. Efficacy Analyses ........................................................ 31 8.3.5.2. Safety Analyses ........................................................... 31

9. STUDY CONDUCT CONSIDERATIONS ................................................................. 31 9.1. Posting of Information on Publicly Available Clinical Trial Registers ............ 31 9.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process .......................................................................................... 31 9.3. Quality Control (Study Monitoring) ............................................................... 32 9.4. Quality Assurance ........................................................................................ 32 9.5. Study and Site Closure................................................................................. 32 9.6. Records Retention........................................................................................ 33 9.7. Provision of Study Results to Investigators, Posting of Information

on Publicly Available Clinical Trials Registers, and Publication ................... 33

10. REFERENCES ........................................................................................................ 35

11. APPENDIX 1: SUMMARY OF PROTOCOL AMENDMENT 01 – 2013 JAN 21 ............................................................................................................................. 37

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LIST OF ABBREVIATIONS

AE Adverse Event GCP Good Clinical Practice GSK GlaxoSmithKline HbA1c Haemoglobin A1c ICH International Conference on Harmonisation IEC Independent Ethics Committee IRB Institutional Review Board ISF Investigator Site File ITT Intent to Treat QR Quick Response RAP Reporting and Analysis Plan SAE Serious Adverse Event US United States WHO World Health Organization

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

NONE SAS

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PROTOCOL SUMMARY

Rationale

The GSK Access to Medicines project is currently investigating how small pack sizes could be used to improve compliance and behaviour when taking high-quality medicines. The overall premise is that cost of the existing pack size may represent an impediment to purchase, and thereby, an impediment to treatment compliance. If so, a proportionally lower-cost, smaller pack size could lead to better treatment compliance. This study is a pilot study evaluating subjects with type II diabetes in Argentina; this will be the first of several planned studies that will collectively evaluate small pack medication for the treatment of chronic non-communicable diseases in populations in emerging markets.

Objective(s)

The objective of the study is to test the hypothesis that the introduction of a metformin small pack does not adversely affect subject compliance or behaviour when compared against a large pack, when the factor of cost is removed.

In addition, the study will generate information about the subjects’ current metformin purchase practice, as observed in the first 8-week observational study period.

The objective of evaluating compliance with a small pack of metformin as compared with compliance with a large pack will include measuring change from baseline in haemoglobin A1c (HbA1c), a well-established biomarker of diabetes disease control which is commonly used in traditional randomised controlled trials of effectiveness of metformin. Compliance, defined as percentage of pills taken and dispensed, will also be recorded and calculated.

Study Design

This will be a 28-week, open-label, randomised, parallel-group study comparing a small pack of metformin with a large pack in adult subjects aged at least 18 years diagnosed with type II diabetes.

Subjects with diagnosed and treated type II diabetes will be recruited and followed at local pharmacies in Argentina. Initially all subjects will be followed for 8 weeks after point of enrolment in an observational manner. During the 8-week observational phase, subjects will purchase metformin and visit the pharmacy per their normal routines. At the end of Week 8, each subject will be randomised to one of two treatment arms to initiate a 20-week interventional phase.

Subjects will be randomised to receive either the small pack treatment or a large pack treatment, both of which will be issued without payment, in order to remove the potential effect of cost on compliance. If a subject is taking metformin twice a day, one small pack will be provided (sufficient for 5 days of treatment). Subjects on metformin three times a day will receive two small packs at each visit (sufficient for 6 days of treatment). The small packs will be available

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at each site in the following doses: 500 mg, 850 mg, and 1000 mg. The large pack will consist of 1 month’s supply of metformin.

There are no scheduled visits for the study, as subject visits to the pharmacy will be based on their needs for further medication and their ability to return to the pharmacy to do so. Once randomised at Week 8, each subject will follow the regimen of his or her treatment arm for an additional 20 weeks. The study will in no way alter the metformin dosage regimen for the subjects’ diabetes management. However, a change of metformin dose is permitted if prescribed during the study by the subject’s physician. Metformin small pack is currently not a marketed product. Therefore, subjects receiving non GSK brand metformin who are randomised to the small pack arm will have their medication switched to GSK metformin during the interventional phase. The criterion under investigation is the package size provided at each pharmacy visit.

HbA1c will be assessed for all subjects at three time points: enrolment (Week 0), baseline (Week 8), and end of study (Week 28). During the corresponding pharmacy visit for each of these time points, HbA1c will be tested with a point-of-care device, which requires a finger prick to obtain blood and provides an immediate result upon analysis in the device.

The study seeks to enrol 288 subjects (in order to randomise 274 subjects, assuming a 5% drop-out rate between enrolment and randomisation). The study assumes 274 subjects will be randomised among two equally distributed randomisation arms; therefore, each randomisation arm will contain 137 subjects. Furthermore, the study assumes a 10% drop-out rate post randomisation, resulting in 123 subjects per arm completing the study.

Study Endpoints/Assessments

Primary endpoint

• Change from baseline in HbA1c The study is designed to show non-inferiority of metformin small pack to metformin large pack in the treatment of type II diabetes, with the primary outcome being the difference in change from baseline (i.e., Week 28 – Week 8) in HbA1c between treatment arms, with a non-inferiority margin of 0.5%. Secondary Endpoints

• Percent compliance throughout the interventional phase of study • Percent compliance throughout the observational study phase • Number of days zero metformin pills were taken • Percentage of subjects with diabetes disease management modifications during

the study • Percentage of subjects requiring a nonroutine visit to a health care professional for

diabetes during the study • Percentage of subjects who prefer their treatment regimens during the study • Reason for missed days or doses throughout the study • Percentage of subjects withdrawn from study

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1. INTRODUCTION

1.1. Background

Diabetes mellitus has a rapidly growing impact worldwide, increasing in prevalence by more than 100% between 1980 and 2008 (Danaei et al, 2011). A systematic analysis of population-based studies of diabetes prevalence (2.7 million participants, 370 country-years) determined that an estimated 347 million adults worldwide have diabetes, with age-standardised prevalence in 2008 of 9.8% for men and 9.2% for women. Prevalence was highest in Oceania, North Africa, the Middle East, and the Caribbean. In 2000, prevalence of self-reported diabetes for males in Latin American and Caribbean cities ranged from 7.3% in Havana, Cuba, to 22.4% in Mexico City, Mexico; for females, it ranged from 11.4% in Buenos Aires, Argentina, to 23.6% in Bridgetown, Barbados (Andrade, 2009).

Diabetes, a chronic disease, has serious health consequences that can be prevented only with careful control of blood glucose levels; however, adherence to regimens may be compromised by a number of factors (Kindmalm et al, 2007). Access to medication for chronic diseases in developing countries may be impaired by restrictions on availability and affordability (Lu et al, 2011; Cameron et al, 2009; Keuguong, 2009). An analysis of data from 45 surveys in a broad range of countries (primarily in Africa, the Middle East, Asia-Pacific, and Latin America, and primarily low- to middle-income) found that, in general, 15 basic medications used to treat common conditions were available in 38% of outlets in the public sector and 64% in the private sector (Cameron et al, 2009).

Meanwhile, the cost burden for medications in developing countries is often prohibitively high in proportion to the country’s and the individual’s income, and medication costs are more often paid out of pocket in developing countries than in developed countries (Lu et al, 2011; McIntyre et al, 2006). A World Health Organization (WHO) analysis found that the percentage of a country’s total health care expenditures incurred for pharmaceuticals increased with decreasing income group, being 19.7% in 46 high-income countries, 23.1% in 37 upper-middle income countries, 27.6% in 44 lower-middle income countries, and 30.4% in 34 low-income countries (Lu et al, 2011). The proportion of pharmaceuticals paid for out of pocket was about two thirds in lower-middle-income countries and more than three quarters in low-income countries. To date, no published data is available in Argentina regarding out of pocket pharmacy expenses. GSK performed an in country research study consisting of 100 pharmacies and found that 63% of patients pay out of pocket for a portion of their metformin medication [unpublished]. An evaluation of health care expenditures in developing countries from 1996 to 2000 for a variety of disease states found that direct costs for health care as a percentage of household income ranged from 3% in Paraguay to 16% in Guatemala, and medication costs often formed a substantial proportion of direct costs (McIntyre et al, 2006). As a percentage of income, health expenditures were disproportionately high for the poor, with the total cost of illness often more than 10% of household income.

There is evidence that affordability of medications, particularly for chronic diseases, can interfere with adherence to treatment regimens. In a Nigerian population with type II diabetes, cost was cited by 36% as a reason for unintentional poor adherence; the most

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common form of intentional nonadherence was omission of individual doses, for reasons including fear of excessive medication use, inconvenience, and taste (Adisa et al, 2009). Among a sociodemographically diverse, chronically ill population in the United States (US), 18% reported that the drug costs had led them to restrict medication use (Heisler et al, 2005). In surveys and qualitative studies among Chinese patients, from 3% to 45% have reported interrupting, suspending, or failing to initiate tuberculosis treatment because of the cost of medication (Long et al, 2011). In developed countries, the percentage of dialysis patients who reported that cost sometimes led them to forgo medication purchases covered a wide range, from 3% in Japan to 29% in the United States (Hirth et al, 2008). The latter study found that, across countries, there was a significant correlation between the percentage of patients reporting any out-of-pocket medication expenditures and the percentage showing nonadherence (R2=0.298).

Evidence from Latin America confirms that diabetes treatment regimens can be a cost burden on households, potentially impairing blood glucose control. In 2005, a majority (52%) of total health expenditures in Mexico for diabetes were paid for out of pocket, with an additional 45% paid for by the government and 3% by private insurance (Arredondo and Barceló, 2007).

Adherence to diabetes treatment is associated with attainment of HbA1c goals. In a Swedish population of patients with type II diabetes recruited from six health centres in 2006, those considered nonadherent to treatment, with <80% of refills obtained, had significantly (p=0.025) higher mean HbA1c than adherent patients (Kindmalm et al, 2007). Similar results were found in patients who had been newly diagnosed with and initiated treatment for diabetes between 1992 and 2001 in the United States (Adams et al, 2008). HbA1c has been used as an indicator of adherence to diabetes treatment (O’Hea et al, 2009).

1.2. Rationale

The GSK Access to Medicines project is currently investigating how small pack sizes could be used to improve adherence to high-quality medicines for lower socioeconomic groups in populations in emerging markets. Patients in this population make decisions every day based on their finances and the immediate needs of themselves and their families. GSK is keen to understand more about how small packs may make a difference to chronic disease management in the longer term.

Small pack sizes may alter patient compliance and behaviour, since more frequent trips to the pharmacy are required. This study attempts to record and understand whether compliance and behaviour changes occur when patients use small packs and whether those changes adversely affect subjects’ treatment management. GSK has a long history of developing high-quality, evidence-based medicines that put the interests of patients first. The study seeks to gain a better understanding of the impact of small pack sizes on subjects’ utilisation, compliance, and preference. Findings from the study will provide information on the utility of small pack treatments in the diabetic type II patient population. For this study, metformin, a first-line treatment for type II diabetes, was chosen as the optimal chronic disease model to study the impact of small packs on patients, as there is a recognised biomarker (HbA1c) to analyse disease control and the

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magnitude of the disease, as stated in Section 1.1. To our knowledge, this is the first scientific study evaluating the effect of small packs of metformin on HbA1c and compliance; additional studies exploring the needs of patients and the efficacy of small pack treatments may be performed in the future.

2. OBJECTIVE(S)

The objective of the study is to test the hypothesis that the introduction of a metformin small pack does not adversely affect subjects’ compliance or behaviour when compared against a large pack, when the factor of cost is removed.


The objective of evaluating compliance with a small pack of metformin compared with a large pack will include measuring change from baseline in HbA1c, a well-established biomarker of diabetes disease control, which is commonly used in traditional randomised controlled trials of the effectiveness of metformin. Compliance, defined as percentage of pills taken and dispensed, will also be recorded and calculated.

3. INVESTIGATIONAL PLAN

3.1. Study Design

The study is an open-label, randomised, parallel-design study comparing use of a small pack of metformin with use of a large pack. The study is site-based, with local pharmacies serving as the sites and pharmacists as principal investigators for the sites. In addition, the study will have an overall National Coordinator who is a medical doctor specialising in diabetes care in Argentina to oversee implementation of the study protocol and provide scientific aid to pharmacy sites when needed. Prior to enrolment, all subjects will receive and sign the informed consent form, which will be available in print as well as by video recording. All subjects will be enrolled and initially followed for an 8-week observational phase. During the 8-week observational phase, subjects will visit the pharmacy and purchase metformin following their usual routines. The 8-week observational period will enable the study to evaluate metformin dispensing and estimated compliance in a real-world setting with no intervention. At the conclusion of the 8-week observational phase, all subjects will be randomised to one of two treatment arms to initiate a 20-week interventional phase. The treatment arms assignments are as follows:

Treatment Arms: metformin small pack vs. metformin large pack

Currently, there are no marketed small packs of metformin available. Small pack metformin will be provided by GSK as GSK brand metformin. Therefore subjects taking

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a non GSK brand metformin will be required to switch to GSK brand metformin if they are assigned to a small pack treatment arm.

Subjects receive the medication free of charge throughout the interventional phase of the study. During the interventional phase, subjects will visit their pharmacies to receive medication refills, with timing and quantity of visits established in accordance with their needs for additional metformin. The pharmacy visit at Week 8, signifying the start of the interventional phase, will occur at the first visit that is at least 52 days after date of enrolment. The pharmacy visit that signifies Week 28, end of study, will occur at the first visit that is at least 137 days after the date of the Week 8 visit.

The overall study flow is displayed in the figure below.

The study will be conducted in pharmacies, the setting in which patients usually purchase their medications. The primary outcome will be change from baseline in HbA1c, where baseline is defined at Week 8, or the initiation of the interventional phase. HbA1c will be collected for all subjects at study enrolment (Week 0), initiation of interventional phase (Week 8), and end of study (Week 28). Subjects will also provide details of any missed doses at each visit to the pharmacy; this information will be collected on a pharmacist-administered questionnaire. In addition, at the end of study visit, subjects will be asked questions regarding their satisfaction with the pack size they received and reasons for missing doses throughout the interventional phase.

Protocol waivers or exemptions will not be allowed, with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct.

Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Investigator Site File (ISF). The ISF will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

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3.2. Discussion of Design

The study is designed to assess non-inferiority of change in HbA1c between subjects prescribed metformin small pack and those prescribed a large pack. The overall objective of the study is to evaluate compliance and patient behaviour. HbA1c is a well-documented biomarker of disease control in diabetic patients. Therefore, for this study a biomarker of disease control will be the primary outcome to provide insight regarding compliance and behaviour. Diabetes disease management may also include lifestyle choices such as diet and exercise, which can affect HbA1c levels in patients with type II diabetes. For this study, it is assumed that lifestyle choices will remain constant throughout the study period. Body mass index will be collected at enrolment for all subjects, and this data will be controlled for in the analysis of primary endpoint.

As a secondary outcome, metformin compliance will be estimated and compared between treatment arms. It is not desirable for the study to influence subject compliance, since a real-world assessment is of primary interest. Therefore, no compliance diaries will be utilised. Compliance for the study will be estimated as a percentage, with the denominator being the number of pills dispensed by the pharmacist and the numerator the number of pills taken, accounting for any pills that the subject has remaining at subsequent pharmacy visits. At each pharmacy visit, the subject will bring in remaining metformin pills, which will be removed from the numerator estimate of compliance.

It is of interest to learn how size of pack and quantity affect patient behaviour and disease management when cost is removed from the scenario. The impact of quantity of tablets and pack size will be evaluated without the bias introduced by payment.

The data points collected for the study relate to prescribing patterns among the population of interest. Therefore, pharmacies, which dispense the medication, will have the most reliable ‘real world’ information for evaluating the subjects’ metformin utilisation.

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1. Number of Subjects

The study seeks to enrol 288 subjects (in order to randomise 274 subjects, assuming a 5% drop-out rate between enrolment and randomisation) from 13-15 pharmacies throughout Argentina. The study assumes 274 subjects will be randomised among two equally distributed treatment arms; therefore, each randomisation arm will contain 137 subjects. Furthermore, the study assumes a 10% drop-out rate post randomisation, resulting in an anticipated 123 subjects per arm completing the study.

4.2. Inclusion Criteria

Deviations from both inclusion and exclusion criteria are prohibited because they can potentially jeopardise the scientific integrity of the study, regulatory acceptability, or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

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Subjects eligible for enrolment in the study must meet all of the following criteria:

• Males and females of age ≥18 years

• Diagnosis of type II diabetes

• HbA1c value no higher than 9.0%

• Evidence of physician-supplied prescription for metformin use

• Stable dose of metformin for 3 months prior to enrolment

• Written informed consent from the subject

4.3. Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled in the study:

• Current use of any anti-diabetic medication other than metformin

4.4. Withdrawal Criteria

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from the study at any time. There are no pre-specified reasons for which a subject may be withdrawn from the study. All subjects will have been previously exposed to metformin and will be on a stable dose prior to study enrolment. The sample size assumes that 10% of subjects may be lost to follow-up during the study. An enrolled subject will be considered lost to follow-up if no data are collected at the Week 28 visit. The HbA1c test will be performed at the Week 28 visit, and this result is required for the primary outcome of the study.

If a subject is lost to follow-up during the study the pharmacy will attempt to follow-up with the subject via a telephone conversation to gain a better understanding for reason of study discontinuation. If the reason for discontinuation involves an adverse event (AE) or serious adverse event (SAE) then the procedures in Section 6.3. should be followed.

4.5. Screen Failures

Subjects who are consented, but who do not meet the inclusion and exclusion criteria will be considered screen failures. Demographic data for these patients will be collected.

5. STUDY TREATMENTS

5.1. Investigational Product and Other Study Treatment

The contents of the label will be in accordance with all applicable regulatory requirements.

Investigational product must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the investigational product

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will be limited to the investigator and authorised site staff. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

Dosing of metformin will not be dictated by the protocol. Each subject will be on an individualised dose depending on the individual’s diabetes treatment needs. Subjects will remain on their prescribed dose of metformin throughout the study, unless a change of metformin dose is prescribed by the patient’s physician. During the observational phase, subjects will purchase metformin under usual practice, and no drugs will be provided by GSK. During the interventional phase, subjects will continue to take metformin treatment, and small packs of metformin will be provided to sites by GSK.

A single small pack of metformin will consist of a blister package containing 10 pills with a patient information leaflet in local language. If a subject is taking metformin twice a day, one small pack will be provided (sufficient for 5 days of treatment). Subjects on metformin three times a day will receive two small packs at each visit (sufficient for 6 days of treatment). The small packs will be available at each site in the following doses: 500 mg, 850 mg, and 1000 mg. The large pack will consist of 1 month’s supply of metformin. Subjects are not permitted to receive more metformin pills than is described above for each treatment arm at each visit.

The small pack size is currently not a marketed product. Small pack metformin will be provided by GSK as GSK brand metformin. Therefore, enrolled subjects will have their treating physician notified of their participation in the study and the possibility that their metformin brand may be switched during the interventional phase, if the patient is randomised to a small pack arm. At study closure, all remaining small packs in pharmacies will be returned to GSK and subjects who received small packs will be switched back to their original metformin brand. Subjects not randomised to the small pack arms will remain on their original metformin brand throughout the entire study.

All small packs provided to subjects will contain a quick response (QR) code on the package that links to a GSK website (vivircondiabetes.com.ar). If a subject chooses to view the website they will find details regarding lifestyle information for patients living with diabetes.

5.2. Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomisation schedule. Subjects will be randomised with a 1:1 allocation among the following: A: metformin small pack B: metformin large pack

The randomisation codes will be electronically generated by a statistician for the contract research organisation and distributed to each site for implementation. Interactive voice response will not be used for the study.

Each subject will be assigned a study identifier at time of study enrolment. At Week 8, the interventional phase will begin, and each subject will be assigned a randomisation

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number signifying the appropriate treatment arm. Once a randomisation number has been assigned, it must not be re-assigned.

5.3. Blinding

The study will be open-label, and no subject or site will be blinded to the subject treatment.

5.4. Product Accountability

In accordance with local regulatory requirements, the investigator, designated site staff, or head of the pharmacy institution (where applicable) must document the amount of investigational product dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study.

5.5. Treatment Compliance

At each visit to the site after enrolment, the subject will provide details on days when he or she took no pills. In addition, the site will record the number of pills dispensed at every subject visit, and each subject will be required to bring in any remaining pills from the previous visit. Furthermore, the site will collect each subject’s baseline metformin treatment regimen and ask each subject if his or her daily dosage has remained stable since the last visit. Compliance will be calculated as a proportion, with the denominator being the expected number of pills taken and the numerator being the estimated actual number of pills taken.

• Expected pill count will be calculated as number of days between current and previous pharmacy visits multiplied by the number of pills prescribed daily.

• Actual pill count will be calculated as the number of pills dispensed at the previous pharmacy visit minus the number of pills remaining at current pharmacy.

5.6. Concomitant Medications and Non-Drug Therapies

5.6.1. Permitted Medications and Non-Drug Therapies

Any medication used to treat a medical condition other than diabetes is allowed at study enrolment and throughout the study. Details on concomitant medications will be collected for all subjects at study enrolment.

For enrolment into the study, subjects must be receiving metformin monotherapy for treatment of diabetes. Other medications used to treat diabetes are not permitted at time of enrolment. After a subject’s enrolment, it is possible that additional diabetes medication may be prescribed, which will not necessitate study discontinuation. Details regarding the type of diabetes medication, dose, frequency, and relevant start and stop dates will be collected for all subjects.

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5.7. Treatment after the End of the Study

It is expected that subjects will continue to access metformin therapy after the end of the study by continuing to purchase medication in the same manner they did prior to enrolment. For any subject with very poorly controlled diabetes as indicated by the HbA1c result at Week 28, the pharmacist will advise the subject to see their regular health care physician in order to evaluate treatment. If this is difficult for the subject to do the pharmacist will contact the subject’s treating physician on their behalf explaining that a visit would be beneficial to evaluate the health status of the subject. In the case the subject status is considered serious, advice would be sought from the National Coordinator.

5.8. Treatment of Study Treatment Overdose

Subjects are expected to take their dosing regimens of metformin as prescribed by their physician. For subjects taking Oxemet, the maximum daily dose for adults is 3000 mg/day (SmPC Oxemet available in SPM). For subjects taking a generic metformin preparation, the maximum recommended daily dose in adults ranges from 2550 mg to 3000 mg (consult product labelling). AE reports will be collected and evaluated regarding overdosage. In the event of an overdose, the subject should initially contact their physician for notification. If this is difficult for the subject to do the pharmacist will contact the subject’s treating physician on their behalf to inform about the overdose. If a subject experiences an overdose, the medical monitor will be informed to support the pharmacist on how to report the case.

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6. STUDY ASSESSMENTS AND PROCEDURES

Table 1 Time and Events Table

Procedures Observational Phase Interventional Phase

Screen/Enrolment Week 0

Successive Visits

Week1 8

Successive Visits

Week2 28

Written Informed Consent X

Subject Demography X

Socioeconomic Details X

Medical History X

Diabetes History X

Diabetes Therapy History X

Inclusion/Exclusion Criteria3 X

HbA1c Test X X X

Concomitant Medications X X

Requirement to see HCP? X X X X X

Add-on Diabetes Therapy Description

X X X X

Adverse Events X X X X

Serious Adverse Events X X X X

Pills Dispensed / Returned4 X X X X X

Missed Doses Update X X X X

Visits to HCP or Other Pharmacy

X X X X

Updates to Diabetes Management

X X X X

Preference Questionnaire X

1. Defined as the first pharmacy visit that is at least 52 days after date of enrolment 2. Defined as the first pharmacy visit that is at least 137 days after date of Week 8 visit 3. Verification of current metformin prescription required 4. Metformin pill dispensing shall be in accordance with Section 5.1 of the protocol. At each visit, subjects are not permitted to receive more pills

than their randomisation arm allows. Note: The pharmacy will attempt to follow-up with the subject via a telephone conversation at any time if the patient is deemed lost to follow-up.

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6.1. Study Assessments

Enrolment

During the enrolment visit, the following assessments will be performed: Inclusion/Exclusion, Demographic and Lifestyle, Socioeconomic, Diabetes History, Medical History and Concomitant Medications.

Inclusion/Exclusion:

• Each criterion will be verified prior to study enrolment • Each subject will have an HbA1c test and results recorded at time of visit

Demographic and Lifestyle:

• Subject age at enrolment, date of birth, gender, race, ethnicity, height, weight • Estimated distance from home to pharmacy • Details regarding history and current use of tobacco and alcohol • Current exercise routine

Socioeconomic:

• Number of people in household; individual and household total income • Employment status and occupation of each member of household • Education level of each member of household

Diabetes History:

• Estimated date of diabetes diagnosis • Previous treatments for diabetes • Dosing and date details of metformin use

Medical History and Concomitant Medications:

• Details on other current and past chronic medical conditions • Names and start dates for all medications currently in use

Successive Visits (Including Week 8 and Week 28 Visits) Throughout the study, when a subject visits the pharmacy to receive a refill of metformin, the following data points will be collected:

• Descriptions of any AE or SAE • Information on updates to the subject’s diabetes management • Information on any subject visit to another pharmacy or doctor for diabetes

management • Number of pills dispensed and number remaining from last pharmacy visit • Number of days that no metformin was taken

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In addition, if, at any point during the study, a subject’s diabetes deteriorates significantly (including a HbA1c reading more than 9% at Week 8), the pharmacist will advise the patient to see their regular health care physician in order to evaluate treatment. If this is difficult for the subject to do the pharmacist will contact the subject’s treating physician on their behalf explaining that a visit would be beneficial to evaluate the health status of the subject. In the case the subject’s status is considered serious advice will be sought from the National Coordinator.

Additional Assessments At enrolment, Week 8 and Week 28, each subject will have HbA1c tested during the pharmacy visit. At the Week 28 (end of study) visit, each subject will answer treatment preference questions. The subject will be asked whether he or she has been satisfied with the treatment regimen provided and believes the treatment regimen enabled them to take the metformin as prescribed. In addition, the subjects will be asked to provide reasons for missing any single or daily doses throughout the study.

6.2. Efficacy

Primary Endpoint

• Change from baseline in HbA1c

Secondary Endpoints

• Percent compliance throughout interventional phase of study • Percent compliance throughout the observational study phase • Number of days zero metformin pills were taken • Percentage of subjects with diabetes disease management modifications during

the study • Percentage of subjects requiring a non-routine health care professional visit (for

diabetes) during the study • Percentage of subjects who prefer their treatment regimens during the study • Reason for missed days or doses throughout the study • Percentage of subjects withdrawn from study

6.3. Safety

6.3.1. Adverse Events

The investigator or site staff will be responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE.

6.3.1.1. Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

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Note: An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Events meeting the definition of an AE include:

• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition

• New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study

• Signs, symptoms, or the clinical sequelae of a suspected interaction

• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-harming intent. This should be reported regardless of sequelae.

‘Lack of efficacy’ or ‘failure of expected pharmacological action’ per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.

Events that do not meet the definition of an AE include:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE

• Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital)

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen

• The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition

6.3.1.2. Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a. Results in death

b. Is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c. Requires hospitalisation or prolongation of existing hospitalisation

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NOTE: In general, hospitalisation signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the AE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d. Results in disability/incapacity

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect

f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

6.3.2. Pregnancy

Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to PPD within 2 weeks of awareness of its occurrence. PPD will then send the details to GSK. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child.

Pregnancy complications and elective terminations for medical reasons must be reported as AEs or SAEs. Spontaneous abortions must be reported as SAEs.

Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment must be promptly reported to PPD who will then report to GSK.

In addition, the investigator must attempt to collect pregnancy information on any female partners of male study subjects who become pregnant while the subject is enrolled in the

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study. Pregnancy information must be reported to PPD and then to GSK as described above.

6.3.3. Medical Devices

For this study, HbA1c recordings will be performed with the Affinion AS 100 Analyzer, manufactured and supplied by Alere Inc. The Affinion machine is a point-of-care device, which requires a small finger prick and provides an instant HbA1c reading.

Incidents using the Affinion machine, including those resulting from malfunctions of the device, must be detected, documented, and reported by the investigator throughout the study as indicated in Section 6.3.5. An incident can be defined as any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which, directly or indirectly might lead to or might have led to the death of a patient, or user or of other persons or to a serious deterioration in their state of health.

A malfunction is defined as a failure of a device to perform in accordance with its intended purpose when used in accordance with the manufacturer’s instructions.

6.3.4. Time Period and Frequency of Detecting AEs and SAEs

The investigator or site staff is responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE.

AE reports will be collected from the start of study treatment until Week 28.

SAE reports will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be reported to PPD within 24 hours, as indicated in Section 6.3.5. PPD will then send the details to GSK.

6.3.5. Prompt Reporting of SAEs and Other Events to GSK

SAEs, pregnancies, and medical device incidents will be reported promptly by the investigator to PPD and PPD will report to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event.

Initial Reports Follow-up Information on a Previous Report Type of Event Time Frame Documents Time Frame Documents

All SAEs 24 hours SAE data collection tool

24 hours Updated SAE data collection tool

Pregnancy 2 weeks Pregnancy Notification Form

2 weeks Pregnancy Follow-up Form

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The method of detecting, recording, evaluating, and following up AEs and SAEs plus procedures for completing and transmitting SAE reports to PPD are provided in the ISF. Procedures for post-study AEs/SAEs are provided in the ISF.

Procedures for documenting, transmitting, and following up medical device incidents along with the regulatory reporting requirements for medical devices are provided in the ISF.

6.3.5.1. Regulatory Reporting Requirements for SAEs

Prompt notification of SAEs by the investigator to PPD is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. PPD will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing any SAE or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the ISF. PPD will notify the IRB/IEC, if appropriate according to local requirements.

7. DATA MANAGEMENT

For this study, all data except adverse events will be captured with a smart phone. An application will be installed on the smart phone to allow pharmacy staff to enter data collected verbally from subjects during pharmacy visits, pharmacy site-reported data, and biometric readings from the HbA1c device manufactured and supplied by Alere Inc. Logic checks will be built into the smart phone application to enable optimal data quality at the source. Data may be transmitted from the smart phone immediately following data entry into a database managed by Exco InTouch. If there is no connectivity, the smart phone application will work offline and will reconnect and transmit the data when connectivity is resumed. Data will be available for key stakeholders to review via a secure online reporting portal. The occurrence of an AE will be captured on the smart phone, but the details of all AE data will be collected on paper case report forms. HbA1c recordings will be performed with the Affinion AS 100 Analyzer. The Affinion machine is a point-of-care device, which requires a small finger prick and provides an instant HbA1c reading. Each pharmacy site will have a machine. When the subject visits the pharmacy at Weeks 0, 8, and 28, the test will be performed. Once the result is available it will be electronically submitted to the pharmacist’s smart phone.

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Clinical data will be managed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removal of errors and inconsistencies in the data. Terms for AEs and concomitant medications will be coded with MedDRA and an internal validated medication dictionary, GSKDrug.

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

8.1. Hypotheses

This study is designed to show non-inferiority of metformin small pack to metformin large pack in the treatment of type II diabetes.

The null hypothesis is that metformin small pack is inferior to metformin large pack by a margin of 0.5% or larger in the mean change from baseline in HbA1c. Under rejection of the null, the alternative hypothesis is that metformin small pack is non-inferior to metformin large pack.

8.2. Study Design Considerations

8.2.1. Sample Size Assumptions

The sample size will be based on the primary endpoint of change from baseline in HbA1c assuming a non-inferiority margin of 0.5% and a standard deviation of 1.2%, with 90% power and a one-sided significance level of 0.025.

Assuming the allocation ratio of 1:1 for metformin small pack versus large pack, a total of 123 subjects, per treatment arm, will be required to complete the study (i.e. have baseline and Week 28 HbA1c tests performed).

The study assumes that 10% will be lost post randomisation; therefore, 137 subjects will be randomised into each treatment group (a total of 274 randomised), and a total of 288 subjects will be enrolled for the entire study (assuming a 5% withdrawal rate between enrolment and randomisation).

The study will be performed as a pilot study to evaluate a small pack medication for treatment of a chronic non-communicable disease. Although a tighter non-inferiority margin is typically seen in diabetes studies when regulatory approval is sought for label modification, the current non-inferiority margin is appropriate for this study, as this is a first step in evaluating the feasibility of developing small pack sizes for the current population. The selected standard deviation is reflective of estimated variability in clinical studies evaluating change from baseline in HbA1c. Variability in HbA1c is reduced when the endpoint is change from baseline in HbA1c, since each subject’s baseline measurement serves as a self control. In addition, the diabetes severity among the population of interest is considered to be homogenous, since all subjects will have been using a stable dose of metformin monotherapy as a treatment regimen. This will eliminate additional variability from more severe diabetes cases.

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8.2.2. Sample Size Re-estimation

Sample size re-estimation is not planned for the study.

8.3. Data Analysis Considerations

8.3.1. Analysis Populations

• Safety Population: The safety population will include all subjects who received ≥1 dose of study medication. This is the primary population for evaluation of safety parameters. Data will be analysed according to the actual treatment the subject received.

• ITT Population: The ITT population will include all subjects who are randomly assigned to treatment and received ≥1 dose (or any portion of a dose) of study medication and have an HbA1c test performed at Week 8. The ITT population will be the primary efficacy population for the study, and data will be analysed according to the subject’s assigned treatment.

The treatment assignment will occur at Week 8. Therefore, data summarisations on the study population prior to randomisation at Week 8 will be performed on all enrolled subjects, which will be defined as the ‘observational population’. If an enrolled subject withdraws from the study prior to the Week 8 visit, all available data on the subject will be included in the observational population.

8.3.2. Analysis Data Sets

The primary efficacy endpoint is change from baseline (Week 8) to Week 28 in HbA1c. The efficacy analysis will be based upon the ITT population. All subjects receiving metformin will be included in the ITT population as long as the HbA1c test was performed at baseline (Week 8). There will be no imputation in the datasets for missing HbA1c values.

All AEs among the safety population will be assessed, reported, and analysed. Therefore, subjects with AEs who are lost to follow-up will be evaluated with regard to safety outcomes. Subjects who are lost to follow-up before Week 8 will be included in the observational population only.

8.3.3. Treatment Comparisons

8.3.3.1. Primary Comparisons of Interest

The primary comparison of interest will be the difference in the change from baseline in HbA1c between treatment arms. The change from baseline in HbA1c will be analysed with a multivariable mixed model, with treatment arm as the primary covariate of interest. In addition, the primary model will control for the following additional covariates: sex, age, duration of diabetes, body mass index, income level, education level, and need for add-on diabetes medications.

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In addition, the difference in mean change from baseline will be calculated between the treatment arms (small pack – large pack), and the 2-sided 95% confidence interval for the difference in mean change in HbA1c will be calculated. If the pre-specified non-inferiority margin (0.5%) lies outside of the upper bound of the 95% confidence interval for the difference in mean change in HbA1c, then the null hypothesis will be rejected and small pack will be considered non-inferior to the large pack.

8.3.3.2. Other Comparisons of Interest

The following additional comparisons will be performed between the treatment arms:

• Mean estimated metformin compliance percentage throughout observational and interventional phases

• Frequency and proportion of days with no metformin dose taken • Proportion of subjects prescribed add-on diabetes therapy during study • Proportion of subjects requiring a non-standard visit to a health care professional

for diabetes management during study • Proportion of subjects who prefer to remain on the assigned treatment style at end

of study • Summary of reasons for missed days/doses throughout the study • Proportion of subjects withdrawn from the study

If there are sufficient numbers of subjects in each income category, then a summary description of the relationship of income levels with disease control status (HbA1c) and/or compliance to small or large pack will be conducted. The above comparisons will be evaluated using student’s t-test for continuous outcomes and chi-squared tests for categorical outcomes. Multivariable models may also be performed to control for covariates of interest.

8.3.4. Interim Analysis

Interim results for this study will be used to evaluate study population characteristics. As such, an interim look will be performed during the study to support this activity. There is no intention to stop the study or change the study as a consequence of this interim look. No alpha-level adjustment is planned.

8.3.5. Key Elements of Analysis Plan

A reporting and analysis plan (RAP) describing the data analysis in more detail will be finalised prior to database lock.

Statistical differences between metformin small pack and large pack will be described. Summary statistics will be presented accordingly. All primary statistical analyses and reporting will be performed separately for each of the treatment arms. Data analysis will be performed with SAS® Version 9.1 or later.

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8.3.5.1. Efficacy Analyses

Analysis of the primary outcome, change from baseline in HbA1c, will be summarised among the ITT population in a mixed model as described in Section 8.3.3.1. Sensitivity evaluations of the primary comparison will be performed and may include analyses stratified by potentially influential covariates, such as demographic and socioeconomic factors, duration of diabetes, presence of other comorbid diseases, and modifications in diabetes treatment. In addition, a sensitivity model will be performed, which will control for the pharmacy site. To control for confounding factors, multivariable mixed models will be utilised.

8.3.5.2. Safety Analyses

All safety analyses will be performed on the safety population. Frequencies and proportions of AEs and SAEs will be summarised overall and separately for each treatment arm. No formal statistical analysis is planned for the safety data. Full details of safety analyses will be described in the RAP.

9. STUDY CONDUCT CONSIDERATIONS

9.1. Posting of Information on Publicly Available Clinical Trial Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrolment of subjects begins.

9.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable country-specific regulatory requirements.

The study will be conducted in accordance with all applicable regulatory requirements.

The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:

• IRB/IEC review and favourable opinion/approval of study protocol and any subsequent amendments

• Subject informed consent

• Investigator reporting requirements

GSK will provide full details of the above procedures, either verbally, in writing, or both.

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Written informed consent must be obtained from each subject prior to participation in the study. Details contained in the informed consent form will be available for subjects in paper format as well as via video recording. The population under study may have a lower rate of literacy than the general population. Therefore, the option for subjects to review key study aspects related to the informed consent using a short video will be offered to all subjects to ensure proper understanding of study procedures.

9.3. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK-approved monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. During review of data collection procedures, the discussion will include identification, agreement, and documentation of data items for which the case report form will serve as the source document.

GSK will monitor the study to ensure the following:

• The data are authentic, accurate, and complete

• The safety and rights of subjects are being protected

• The study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements

The investigator and the head of the medical institution (where applicable) agree to allow the monitor direct access to all relevant documents.

9.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an assessment, audit, or inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues, and to implement any corrective and/or preventative actions to address any findings/issues identified.

9.5. Study and Site Closure

The end of the study will occur when the last remaining subject has completed the final visit assessments, i.e. date of last subject, last visit and all queries relating to subject data have been answered. Upon completion or termination of the study, the GSK-approved monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK standard operating procedures.

GSK reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe non-

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compliance. If GSK determines that such action is required, GSK will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, GSK will provide advance notice to the investigator or head of the medical institution of the impending action.

If a study is suspended or terminated for safety reasons, GSK will promptly inform all investigators, heads of the medical institutions (where applicable), and/or institutions conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.

9.6. Records Retention

Following closure of the study, the investigator or head of the pharmacy institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.

Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions.

GSK will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK standard operating procedures, and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.

9.7. Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers, and Publication

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

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GSK will also provide the investigator with the full summary of the study results. The investigator will be encouraged to share the summary results with the study subjects, as appropriate.

GSK aims to post a result summary to the GSK Clinical Study Register and other publicly available registers no later than 8 months after the last subject’s last visit. In addition, the aim is to submit a manuscript to a peer-reviewed journal for publication within 18 months of the last subject’s last visit. GSK also aims to publish the full study protocol on the GSK Clinical Study Register at the time the results of the study are published as a manuscript in the scientific literature.

When manuscript publication in a peer-reviewed journal is not feasible, further study information will be posted to the GSK Clinical Study Register to supplement the results summary.

A manuscript will be progressed for publication in the scientific literature if the results provide important scientific or medical knowledge.

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Andrade F. Estimating diabetes and diabetes-free life expectancy in Mexico and seven major cities in Latin America and the Caribbean. Rev Panam Salud Publica. 2009;26(1):9-16.

Arredondo A, Barceló A. The economic burden of out-of-pocket medical expenditures for patients seeking diabetes care in Mexico. Diabetologia. 2007;50:2408-2409.

Cameron A, Ewen M, Ross-Degnan D, Ball D, Laing R. Medicine prices, availability, and affordability in 36 developing and middle-income countries: a secondary analysis. Lancet. 2009;373:240–249.

Danaei G, Finucane MM, Lu Y, et al; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet. 2011;378(9785):31-40.

Heisler M, Wagner TH, Piette JD. Patient strategies to cope with high prescription medication costs: who is cutting back on necessities, increasing debt, or underusing medications? J Behav Med. 2005 28(1):43-51.

Hirth RA, Greer SL, Albert JM, Young EW, Piette JD. Out-of-pocket spending and medication adherence among dialysis patients in twelve countries. Health Aff (Millwood). 2008;27(1):89-102.

Keugoung B. The availability of drugs for rich and poor people in developing countries. Lancet Infect Dis. 2009;9(10):586-587.

Kindmalm L, Melander A, Nilsson JL. Refill adherence of antihyperglycaemic drugs related to glucose control (HbA1c) in patients with type 2 diabetes. Acta Diabetol. 2007;44(4):209-213.

Long Q, Smith H, Zhang T, Tang S, Garner P. Patient medical costs for tuberculosis treatment and impact on adherence in China: a systematic review. BMC Public Health. 2011;11:393.

Lu Y, Hernandez P, Abegunde D, Edejer T. The world medicines situation 2011: medicine expenditures. Geneva: World Health Organization; 2011. Available at: http://apps.who.int/medicinedocs/documents/s18767en/s18767en.pdf. Accessed February 6, 2012.

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McIntyre D, Thiede M, Dahlgren G, Whitehead M. What are the economic consequences for households of illness and of paying for health care in low- and middle-income country contexts? Soc Sci Med. 2006;62(4):858-865.

O'Hea EL, Moon S, Grothe KB, et al. The interaction of locus of control, self-efficacy, and outcome expectancy in relation to HbA1c in medically underserved individuals with type 2 diabetes. J Behav Med. 2009;32(1):106-117.

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11. APPENDIX 1: SUMMARY OF PROTOCOL AMENDMENT 01 – 2013 JAN 28

Rationale for Changes

1. Corrected wording of acceptable age restriction in the protocol description to be

consistent with inclusion criteria.

2. Updated sponsor signature page with new sponsor representative

3. Updated sponsor information page with PPD medical monitor and

pharmacovigilance contact details.

4. Added text regarding pharmacy phone call lost to follow-up patients.

5. Added text describing the QR code that will appear on the GSK package for the

small pack.

6. Updated treatment management for poorly controlled diabetes cases

7. Updated serious adverse event reporting for pharmacies to contact PPD who will

then follow up with GSK.

8. Changed informed consent aide from audio format to video format.

9. Removed all references to Cohort A

10. Removed inclusion criteria pertaining to income level status and part or full purchase of metformin

11. Revision of maximum daily dose permitted and action to be taken

12. Removal of HCP visit other than that recommendation to consult the physician treating the subject

This amendment applies to all sites.

Specific Changes

1. Title Page – Protocol Description Original Text:

Title: A pharmacy-based open study to demonstrate that metformin small packs do not adversely affect compliance when compared with medicine taken in current practice for subjects diagnosed with type II diabetes who are established on treatment

MTF116086 is an open-label, randomised, parallel-design study to demonstrate non-inferiority of the metformin small pack to either the subject’s usual metformin pack or a

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large monthly pack of metformin in adult subjects aged over 18 years with type II diabetes. The aim is to test the hypothesis that the introduction of a metformin small pack does not adversely affect subjects’ treatment compliance or behaviour when compared against current metformin purchase practices or a large monthly pack when the factor of cost has been removed. All subjects will enter an initial 8-week observational study phase during which usual purchase behaviour and compliance with metformin use will be observed and recorded. At the end of the observational phase, subjects will be randomised between two cohorts, A or B, for a treatment period of 20 weeks. Subjects in Cohort A will continue to purchase their medication and be further randomised between two treatment arms: a metformin small pack arm or a usual metformin product arm. Subjects in Cohort A will be compensated at the end of the study for the payment of medication during the study. Subjects in Cohort B will be provided with medication free of charge so that the effect of pack size can be studied when the effect of cost has been removed. These subjects will be randomised between two arms: metformin small pack arm or large, monthly metformin pack arm. The primary endpoint for both cohorts will be the mean change from baseline (Week 8) to end of treatment (Week 28) in haemoglobin A1c (HbA1c). Other assessments will include tablet compliance and subject pack preference. Throughout the duration of the study, subjects will remain on their recommended metformin dosing regimens. The only factors modified during the interventional phase will be the pack size, medication payment, and metformin brand for those randomised to small pack arm.

Subjects in Cohort A will continue to purchase their medication and be further randomised between two treatment arms: a metformin small pack arm or a usual metformin product arm.

Subject: Medication compliance, Metformin, Socioeconomic category

Revised Text:

Title: A pharmacy based open study to evaluate whether pack size affects compliance for subjects diagnosed with diabetes type II who are established on metformin treatment

MTF116086 is an open-label, randomised, parallel-design study to demonstrate non-inferiority of the metformin small pack to a large monthly pack of metformin in adult subjects aged 18 years or older with type II diabetes. The aim is to test the hypothesis that the introduction of a metformin small pack does not adversely affect subjects’ treatment compliance or behaviour when compared against a large monthly pack when the factor of cost has been removed. All subjects will enter an initial 8-week observational study phase during which usual purchase behaviour and compliance with metformin use will be observed and recorded. At the end of the observational phase, subjects will be randomised between two treatment arms for a treatment period of 20 weeks, one arm using the small pack and the other the large pack. Subjects will be provided with medication free of charge so that the effect of pack size can be studied when the effect of cost has been removed. Subjects will be randomised between two arms: metformin small pack arm or large, monthly metformin pack arm. The primary endpoint will be the mean change from baseline (Week 8) to end of treatment (Week 28) in haemoglobin A1c (HbA1c). Other assessments will include tablet compliance and subject pack preference.

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Throughout the duration of the study, subjects will remain on their recommended metformin dosing regimens, unless a change of metformin dose is prescribed by their physician. The only factors modified during the interventional phase will be the pack size, the metformin brand for those randomised to small pack arm, and the provision of medication by GSK. Subject: Medication compliance, Metformin, Socioeconomic

2. Author Page

1PPD Inc.; 2Emerging Markets R&D; 3Clinical Statistics; 4Cardiovascular/Metabolic MPC; 5Worldwide Epidemiology, R&D

Revised Text:

Author(s):

1PPD Inc.; 2Emerging Markets R&D; 3Clinical Statistics; 4Cardiovascular/Metabolic MPC; 5Worldwide Epidemiology, R&D; 6Safety Evaluation & Risk Management

3. Sponsor Signature PageOriginal Text:

MBChB, PhD, MRCP Senior Vice President

Emerging Markets R&D

Date

Revised Text:

M.B., B.S Director, Emerging Markets Research & Development

Date

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Original Text:

Author(s):


40

4. Sponsor Information Page Original Text:

Medical Monitor Contact Information Dr MD Medical Director, GlaxoSmithKline Argentina S.A Carloe Casares 3690, B1606ACM-Victoria Buenos Aires Argentina Telephone: Revised Text:

Primary Medical Monitor Contact Information

Dr MD

Medical Director, PPD Maipu 1300, piso 15 C1006ACT, Buenos Aires Argentina Telephone: /

GSK Medical Monitor Contact Information

Dr MRCP, DCPSA, FFPM

Emerging Markets R&D GlaxoSmithKline R&D 980 Great West Road Brentford, TW8 9GS United Kingdom e-mail: Telephone (cell phone): Sponsor Serious Adverse Events (SAEs) Contact Information:

PPD Pharmacovigilance

Maipu 1300, piso 15 C1006ACT, Buenos Aires Argentina Telephone:

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Fax: Toll free #s: Telefónica: Telecom: Alternative number (paid)

5. Section 1.2 Rationale Original Text: The GSK Access to Medicines project is currently investigating how small pack sizes could be used to improve affordability of, access to, and adherence to high-quality medicines for socioeconomic groups C- and D in populations in emerging markets. The C- and D socioeconomic groups are defined by monthly household income ranging between $712 to $1,402 US dollars, with monthly range per category as $712 to $874 in group D and $875 to $1,402 in group C3. Individuals in socioeconomic group D are characterised as having semi-skilled and unskilled manual jobs, such as assembly line workers, refuse collectors, or messengers. Individuals in socioeconomic group C- are typically employed as supervisory and skilled manual workers, clerical or junior managerial positions such as shop floor supervisors, bank clerks, or sales persons. Market research indicates that patients in these socioeconomic groups (C-/D) ⎯ the ‘have less’ population ⎯ typically spend the majority of their daily or weekly earnings on essential living items, leaving only a small amount of money for other goods such as medicines. Patients in this population make decisions every day based on their finances and the immediate needs of themselves and their families. GSK is keen to understand more about the ‘have less ‘population and how small packs may make a difference to their chronic disease management in the longer term. Some medicines can be made more affordable by reducing pack sizes, which increases affordability by spreading the cost of a prescription over time. Small pack sizes may alter patient compliance and behaviour, since more frequent trips to the pharmacy are required, and this study attempts to record and understand whether changes occur and whether those changes adversely affect subjects’ compliance. However, there is little evidence of medicine utilisation patterns among ‘have less’ patients, particularly in the emerging markets. GSK has a long history of developing high-quality, evidence-based medicines that put the interests of patients first. The study seeks to gain a better understanding of the impact of small pack sizes on subjects’ utilisation, compliance, and preference. Findings from the study will provide information on the utility of small pack treatments in the ‘have less’ patient population of interest. For this study, metformin, a first-line treatment for type II diabetes, was chosen as the optimal chronic disease model to study the impact of small packs on ‘have less’ patients, as there is a recognised biomarker (HbA1c) to analyse disease control and the magnitude of the disease, as stated in Section 1.1. To our knowledge, this is the first scientific study evaluating the effect of small packs of

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metformin on HbA1c and compliance in this socioeconomic population; additional studies exploring the needs of patients and the efficacy of small pack treatments may be performed in the future.

Revised Text: The GSK Access to Medicines project is currently investigating how small pack sizes could be used to improve adherence to high-quality medicines for lower socioeconomic groups in populations in emerging markets. Patients in this population make decisions every day based on their finances and the immediate needs of themselves and their families. GSK is keen to understand more about how small packs may make a difference to chronic disease management in the longer term.

Small pack sizes may alter patient compliance and behaviour, since more frequent trips to the pharmacy are required. This study attempts to record and understand whether compliance and behaviour changes occur when patients use small packs and whether those changes adversely affect subjects’ treatment management. GSK has a long history of developing high-quality, evidence-based medicines that put the interests of patients first. The study seeks to gain a better understanding of the impact of small pack sizes on subjects’ utilisation, compliance, and preference. Findings from the study will provide information on the utility of small pack treatments in the diabetic type II patient population. For this study, metformin, a first-line treatment for type II diabetes, was chosen as the optimal chronic disease model to study the impact of small packs on patients, as there is a recognised biomarker (HbA1c) to analyse disease control and the magnitude of the disease, as stated in Section 1.1. To our knowledge, this is the first scientific study evaluating the effect of small packs of metformin on HbA1c and compliance; additional studies exploring the needs of patients and the efficacy of small pack treatments may be performed in the future.

6. Section 2 Objective

Original Text:

Objective(s)

The objective of the study is to test the hypothesis that the introduction of a metformin small pack does not adversely affect subject compliance or behaviour when compared

1. Against the subject’s current metformin purchase practices; and 2. Against a large pack, when the factor of medicine cost is removed.

The objective of evaluating compliance with a small pack of metformin as compared with compliance with usual pack will include measuring change from baseline in haemoglobin A1c (HbA1c), a well-established biomarker of diabetes disease control which is commonly used in traditional randomised controlled trials of effectiveness of metformin. Compliance, defined as percentage of pills taken and dispensed, will also be recorded and calculated.

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Revised Text:

Objective(s)

The objective of the study is to test the hypothesis that the introduction of a metformin small pack does not adversely affect subject compliance or behaviour when compared against a large pack, when the factor of cost is removed.


The objective of evaluating compliance with a small pack of metformin as compared with compliance with a large pack will include measuring change from baseline in haemoglobin A1c (HbA1c), a well-established biomarker of diabetes disease control which is commonly used in traditional randomised controlled trials of effectiveness of metformin. Compliance, defined as percentage of pills taken and dispensed, will also be recorded and calculated.

7. Section 3.1. Study Design

Original Text:

Study Design

The study is an open-label, randomised, parallel-design study comparing use of a small pack of metformin with use of either usual pack or large pack. The study is site-based, with local pharmacies serving as the sites and pharmacists as principal investigators for the sites. In addition, the study will have an overall clinical coordinator who is medical doctor specialising in diabetes care in Argentina to oversee implementation of the study protocol and provide scientific aid to pharmacy sites when needed. Prior to enrolment, all subjects will receive and sign the informed consent form, which will be available in print as well as by video recording. All subjects will be enrolled and initially followed for an 8-week observational phase. During the 8-week observational phase, subjects will visit the pharmacy and purchase metformin following their usual routines. The 8-week observational period will enable the study to evaluate metformin dispensing and estimated compliance in a real-world setting with no intervention. At the conclusion of the 8-week observational phase, all subjects will be randomised among four treatment arms to initiate a 20-week interventional phase. Each subject will belong to either Cohort A or Cohort B, depending on the randomised treatment arm. The treatment arms and corresponding cohort assignments are as follows:

Cohort A: Pay/metformin small pack vs. Pay/metformin usual pack

Cohort B: Free/metformin small pack vs. Free/metformin large pack

Currently, there are no marketed small packs of metformin available. Small pack metformin will be provided by GSK as GSK brand metformin. Therefore subjects

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taking a non GSK brand metformin will be required to switch to GSK brand metformin if they are assigned to a small pack treatment arm.

Treatment assignments that correspond to Cohort A require the subject to pay for their metformin throughout the entire study, while treatment assignments corresponding to Cohort B receive the medication free of charge throughout the interventional phase of the study. As Cohort A subjects will have to pay for metformin throughout the study, a pharmacy voucher will be offered at the end of the study to compensate for the payment for medication made during the study. During the interventional phase, subjects will visit their pharmacies to receive medication refills, with timing and quantity of visits established in accordance with their needs for additional metformin. The pharmacy visit signifying Week 8, the start of the interventional phase, will occur at the first visit that is at least 52 days after date of enrolment. The pharmacy visit that signifies Week 28, end of study, will occur at the first visit that is at least 137 days after the date of the Week 8 visit.


GSK SMALL PACK ‘PAY’Metformin arm

USUAL ‘PAY’ Metformin arm

GSK SMALL PACK ‘’FREE’Metformin arm

LARGE PACK ‘FREE’Metformin arm

Observational phase

Interventionalphase

0weeks

8 weeks

28weeks

Usual Metformin medicationpurchased

COHORT A

COHORT B

Observational Phase is same for all arms

Randomisation

The study will be conducted in pharmacies, the setting in which patients in lower socioeconomic groups (C-/D) frequently purchase their medications. The primary outcome for both cohorts will be change from baseline in HbA1c, where baseline is defined at Week 8, or the initiation of the interventional phase.

Revised Text:

Study Design

The study is an open-label, randomised, parallel-design study comparing use of a small pack of metformin with use of a large pack. The study is site-based, with local pharmacies serving as the sites and pharmacists as principal investigators for the sites. In addition, the study will have an overall National Coordinator who is a medical doctor specializing in diabetes care in Argentina to oversee implementation of the study protocol

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and provide scientific aide to pharmacy sites when needed. Prior to enrolment, all subjects will receive and sign the informed consent form, which will be available in print as well as by video recording. All subjects will be enrolled and initially followed for an 8-week observational phase. During the 8-week observational phase, subjects will visit the pharmacy and purchase metformin following their usual routines. The 8-week observational period will enable the study to evaluate metformin dispensing and estimated compliance in a real-world setting with no intervention. At the conclusion of the 8-week observational phase, all subjects will be randomised to one of two treatment arms to initiate a 20-week interventional phase. The treatment arms assignments are as follows:

Treatment Arms: metformin small pack vs. metformin large pack

Currently, there are no marketed small packs of metformin available. Small pack metformin will be provided by GSK as GSK brand metformin. Therefore subjects taking a non GSK brand metformin will be required to switch to GSK brand metformin if they are assigned to a small pack treatment arm.

Subjects receive the medication free of charge throughout the interventional phase of the study. During the interventional phase, subjects will visit their pharmacies to receive medication refills, with timing and quantity of visits established in accordance with their needs for additional metformin. The pharmacy visit at Week 8, signifying the start of the interventional phase, will occur at the first visit that is at least 52 days after date of enrolment. The pharmacy visit that signifies Week 28, end of study, will occur at the first visit that is at least 137 days after the date of the Week 8 visit.


The study will be conducted in pharmacies, the setting in which patients usually purchase their medications. The primary outcome will be change from baseline in HbA1c, where baseline is defined at Week 8, or the initiation of the interventional phase.

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8. Study Endpoints

Original Text:

The study is designed to show non-inferiority of metformin small pack to metformin comparator pack in the treatment of type II diabetes for each cohort, with the primary outcome being the difference in change from baseline (i.e., Week 28 – Week 8) in HbA1c between treatment arms, with a non-inferiority margin of 0.5%.

Revised Text:

The study is designed to show non-inferiority of metformin small pack to metformin large pack in the treatment of type II diabetes, with the primary outcome being the difference in change from baseline (i.e., Week 28 – Week 8) in HbA1c between treatment arms, with a non-inferiority margin of 0.5%.

9. Section 3.2 Discussion of Design Original Text: The study is designed to assess non-inferiority of change in HbA1c between subjects prescribed metformin small pack and those prescribed a comparator. At each pharmacy visit, the subject will bring in remaining metformin pills, which will be removed from the numerator estimate of compliance. However, subjects in Cohort A, who pay for all metformin, will be allowed to keep any remaining pills.

The study has two cohorts running in parallel. In Cohort A, subjects will be required to pay for their study medication, while in Cohort B, study medication will be provided to the subjects for free. As cost is the primary rationale for developing small pack medications in this population, it is necessary to evaluate patient behaviour and disease management under the real-world naturalistic environment for this population of subjects with type II diabetes. Therefore, payment for medications will be required for subjects in Cohort A. The payment will be aligned with the price per pill of the subject’s original metformin if they are required to switch to GSK brand metformin. In addition, it is of interest to learn how size of pack and quantity affect patient behaviour and disease management when cost is removed from the scenario. In Cohort B, the impact of quantity of tablets and pack size will be evaluated without the bias introduced by payment.

Local pharmacies will be used as the sites, and the subject interaction will occur with the pharmacists, who are the principal investigators at each site. The data points collected for the study relate to prescribing patterns among the population of interest. Therefore, pharmacies, which dispense the medication, will have the most reliable ‘real world’ information for evaluating the subjects’ metformin utilisation. All participating pharmacies will randomise subjects to both Cohorts A and B. This will ensure that immeasurable biases associated with the geographical or socioeconomic characteristics of

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pharmacies do not confound study findings for each cohort. In addition, allowing all pharmacies to include subjects for both cohorts will reduce the likelihood of slower enrolment for a particular cohort.

Revised Text: The study is designed to assess non-inferiority of change in HbA1c between subjects prescribed metformin small pack and those prescribed a large pack. At each pharmacy visit, the subject will bring in remaining metformin pills, which will be removed from the numerator estimate of compliance.

It is of interest to learn how size of pack and quantity affect patient behaviour and disease management when cost is removed from the scenario. The impact of quantity of tablets and pack size will be evaluated without the bias introduced by payment.

The data points collected for the study relate to prescribing patterns among the population of interest. Therefore, pharmacies, which dispense the medication, will have the most reliable ‘real world’ information for evaluating the subjects’ metformin utilisation.

10. Section 4.1 Number of Subjects

Original Text:

The study seeks to enrol and randomise 324 subjects from 20 pharmacies throughout Argentina. The study assumes 324 subjects will be randomised among four equally distributed randomisation arms; therefore, each randomisation arm will contain 81 subjects. Furthermore, the study assumes a 10% drop-out rate, resulting in an anticipated 73 subjects per arm completing the study.

Revised Text:

The study seeks to enrol 288 subjects (in order to randomise 274 subjects, assuming a 5% drop-out rate between enrolment and randomisation) from 13-15 pharmacies throughout Argentina. The study assumes 274 subjects will be randomised among two equally distributed treatment arms; therefore, each randomisation arm will contain 137 subjects. Furthermore, the study assumes a 10% drop-out rate post randomisation, resulting in an anticipated 123 subjects per arm completing the study.

11. Section 4.2 Inclusion Criteria

Original Text:


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• Socioeconomic groups C-/D o Monthly household income between $712 and $1,402 US dollars or

$3,100 and $6,100 Argentine peso

• Payment ‘out of pocket’ for part or whole of metformin treatment


Revised Text:









12. Section 4.4 Withdrawal Criteria Original Text:

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from the study at any time. There are no pre-specified reasons for which a subject may withdraw from the study. All subjects will have been previously been exposed to metformin and will be on a stable dose prior to study enrolment. The sample size assumes that 10% of subjects may be lost to follow-up during the study. An enrolled subject will be considered lost to follow-up if no data are collected at the Week 28 visit. The HbA1c test will be performed at the Week 28 visit, and this result is required for the primary outcome of the study.

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Revised Text:

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from the study at any time. There are no pre-specified reasons for which a subject may withdraw from the study. All subjects will have been previously exposed to metformin and will be on a stable dose prior to study enrolment. The sample size assumes that 10% of subjects may be lost to follow-up during the study. An enrolled subject will be considered lost to follow-up if no data are collected at the Week 28 visit. The HbA1c test will be performed at the Week 28 visit, and this result is required for the primary outcome of the study.

If a subject is lost to follow-up during the study the pharmacy will attempt to follow-up with the subject via a telephone conversation to gain a better understanding for reason of study discontinuation. If the reason for discontinuation involves an adverse event (AE) or serious adverse event (SAE) then the procedures in Section 6.3.1.1 should be followed.

13. Screening/Run-in Failures

Old Text: No screen failures are anticipated, as each subject must meet the inclusion and exclusion criteria prior to study enrolment.

Revised Text:

Screen Failures Subjects who are consented, but who do not meet the inclusion and exclusion criteria will be considered screen failures. Demographic data for these patients will be collected.

14. Section 5.1 Investigational Product and Other Study Treatment

Original Text:

Dosing of metformin will not be dictated by the protocol. Each subject will be on an individualised dose depending on the individual’s diabetes treatment needs. During the observational phase, subjects will purchase metformin under usual practice, and no drugs will be provided by GSK. During the interventional phase, subjects will continue to take metformin treatment, and small packs of metformin will be provided to sites by GSK.

A single small pack of metformin will consist of a blister package containing 10 pills with a patient information leaflet in local language. For Cohort B, if a subject is taking metformin twice a day, one small pack will be provided (sufficient for 5 days of treatment). Cohort B subjects on metformin three times a day will receive two small packs at each visit (sufficient for 6 days of treatment). In Cohort A, subjects may choose to purchase more than one small pack to cover a period of treatment. The small packs will be available at each site in the following doses: 500 mg, 850 mg, and 1000 mg. In Cohort B, the large pack will consist of 1 month’s supply of metformin. Cohort B

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subjects are not permitted to receive more metformin pills than is described above for each treatment arm at each visit.

The small pack size is currently not a marketed product. Small pack metformin will be provided by GSK as GSK brand metformin. Therefore, enrolled subjects will have their treating physician notified of their participation in the study and the possibility that their metformin brand may be switched during the interventional phase, if the patient is randomised to a small pack arm. The cost of the small pack for Cohort A subjects will be adjusted to reflect the price per tablet of the subject’s initial metformin brand. At study closure, all remaining small packs in pharmacies will be returned to GSK and subjects who received small packs will be switched back to their original metformin brand. Subjects not randomised to the small pack arms will remain on their original metformin brand throughout the entire study.

Revised Text:

Dosing of metformin will not be dictated by the protocol. Each subject will be on an individualised dose depending on the individual’s diabetes treatment needs. Subjects will remain on their prescribed dose of metformin throughout the study, unless a change of metformin dose is prescribed by the patient’s physician. During the observational phase, subjects will purchase metformin under usual practice, and no drugs will be provided by GSK. During the interventional phase, subjects will continue to take metformin treatment, and small packs of metformin will be provided to sites by GSK.

A single small pack of metformin will consist of a blister package containing 10 pills with a patient information leaflet in local language. If a subject is taking metformin twice a day, one small pack will be provided (sufficient for 5 days of treatment). Subjects on metformin three times a day will receive two small packs at each visit (sufficient for 6 days of treatment). The small packs will be available at each site in the following doses: 500 mg, 850 mg, and 1000 mg. The large pack will consist of 1 month’s supply of metformin. Subjects are not permitted to receive more metformin pills than is described above for each treatment arm at each visit.

The small pack size is currently not a marketed product. Small pack metformin will be provided by GSK as GSK brand metformin. Therefore, enrolled subjects will have their treating physician notified of their participation in the study and the possibility that their metformin brand may be switched during the interventional phase, if the patient is randomised to a small pack arm. At study closure, all remaining small packs in pharmacies will be returned to GSK and subjects who received small packs will be switched back to their original metformin brand. Subjects not randomised to the small pack arms will remain on their original metformin brand throughout the entire study.

15. Section 5.2 Treatment Assignment Original Text: Subjects will be assigned to study treatment in accordance with the randomisation schedule. Subjects will be randomised with a 1:1:1:1 allocation among the following: pay/metformin small pack, pay/metformin usual pack, free/metformin small pack, or

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free/metformin large pack. The pay arms will belong to Cohort A while the free arms will be Cohort B. Randomisation will be stratified by socioeconomic level (C-/D) at both the cohort and the treatment arm level at each site.

Revised Text:

Subjects will be assigned to study treatment in accordance with the randomisation schedule. Subjects will be randomised with a 1:1 allocation among the following: A: metformin small pack B: metformin large pack

16. Section 5.5 Treatment Compliance

Original Text: At each visit to the site after enrolment, the subject will provide details on days when he or she took no pills. In addition, the site will record the number of pills dispensed at every subject visit, and each subject will be required to bring in any remaining pills from the previous visit. Subjects in Cohort A will be allowed to keep any remaining pills. Furthermore, the site will collect each subject’s baseline metformin treatment regimen and ask each subject if his or her daily dosage has remained stable since the last visit. Compliance will be calculated as a proportion, with the denominator being the expected number of pills taken and the numerator being the estimated actual number of pills taken.


• Actual pill count will be calculated as the number of pills dispensed at the previous pharmacy visit minus the number of pills remaining at current pharmacy visit.

• For Cohort A, in which subjects will be allowed to keep unused pills, the actual pills will be calculated as described above. An additional compliance calculation will be performed in Cohort A, with the actual pills calculated without subtraction of the pills remaining at the current pharmacy visit. The rationale for having two calculations is that the initial calculation is a conservative estimate based on the data collected. However, since subjects are paying for their medication pack, the assumption is that the subject will use the entire pack before paying for additional medication.

Revised Text: At each visit to the site after enrolment, the subject will provide details on days when he or she took no pills. In addition, the site will record the number of pills dispensed at every subject visit, and each subject will be required to bring in any remaining pills from the previous visit. Furthermore, the site will collect each subject’s baseline metformin

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treatment regimen and ask each subject if his or her daily dosage has remained stable since the last visit. Compliance will be calculated as a proportion, with the denominator being the expected number of pills taken and the numerator being the estimated actual number of pills taken.


• Actual pill count will be calculated as the number of pills dispensed at the previous pharmacy visit minus the number of pills remaining at current pharmacy.

17. Section 5.7. Treatment after the End of the Study Original Text:

Subjects are expected to take their normal dosing regimens of metformin. Although dosing level is subject-specific, the maximum tolerable dose of metformin is 2500 mg/day. Adverse event (AE) reports will be collected and evaluated regarding overdosage. In addition, if a subject experiences an overdose or if any subject’s diabetes becomes poorly controlled, the medical monitor will be informed and make recommendation for further action. In addition, GSK will provide access to a visit with a health care professional.

Revised Text:

It is expected that subjects will continue to access metformin therapy after the end of the study by continuing to purchase medication in the same manner they did prior to enrolment. For any subject with very poorly controlled diabetes as indicated by the HbA1c result at Week 28, the pharmacist will advise the subject to see their regular health care physician in order to evaluate treatment. If this is difficult for the subject to do the pharmacist will contact the subject’s treating physician on their behalf explaining that a visit would be beneficial to evaluate the health status of the patient. In the case the subject status is considered serious, advice would be sought from the National Coordinator.

18. Section 5.8 Treatment of Study Treatment Overdose

Original Text: Subjects are expected to take their normal dosing regimens of metformin. Although dosing level is subject-specific, the maximum tolerable dose of metformin is 2500 mg/day. Adverse event (AE) reports will be collected and evaluated regarding overdosage. In addition, if a subject experiences an overdose or if any subject’s diabetes becomes poorly controlled, the medical monitor will be informed and make recommendation for further action. In addition, GSK will provide access to a visit with a health care professional.

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Revised Text: Subjects are expected to take their dosing regimens of metformin as prescribed by their physician. For subjects taking Oxemet, the maximum daily dose for adults is 3000 mg/day (SmPC Oxemet available in SPM). For subjects taking a generic metformin preparation the maximum recommended daily dose in adults ranges from 2550 mg to 3000 mg (consult product labelling). Adverse event (AE) reports will be collected and evaluated regarding overdosage. In the event of an overdose, the subject should initially contact their physician for notification. If this is difficult for the subject to do the pharmacist will contact the subject’s treating physician on their behalf to inform about the overdose. If a subject experiences an overdose, the medical monitor will be informed to support the pharmacist on how to report the case.

19. Section 6.1 Study Assessments

Original Text:

In addition, if, at any point during the study, a subject’s diabetes deteriorates significantly, the pharmacist will refer the subject to a health care professional to evaluate the subject’s diabetes management.

Additional Assessments

At enrolment, Week 8, and Week 28, each subject will have HbA1c tested during the pharmacy visit. At the Week 28 (end of study) visit, each subject will answer treatment preference questions. The subject will be asked whether he or she has been satisfied with the treatment regimen provided and believes the treatment regimen enabled compliance with the metformin treatment.

Revised Text:

In addition, if, at any point during the study, a subject’s diabetes deteriorates significantly (including a HbA1c reading more than 9% at Week 8), the pharmacist will advise the patient to see their regular health care physician in order to evaluate treatment. If this is difficult for the subject to do the pharmacist will contact the subject’s treating physician on their behalf explaining that a visit would be beneficial to evaluate the health status of the patient. In the case the subject status is considered serious, advice would be sought from the National Coordinator.

Additional Assessments

At enrolment, Week 8 and Week 28, each subject will have HbA1c tested during the pharmacy visit. At the Week 28 (end of study) visit, each subject will answer treatment preference questions. The subject will be asked whether he or she has been satisfied with the treatment regimen provided and believes the treatment regimen enabled them to take the metformin as prescribed.

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20. Section 6.2 Efficacy

Original Text:

Secondary Endpoints

• Percentage of subjects requiring a health care professional visit (for diabetes) during the study

Revised Text: Secondary Endpoints

• Percentage of subjects requiring a nonroutine visit to a health care professional for diabetes during the study

• Proportion of subjects withdrawn from the study

21. Section 6.3.1.1 Definition of an AE

Original Text:


The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the definition of an AE or SAE. ‘Lack of efficacy’ or ‘failure of expected pharmacological action’ also constitutes an AE or SAE.

Revised Text:


22. Section 6.3.2. Pregnancy

Original Text:

Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of awareness of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child.

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Pregnancy complications and elective terminations for medical reasons must be reported as AEs or SAEs. Spontaneous abortions must be reported as SAEs. Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment must be promptly reported to GSK.

In addition, the investigator must attempt to collect pregnancy information on any female partners of male study subjects who become pregnant while the subject is enrolled in the study. Pregnancy information must be reported to GSK as described above.

Revised Text:

Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to PPD within 2 weeks of awareness of its occurrence. PPD will then send the details to GSK. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child.

Pregnancy complications and elective terminations for medical reasons must be reported as AEs or SAEs. Spontaneous abortions must be reported as SAEs.

Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment must be promptly reported to PPD who will then report to GSK.

In addition, the investigator must attempt to collect pregnancy information on any female partners of male study subjects who become pregnant while the subject is enrolled in the study. Pregnancy information must be reported to PPD and then to GSK as described above.

NEW Section 6.3.3 Medical Devices For this study, HbA1c recordings will be performed with the Affinion AS 100 Analyzer, manufactured and supplied by Alere Inc. The Affinion machine is a point-of-care device, which requires a small finger prick and provides an instant HbA1c reading.

Incidents using the Affinion machine, including those resulting from malfunctions of the device, must be detected, documented, and reported by the investigator throughout the study as indicated in Section 6.3.5. An incident can be defined as any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which, directly or indirectly might lead to or might have led to the death of a patient, or user or of other persons or to a serious deterioration in their state of health.

A malfunction is defined as a failure of a device to perform in accordance with its intended purpose when used in accordance with the manufacturer’s instructions.

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23. Section 6.3.4 Time Period and Frequency of Detecting AEs and SAEs

Original Text:

SAE reports will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be reported to GSK within 24 hours, as indicated in Section 5.

Revised Text:

SAE reports will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be reported to PPD within 24 hours, as indicated in Section 6.3.5. PPD will then send the details to GSK.

24. Section 6.3.5 Prompt Reporting of Serious Adverse Events and Other Events to GSK

Original Text:

AE reports will be collected from the start of study treatment and until the follow-up contact.

SAEs, pregnancies, and medical device incidents will be reported promptly by the investigator to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event.

The method of detecting, recording, evaluating, and following up AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in the ISF.

Revised Text:

AE reports will be collected from the start of study treatment and until Week 28.

SAEs, pregnancies, and medical device incidents will be reported promptly by the investigator to PPD and PPD will report to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event.

The method of detecting, recording, evaluating, and following up AEs and SAEs plus procedures for completing and transmitting SAE reports to PPD are provided in the ISF.

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25. Section 6.3.5.1 Regulatory Reporting Requirements for SAEs

Original Text:

Prompt notification of SAEs by the investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

Revised Text:

Prompt notification of SAEs by the investigator to PPD is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met. 26. Section 7.0 Data Management Original Text: Clinical data will be managed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removal of errors and inconsistencies in the data. Terms for AEs and concomitant medications will be coded with MedDRA and an internal validated medication dictionary, GSKDrug. In all cases, subject initials will not be collected or transmitted to GSK according to GSK policy.

Revised Text: Clinical data will be managed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removal of errors and inconsistencies in the data. Terms for AEs and concomitant medications will be coded with MedDRA and an internal validated medication dictionary, GSKDrug.

27. Section 8.1 Hypothesis

28. Original Text:

This study is designed to show non-inferiority of metformin small pack to metformin usual pack (Cohort A) and metformin large pack (Cohort B) in the treatment of type II diabetes.

Cohort A:

The null hypothesis is that metformin small pack is inferior to metformin usual pack by a margin of 0.5% or larger in the mean change from baseline in HbA1c. Under rejection of the null, the alternative hypothesis is that metformin small pack is non-inferior to metformin usual pack.

Cohort B:

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Revised Text: This study is designed to show non-inferiority of metformin small pack to metformin large pack in the treatment of type II diabetes.

29. Section 8.2.1 Sample Size Assumptions Original Text: The sample size for each cohort will be based on the primary endpoint of change from baseline in HbA1c assuming a non-inferiority margin of 0.5% and a standard deviation of 1.0%, with 85% power and a one-sided significance level of 0.025. Assuming the allocation ratio of 1:1 for metformin small pack versus comparator, a total of 73 subjects will be required per treatment arm.

In order to evaluate the pre-specified hypotheses, 146 subjects will be required to have baseline and Week 28 HbA1c tests performed. The study assumes that 10% will be lost to follow-up; therefore, 162 subjects will be enrolled for each cohort, and a total of 324 subjects will be enrolled for the entire study.

Revised Text:

The sample size will be based on the primary endpoint of change from baseline in HbA1c assuming a non-inferiority margin of 0.5% and a standard deviation of 1.2%, with 90% power and a one-sided significance level of 0.025. Assuming the allocation ratio of 1:1 for metformin small pack versus large pack, a total of 123 subjects, per treatment arm, will be required to complete the study (i.e. have baseline and Week 28 HbA1c tests performed).

The study assumes that 10% will be lost post randomisation; therefore, 137 subjects will be randomised into each treatment group (a total of 274 randomised), and a total of 288 subjects will be enrolled for the entire study (assuming a 5% withdrawal rate between enrolment and randomisation).

30. Section 8.3.1 Analysis Populations

Original Text: Cohorts A and B will have separate analysis populations. Each cohort will have a safety and intent-to-treat (ITT) population as defined below: The cohort assignment will occur at Week 8. Therefore, data summarisations on the study population prior to randomisation at Week 8 will be performed on all enrolled subjects, which will be defined as the ‘observational population’.

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Revised Text: The treatment assignment will occur at Week 8. Therefore, data summarisations on the study population prior to randomisation at Week 8 will be performed on all enrolled subjects, which will be defined as the ‘observational population’.

31. Section 8.3.3.1 Primary Comparison of Interest

Original Text: The primary comparison of interest will be the difference in the change from baseline in HbA1c between treatment arms within each cohort. The change from baseline in HbA1c will be analysed with a multivariable mixed model, with treatment arm as the primary covariate of interest. In addition, the primary model will control for the following additional covariates: sex, age, duration of diabetes, body mass index, income level, education level, and need for add-on diabetes medications.

In addition, the difference in mean change from baseline will be calculated between the treatment arms (small pack – comparator), and the 2-sided 95% confidence interval for the difference in mean change in HbA1c will be calculated. If the pre-specified non-inferiority margin (0.5%) lies outside of the upper bound of the 95% confidence interval for the difference in mean change in HbA1c, then the null hypothesis will be rejected and small pack will be considered non-inferior to the comparator.

Revised Text: The primary comparison of interest will be the difference in the change from baseline in HbA1c between treatment arms. The change from baseline in HbA1c will be analysed with a multivariable mixed model, with treatment arm as the primary covariate of interest. In addition, the primary model will control for the following additional covariates: sex, age, duration of diabetes, body mass index, income level, education level, and need for add-on diabetes medications.

In addition, the difference in mean change from baseline will be calculated between the treatment arms (small pack – large pack), and the 2-sided 95% confidence interval for the difference in mean change in HbA1c will be calculated. If the pre-specified non-inferiority margin (0.5%) lies outside of the upper bound of the 95% confidence interval for the difference in mean change in HbA1c, then the null hypothesis will be rejected and small pack will be considered non-inferior to the large pack.

32. Section 8.3.3.2 Other Comparisons of Interest

Original Text: For each cohort, the following additional comparisons will be performed between the treatment arms:

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• Frequency and proportion of days with no metformin dose taken • Proportion of subjects prescribed add-on diabetes therapy during study • Proportion of subjects visiting a health care professional for diabetes management

during study • Proportion of subjects who prefer to remain on the assigned treatment style at end

of study Summary of reasons for missed days/doses throughout the study

Revised Text: The following additional comparisons will be performed between the treatment arms:


• Frequency and proportion of days with no metformin dose taken • Proportion of subjects prescribed add-on diabetes therapy during study • Proportion of subjects requiring a non-standard visit to a health care professional

for diabetes management during study • Proportion of subjects who prefer to remain on the assigned treatment style at end

of study • Summary of reasons for missed days/doses throughout the study

If there are sufficient numbers of subjects in each income category, then a summary description of the relationship of income levels with disease control status (HbA1c) and/or compliance to small or large pack will be conducted

33. Section 8.3.5 Key Elements of Analysis Plan

Original Text:

Statistical differences between metformin small pack and comparator will be described. Summary statistics will be presented accordingly. All primary statistical analyses and reporting will be performed separately for each of the cohorts. Exploratory evaluations may be performed comparing outcomes among treatment arms between Cohorts A and B. Data analysis will be performed with SAS® Version 9.1 or later.

Revised Text:

Statistical differences between metformin small pack and large pack will be described. Summary statistics will be presented accordingly. All primary statistical analyses and reporting will be performed separately for each of the treatment arms. Data analysis will be performed with SAS® Version 9.1 or later.

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34. Section 8.3.5.2 Safety Analysis Original Text: All safety analyses will be performed on the safety population. Frequencies and proportions of AEs and SAEs will be summarised overall and separately for each treatment arm. No formal statistical analysis is planned for the safety data. Cohorts A and B will be summarised separately. Full details of safety analyses will be described in the RAP. Revised Text: All safety analyses will be performed on the safety population. Frequencies and proportions of AEs and SAEs will be summarised overall and separately for each treatment arm. No formal statistical analysis is planned for the safety data. Full details of safety analyses will be described in the RAP.

35. Section 9.2 Regulatory and Ethical Considerations, Including the Informed Consent

Process

Original Text:

Details contained in the informed consent form will be available for subjects in paper format as well as via an audio recording. The population under study may have a lower rate of literacy than the general population. Therefore, the option for subjects to listen to the informed consent details will be offered to all subjects to ensure proper understanding of study procedures.

Revised Text:

Details contained in the informed consent form will be available for subjects in paper format as well as via video recording. The population under study may have a lower rate of literacy than the general population. Therefore, the option for subjects to review key study aspects related to the informed consent using a short video will be offered to all subjects to ensure proper understanding of study procedures.

36. Section 9.5 Study and Site Closure

Original Text:

Upon completion or termination of the study, the GSK-approved monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK standard operating procedures.

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Revised Text:

The end of the study will occur when the last remaining subject has completed the final visit assessments, i.e. date of last subject, last visit and all queries relating to subject data have been answered. Upon completion or termination of the study, the GSK-approved monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK standard operating procedures.

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