statistical analysis plan · 1 or 2 of the allowed antianginal medications with at least 50% of...

STATISTICAL ANALYSIS PLAN Study Title: A Phase 4, Randomized, Double-Blind, Placebo-Controlled,

Parallel Study of Ranolazine in Subjects with Chronic Stable Angina and Coronary Artery Disease with a History of Type 2 Diabetes Mellitus

Name of Test Drug: Ranolazine Study Number: GS-US-259-0133 Protocol Version: Amendment 2 Protocol Date: 1 February 2012 Analysis Type: Final (End of Study) Analysis Plan Version: 3.0 Analysis Plan Date: 14 November 2012 Analysis Plan Author: Stella Lee, Ann Olmsted

CONFIDENTIAL AND PROPRIETARY INFORMATION

Ranolazine GS-US-259-0133 Statistical Analysis Plan Version 3.0

CONFIDENTIAL 14 November 2012

TABLE OF CONTENTS

TABLE OF CONTENTS ....................................................................................................................................... 2 LIST OF IN-TEXT TABLES ................................................................................................................................. 3 LIST OF IN-TEXT FIGURES ............................................................................................................................... 3 LIST OF ABBREVIATIONS ................................................................................................................................ 4 1. INTRODUCTION ......................................................................................................................................... 5

1.1. Study Objectives ............................................................................................................................... 5 1.2. Study Design ..................................................................................................................................... 5 1.3. Sample Size and Power ................................................................................................................... 12

2. TYPE OF PLANNED ANALYSIS ............................................................................................................. 13 3. GENERAL CONSIDERATIONS FOR DATA ANALYSES ..................................................................... 14

3.1. Analysis Sets ................................................................................................................................... 14 3.2. Subject Groups ................................................................................................................................ 15 3.3. Strata and Covariates ...................................................................................................................... 15 3.4. Examination of Subject Subsets ...................................................................................................... 15 3.5. Multiple Comparisons ..................................................................................................................... 15 3.6. Missing Data ................................................................................................................................... 17 3.7. Definitions, Data Handling Conventions, and Transformations ..................................................... 18 3.8. Visit Windows ................................................................................................................................ 20

3.8.1. Definition of Study Day 1 ............................................................................................. 20 3.8.2. Analysis Windows ........................................................................................................ 20 3.8.3. Selection of Data in the Event of Multiple Records in a Window ................................ 21

4. SUBJECT DISPOSITION ........................................................................................................................... 22 4.1. Subject Enrollment .......................................................................................................................... 22 4.2. Disposition of Subjects ................................................................................................................... 22 4.3. Extent of Exposure .......................................................................................................................... 22

4.3.1. Duration of Exposure to Study Drug ............................................................................. 22 4.3.2. Adherence with Study Drug .......................................................................................... 23

4.4. Protocol Deviations and Major Eligibility Violations ..................................................................... 23 5. BASELINE DATA ...................................................................................................................................... 24

5.1. Demographics and Baseline Characteristics ................................................................................... 24 5.2. Medical History .............................................................................................................................. 24

6. EFFICACY ANALYSES ............................................................................................................................ 25 6.1. Definition of the Primary Efficacy Endpoint .................................................................................. 25 6.2. Statistical Hypothesis for the Primary Efficacy Endpoint ............................................................... 25 6.3. Analysis of the Primary Efficacy Endpoint ..................................................................................... 25 6.4. Secondary Efficacy Endpoints ........................................................................................................ 28

6.4.1. Definition of Secondary Efficacy Endpoints ................................................................. 28 6.4.2. Analysis Methods for Secondary Efficacy Endpoints ................................................... 29

6.5. Exploratory Efficacy Endpoints ...................................................................................................... 30 6.5.1. Definition of Exploratory Efficacy Endpoints .............................................................. 30 6.5.2. Analysis Methods for Exploratory Efficacy Endpoints ................................................. 31

6.6. Changes From Protocol-Specified Efficacy Analyses .................................................................... 31 7. SAFETY ANALYSES................................................................................................................................. 33



7.1. Adverse Events and Deaths ............................................................................................................. 33 7.1.1. Adverse Event Dictionary ............................................................................................. 33 7.1.2. Adverse Event Severity ................................................................................................. 33 7.1.3. Relationship of Adverse Events to Study Drug ............................................................. 33 7.1.4. Serious Adverse Events ................................................................................................. 33 7.1.5. Treatment-Emergent Adverse Events ........................................................................... 33 7.1.6. Summaries of Adverse Events and Deaths .................................................................... 34 7.1.7. Additional Analysis of Adverse Events ........................................................................ 35

7.2. Laboratory Evaluations ................................................................................................................... 36 7.3. Body Weight and Vital Signs .......................................................................................................... 36 7.4. Medications ..................................................................................................................................... 36

7.4.1. Prior Medications .......................................................................................................... 36 7.4.2. Concomitant Medications ............................................................................................. 36

7.5. Electrocardiogram Results .............................................................................................................. 37 7.6. Other Safety Measures .................................................................................................................... 37 7.7. Changes From Protocol-Specified Safety Analyses ........................................................................ 37

8. PHARMACOKINETIC ANALYSES ......................................................................................................... 38 9. REFERENCES ............................................................................................................................................ 39 10. SOFTWARE ................................................................................................................................................ 40 11. STATISTICAL ANALYSIS PLAN REVISIONS ...................................................................................... 41 12. APPENDICES ............................................................................................................................................. 47

Appendix 1. Table of Contents for Statistical Tables, Figures, and Listings ..................................... 48 Appendix 2. Questionnaire Scoring ................................................................................................... 54

LIST OF IN-TEXT TABLES

Table 6-1. Proposed Primary and Key Sensitivity Analyses .......................................................... 26

LIST OF IN-TEXT FIGURES

Figure 3-1. Proposed Testing Procedure of Endpoints .................................................................... 17



LIST OF ABBREVIATIONS

AE adverse event BMI body mass index bpm beats per minute eCRF electronic case report form CAD Coronary Artery Disease CSR clinical study report ECG electrocardiogram FAS full analysis set GEE generalized estimating equation(s) GLM generalized linear model HLT high level term HLGT high level group term IVRS interactive voice response system IWRS interactive web response system LLT lower level term mITT modified intent-to-treat MedDRA medical dictionary for regulatory activities PGA Physician’s Global Assessment PGIC Patient’s Global Impression of Change Pla placebo PP per-protocol PT preferred term Q1 first quartile Q3 third quartile QTc QT interval corrected for heart rate QTcB QT interval using Bazett correction for heart rate QTcF QT interval using Fridericia correction for heart rate Ran ranolazine SAE serious adverse event SAP statistical analysis plan SAQ Seattle Angina Questionnaire SD standard deviation SF-36 SF-36 Health Survey SL NTG sublingual nitroglycerin SOC system organ class SS safety analysis set T2DM type 2 diabetes mellitus VAS visual analog scale WHO World Health Organization



1. INTRODUCTION

1.1. Study Objectives

Primary Study Objectives

• To evaluate the efficacy of ranolazine compared to placebo on the average weekly angina frequency in subjects with a history of type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) and chronic stable angina who remain symptomatic despite stable treatment with 1 or 2 concomitant antianginal agents

Secondary Study Objectives

• To evaluate the efficacy of ranolazine compared to placebo on average weekly frequency of sublingual nitroglycerin (SL NTG) use

• To evaluate the efficacy of ranolazine compared to placebo on angina-free days

• To evaluate the efficacy of ranolazine compared to placebo on proportion of subjects achieving at least a 50% reduction in the average weekly angina frequency

• To evaluate the efficacy of ranolazine compared to placebo on health-related QoL

• To evaluate the safety and tolerability of ranolazine compared to placebo

1.2. Study Design

Design Configuration and Subject Population

Randomized, double-blind, placebo-controlled, parallel study in type 2 diabetic subjects with CAD and chronic stable angina receiving a stable dose of 1 or 2 concomitant antianginal agents

Treatment Groups Ranolazine 1000 mg BID vs Placebo

Key Eligibility Criteria

1. At least a 3-month history of chronic stable angina triggered by physical effort and relieved by rest and/or SL NTG

2. CAD documented by one or more of the following:

a. Evidence, either by invasive coronary angiograms or noninvasive CT coronary angiograms, of ≥ 50% stenosis of one or more major coronary arteries



b. History of myocardial infarction (MI) documented by positive CK-MB enzymes, troponins, or electrocardiogram (ECG) changes

c. Cardiac imaging study or exercise test diagnostic for CAD

d. History of coronary revascularization procedure

1. Treatment with 1 or 2 antianginal therapies at a stable dose for at least 2 weeks prior to the 4-week single-blind placebo run-in period. Allowed antianginals are the following:

• beta-blocker (except sotalol)

• CCB

• dihydropyridine

• non-dihydropyridine (diltiazem at a dose of at least 180 mg daily or verapamil at a dose of at least 180 mg daily)

• LAN

2. Documented history of T2DM

Qualifying Criteria for Double-Blind Treatment Phase

The subject must meet continuing eligibility criteria including entry criteria and additional criteria listed below in order to be randomized into the double-blind treatment phase.

1. ≥ 85% adherence to daily documentation of angina frequency and SL NTG use over the last 21 days of the single-blind, placebo run-in period. In addition, there could be no week in the last 21 days of the single-blind placebo run-in period in which angina frequency and SL NTG use was recorded for less than 5 days.

2. An average weekly angina frequency of ≥ 1 and ≤ 28 over the last 21 days of the single-blind, placebo run-in period, provided that there was at least 1 angina episode during each week of the last 21 days of the single-blind, placebo run-in period.

3. ≥ 80% adherence with study drug during the 4-week single-blind, placebo run-in period



Study Periods/Phases

Screening Treatment Period – 8 wks

Qualifying phase (2-week optional wash-out and 4-week single-blind placebo run-in period)

4-6 wks

Randomization

Ranolazine Wk 2 visit

Wk 2 visit

Wk 8 visit

Wk 8 visitPlacebo Antianginal background therapy

FU safety phone call

FU safety phone call

FU - 2 wks

After signing the informed consent form, subjects will enter a 4- to 6-week qualifying phase. Subjects need to be on 1 or 2 of the allowed antianginal medications with at least 50% of subjects being on only 1 of the allowed antianginal medications. The subjects’ concomitant antianginal medication(s) must be at a stable dose for at least 2 weeks prior to initiating the 4-week single-blind, placebo run-in period. Subjects taking more than the allowed number of antianginal medications must stop their additional antianginal therapies, including non-allowed antianginal therapies such as trimetazidine, ivabradine, and nicorandil, 2 weeks prior to initiating the 4-week single-blind, placebo run-in period. Beta-blockers should not be discontinued.

Subjects who meet the qualifying criteria and continue to meet the eligibility criteria will be randomized to either placebo or ranolazine.



Schedule of Assessments

Qualifying Phase

(4 to 6 weeks) Double-blind treatment Phase

(8 weeks)

Screeninga

(1-14 days)

Optional 2-Week

Wash-out periodb

4 Week Run-in Period

(±2 days) Randomi-

zation Wk 2

(D8-D10) Wk 2

(D14±2) Wk 5

(D35±2)

End of Treatment Period/Wk 8 (D56±2)

Early Study Drug Disc/

Early Termc

14-Day Follow up

phone call (±2 days)

Informed consent x

Inclusion/exclusion criteria

x x

Medical history & Demographics

x

Physical examination

x xd xd x x

Vital signse x x x x x

Height x

Weight x x x x x

Waist circumference

x

12-lead ECG x

Laboratory examination (hematology & chemistry)

x



Qualifying Phase


(8 weeks)

Screeninga

(1-14 days)

Optional 2-Week

Wash-out periodb


(±2 days) Randomi-

zation Wk 2

(D8-D10) Wk 2

(D14±2) Wk 5

(D35±2)



Early Termc

14-Day Follow up


Pregnancy testf x x x x x

HbA1c x

Fasting lipid panelg x

CV research blood samplesh

x

SF-36 Health Surveyi

x x x

Seattle Angina Questionnairei

x x x

Rose Dyspnea Scalei

x x x

PGIC scale x x

PGA VASi x x x

Conduct phone call to encourage compliance with study drug dosing

x x



Qualifying Phase


(8 weeks)

Screeninga

(1-14 days)

Optional 2-Week

Wash-out periodb


(±2 days) Randomi-

zation Wk 2

(D8-D10) Wk 2

(D14±2) Wk 5

(D35±2)



Early Termc

14-Day Follow up


Concomitant antianginal administration

x-----------------------------------------------------------------------------------------------------------------------------------------------------x

Discontinuation of additional concomitant antianginal meds

x

Placebo run-in x

Study drug administrationj

x x x x x x

Review of angina frequency, SL NTG use, and daily dyspnea score

x------------------------------------------------------------------------------------------------------------------------------------x

Adverse events x-------------------------------------------------------------------------------------------------------------------------------------------------------x

Concomitant medications

x-------------------------------------------------------------------------------------------------------------------------------------x xk

a ALL Screening procedures must be done within the 14 day screening period. The optional 2-week wash-out period can overlap with the screening period. b Only if subjects need to discontinue or stabilize medications



c Subjects who discontinue study drug before the end of the treatment period must return for an Early Study Drug Discontinuation visit within 48 hours from the last dose of study medication, if possible. Subjects whose participation in the study is terminated prior to completion of the treatment period should return for an early termination visit, within 48 hours from last dose of study medication, if possible.

d Perform abbreviated PE at Randomization and Week 2 visit to capture potential changes from Screening. e Blood pressure and heart rate will be recorded while sitting and standing f Serum pregnancy test for women of child-bearing potential must be conducted at Screening. Urine pregnancy test for women of child-bearing potential must be conducted at

Randomization, at Week 2, and at the end of the treatment period, or at Early Termination. Positive urine pregnancy test will be confirmed by serum pregnancy test. g Must be performed after the subject has fasted for at least 8 hours h CV research blood samples will be collected at Randomization to test for biomarkers related to ischemic heart disease and to determine whether these biomarkers correlate

with severity of angina and may predict response to ranolazine. i Subjects must complete the SF-36 Health Survey, Seattle Angina Questionnaire (SAQ), and Rose Dyspnea Scale, prior to administration of study drug (Randomization). The

investigator will complete the PGA VAS prior to administration of study drug (Randomization). j Study drug will be dispensed at the start of the 4-week run-in period, at Randomization, and at the Week 2 visit. k Concomitant medications will only need to be collected at the 14-day follow-up phone call if the subject experienced an SAE during the 14-day follow-up period.



Randomization Randomization will be stratified by:

• Average number of weekly angina episodes (≥ 1 but < 3 or ≥ 3 but ≤ 28)

• Number of concomitant antianginal agents (1 or 2)

• Geographic region (Russia, Ukraine, and Belarus vs Other).

Site and/or Stratum Enrollment Limits

The proportion of subjects being treated with 2 concomitant antianginal medications will be capped at 50%, and the proportion of subjects with baseline average weekly angina frequency < 3 will be capped at 30%. There are no site enrollment limits.

Study Duration The study duration is anticipated to be approximately 12 months, with 9 months for enrollment and 10 weeks for treatment and follow-up.

1.3. Sample Size and Power

Planned Sample Size

Approximately 900 subjects will be enrolled.

Power Statement A sample size of 900 subjects, randomized in a 1:1 ratio to ranolazine and placebo treatment groups, will provide approximately 90% power assuming a relative reduction of 20% as compared to placebo in weekly angina frequency using a 2-sided test at α = 0.05 (from a generalized linear model [GLM] with the negative binomial distribution and log link), assuming an overdispersion parameter of 1.0 and a placebo angina frequency count of 12 over 6 weeks.



2. TYPE OF PLANNED ANALYSIS

This statistical analysis plan (SAP) pertains to end of study analysis.



3. GENERAL CONSIDERATIONS FOR DATA ANALYSES

3.1. Analysis Sets

Efficacy analyses will be performed on data from the following analysis sets:

• The modified Intent-to-Treat set (mITT) comprises all randomized subjects who received at least 1 dose of randomized study drug, made at least 1 postbaseline number of angina episodes diary report, and did not have any egregious eligibility violations. Subjects will be summarized according to actual treatment received regardless of the allocated treatment. This will be the supportive analysis set for all efficacy analyses.

• The full analysis set (FAS) comprises all mITT subjects who did not discontinue randomized study drug prior to study Day 14 and who reported their number of angina episodes on at least 7 days during the last 6 weeks on treatment. Subjects will be summarized according to randomized treatment regardless of actual treatment received. Statistical analyses of all efficacy endpoints will be based on the FAS, which is considered the primary analysis set.

• The per-protocol set (PP) comprises all FAS subjects who did not have any major protocol deviations affecting efficacy-evaluability, and who met the following 2 requirements over the last 6 weeks on treatment, as determined using data in the clinical database:

— ≥ 80% dosing compliance, and

— ≥ 85% diary compliance

Major protocol deviations will be determined prior to unblinding of treatment groups, and major deviations warranting exclusion from the PP set will be identified. Subjects will be summarized according to actual treatment received regardless of the allocated treatment. This will be the exploratory analysis set for the primary endpoint only.

Sensitivity analyses of the primary endpoint of angina frequency will be performed on additional analysis sets as described in Section 6.3.

Safety analyses will be performed on the safety analysis set (SS), which will include all subjects dosed with randomized study drug, and summaries by treatment will be by actual treatment received. If a subject should inadvertently receive both blinded ranolazine and blinded placebo, safety analyses will include this subject in the ranolazine group.



3.2. Subject Groups

Subjects will be grouped for analyses according to randomized treatment for efficacy analyses using the FAS. Subjects will be grouped according to actual treatment received for efficacy analyses using the mITT or PP set and safety analyses using the SS. If there are no discrepancies between randomized and actual treatment, and the number of subjects in the mITT set who are excluded from the FAS is 20 or fewer, only the primary efficacy analysis will be performed for the mITT set (as a sensitivity analysis). Other efficacy analyses will be performed for the FAS only.

3.3. Strata and Covariates

The following stratification factors will be included in all efficacy analysis models, except for subset analyses defined in Section 3.4:

• Average number of weekly angina episodes at baseline (< 3 or ≥ 3) (if baseline angina frequency is not included in the model as a continuous covariate)

• Number of concomitant antianginal agents (1 [or none], or 2 [or more])

• Geographic region (Russia, Ukraine, and Belarus; or Other)

Subjects will be randomized based on interactive voice response system/interactive web response system (IVRS/IWRS) data. For analyses using average number of weekly angina episodes at baseline strata, stratum membership will be determined from e-diary data. See Section 3.7 for definition of average number of weekly angina episodes at baseline. For analyses using number of concomitant antianginal agents strata, stratum membership will be determined from electronic case report form (eCRF) data.

3.4. Examination of Subject Subsets

Primary analysis of weekly angina frequency will be performed on subsets defined by age (< 65 vs ≥ 65), sex (male vs female), and each stratification factor described in Section 3.3.

3.5. Multiple Comparisons

Hypotheses will be tested at the 5% significance level; tests will be 2-sided. The null hypothesis for the primary and secondary efficacy endpoints will be tested using a closed testing procedure with Hochberg adjustment {17876} to ensure that the family-wise Type I error rate is preserved. First, the null hypothesis of no treatment difference in the primary efficacy endpoint of average weekly angina frequency over the last 6 weeks on treatment will be tested at the 5% level. Provided statistical significance is achieved for the primary efficacy endpoint, the subsequent ordered secondary endpoints will be tested each at the 5% level using Hochberg adjustment within each group. Hochberg procedure will be implemented as follows (see Figure 3-1 for details):



• All endpoints within the group are considered to be statistically significant if all p-values are less than 5%

• Otherwise, the endpoint corresponding to a lower p-value will be significant if the p-value is less than 2.5% (assuming 2 endpoints in the group)

• If only one endpoint is significant within a group of two endpoints, and all preceding endpoints are significant at alpha = 0.05, the “winning” endpoint must be significant at alpha = 0.025 in order to be claimed. No subsequent endpoints will be claimed.

• If neither test within any ordered group is statistically significant, further testing may continue but significance will not be claimed.

Secondary endpoints will be tested in the following order:

1. Average weekly frequency of SL NTG use over the last 6 weeks on treatment

2. Angina-free days over the last 6 weeks on treatment OR proportion of subjects achieving at least a 50% reduction in the average weekly angina frequency over the last 6 weeks on treatment

3. Change from baseline in the SF-36 Mental Component Score OR change from baseline in the Physical Component Score

4. Patient’s Global Impression of Change (PGIC) scale score



Figure 3-1. Proposed Testing Procedure of Endpoints

Primary Endpoint: Angina Frequency

1st Group Secondary Endpoint: SL NTG Frequency

Multiplicity Type-I Error Control

If significant then progress with alpha=0.05

2nd Group Secondary Endpoints: Proportion with at least 50% reduction OR Angina free Days (via Hochberg)

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i.e.

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mad

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prec

edin

g en

dpoi

nt is

sig

nific

ant

If both significant with p<0.05, then progress with alpha=0.05

Claim endpoint success if p <0.05

Claim endpoint success if 2-sided p <0.05 (2-sided)

Claim both endpoint success if the larger p <0.05

Claim only one endpoint success if the smaller p <0.025 and the other p ≥0.05

3rd Group Secondary Endpoints: SF-36 Mental domain score OR Physical domain score (via Hochberg)

Claim both endpoint success if the larger p <0.05

Claim only one endpoint success if the smaller p <0.025 and the other p ≥0.05

4th Group Secondary Endpoint: PGIC Scale Score

If significant then progress with alpha=0.05

If both significant with p<0.05, then progress with alpha=0.05

Exploratory endpoints will be tested at the 5% significance level using 2-sided tests, with no adjustment for multiplicity.

3.6. Missing Data

Missing Data

For missing diary data, see Section 6.3 for sensitivity analyses using different methods of handling missing data. For partially completed questionnaires, see the scoring rules for each questionnaire given in the appendices. Per protocol, the PGA-VAS, SF-36, Rose Dyspnea Scale, and SAQ were to be administered twice, at the Randomization visit and then at the Week 8 or Early Termination visit, and the PGIC Scale was to be administered once, at the Week 8 or Early Termination visit. Scores not obtained will not be imputed.



3.7. Definitions, Data Handling Conventions, and Transformations

The day of study drug discontinuation is defined as the day of last dose. For instance, if the last dose was taken on study Day 13, the day of study drug discontinuation is Day 13 and the subject is not in the FAS. If the last dose was taken on study Day 14, the day of discontinuation is Day 14 and the subject is included in the FAS if the other membership conditions are met.

Diary compliance will be calculated as the fraction of days during the applicable interval in which the subject made a number of angina episodes diary report (including reports of zero episodes). For example, for a subject whose last 6 weeks on treatment interval began on 07 June 2012 and ended on 18 July 2012, and who transmitted a number of angina episodes diary report for 35 days during the interval, diary compliance would be calculated as 35/42 ≅ 0.833 or 83.3%.

Dosing compliance will be calculated as the fraction of days during the applicable interval in which the subject took at least one dose, as determined using data from the Study Drug Administration eCRF.

Baseline angina frequency (attacks/week) is calculated as (number of angina episodes over the last 21 days of the placebo run-in period)/(duration in weeks). Days with missing diary data are excluded from this calculation, ie, baseline angina frequency for subjects with missing diary data is 7(number of episodes)/(number of days with reports).

Baseline SL NTG use (uses/week) is calculated as (number of SL NTG uses over the last 21 days of the placebo run-in period)/(duration in weeks). Days with missing diary data are excluded from this calculation, ie, baseline SL NTG use for subjects with missing diary data is 7(number of uses)/(number of days with reports). If a subject has zero baseline SL-NTG use, this value will be imputed with 50% of the minimum non-zero value across all subjects.

Baseline daily dyspnea score is defined as the average score over the last 21 days of the placebo run-in period, ie, (sum of scores reported during the interval)/(number of days during the interval for which a score was reported).

For quality of life, safety, and other assessments, a baseline value is defined as the last measurement obtained on or prior to the date of the first dose of double-blind study drug. For example, baseline body weight is defined as the last measurement obtained on or prior to the date of the first dose of double-blind study drug. For most subjects, this will be the measurement obtained at the Randomization visit. If it is necessary to derive a baseline value for a subject never dosed with double-blind study drug, for subjects who completed the Randomization visit it will be defined as the last measurement obtained on or prior to the Randomization visit date. For subjects who did not complete the Randomization visit it will be defined as the last measurement obtained.

Age will be calculated as (Screening visit date – birth date) / 365.25, truncated to a whole number. Body mass index (BMI) is calculated as baseline weight (kg) / [height (m)]2. It will



be displayed to 1 decimal place in listings, but will not be rounded or truncated prior to summarization.

Duration of type 2 diabetes mellitus in years is defined as:

(Screening visit date – date of type 2 diabetes mellitus diagnosis)/365.25

For incomplete date of type 2 diabetes mellitus diagnosis, impute using the following algorithm:

If day is missing and month and year are not missing, set to 15th day of month; if day and month are missing and year is not missing, set to July 1st. If imputation yields a date later than the date of the screening visit, set to the date of the screening visit. Otherwise, do not impute.

QTc calculations:

Fridericia's Formula:

3 RRQTFQTc =

Bazett’s Formula:

QTcB = QTRR

where the RR interval (sec) = 60/(ventricular rate [bpm])

P-values in tables, figures, and listings will be displayed according to the TFL convention shown below:

Range Statistical Convention TFL Convention

Greater than or equal to .995 1 1.0

Less than .995 but not less than .1 .xx, eg, .47 0.xx, eg, 0.47

Less than .1 but not less than .001 .xxx, eg, .051 0.xxx, eg, 0.051

Less than .001 < .001 <0.001



3.8. Visit Windows

3.8.1. Definition of Study Day 1

Study Day 1 is defined as the day of first dose of study medication during the double-blind treatment phase.

3.8.2. Analysis Windows

For the endpoints based on diary data, visit window is not applicable; the applicable windows are reporting periods.

The last 21 days of the placebo run-in period are defined as the 21-day interval ending the day before the Randomization visit. The date of the Randomization visit will be obtained from the eCRF database. For example, for a subject with an eCRF Randomization visit date of 9 January 2012, the last 21 days of the placebo run-in period are defined as 19 December 2011 to 8 January 2012.

The last 6 weeks on treatment is defined as the 42-day or shorter interval ending the day before the last dose of double-blind study drug was taken and beginning with the later of:

• Date of last dose of double-blind study drug - 42 days

• Date of first dose of double-blind study drug

For example, for a subject whose last dose of double-blind study drug was taken 5 March 2012 and whose first dose was taken 9 January 2012, the last 6 weeks on treatment are defined as 23 January 2012 to 4 March 2012. For a subject who completed all 8 weeks of the on-treatment diary, the applicable study days would be study Days 15–56, or study Days 2-43 for a subject who discontinued treatment on Day 44, or study Days 1–16 for a subject who discontinued treatment on Day 17.

For subjects who made their last diary report the day before their last dose or earlier, the last 6 weeks on study is defined as identical to the last 6 weeks on treatment. For subjects making diary reports on or after the day of their last dose, the interval is defined as the 42-day or shorter interval ending with the last date for which number of angina episodes was reported and beginning with the later of:

• Date of last number of angina episodes report - 41 days (6 weeks - 1 day)

• Date of first dose of double-blind study drug

The on-treatment period is defined as the interval beginning on the date of first dose of double-blind study drug and ending the day before the last dose of double-blind study drug. The on-study period is defined identically for subjects who made their last diary report the day before their last dose or earlier. For subjects making diary reports on or after the day of



their last dose, it is defined as the interval beginning on the date of first dose of double-blind study drug and ending on the date of the last diary report.

For all randomized subjects except those for whom “Randomized but Subject Never Dosed with Study Drug” was selected on the Study Drug Completion eCRF, the dates of first and last dose of double-blind study drug may be obtained from the eCRF database as follows:

1. Select study drug administration eCRF dosing interval records

2. Set date of first dose of double-blind study drug to earliest start date ≥ max(Randomization visit date, IXRS randomization date)

3. Set date of last dose of double-blind study drug to latest end date ≥ max(Randomization visit date, IXRS randomization date)

4. If no date of last dose of double-blind study drug was obtained, assume the subject never took double-blind study drug

5. If a date of last dose of double-blind study drug was obtained, but no date of first dose of double-blind study drug, assume the subject took the first dose of double-blind study drug on max(Randomization visit date, IXRS randomization date)

For repeated measures analyses, the days in the on-treatment period will be partitioned into 1-week intervals by counting backward from the day before the last dose, combining the earliest interval with the next interval if less than 4 days. The earliest interval is Week 1, the next interval Week 2, and so on. For instance, for a subject who took the first dose of double-blind study drug on the evening of Day 1 and the last dose on the morning of Day 57, Week 1 is Days 1 to 7, Week 2 is Days 8 to 14, Week 3 is Days 15 to 21, Week 4 is Days 22 to 28, Week 5 is Days 29 to 35, Week 6 is Days 36 to 42, Week 7 is Days 43 to 49, and Week 8 is Days 50 to 56. For a subject who discontinued treatment on Day 44, Week 1 is Days 1 to 8, Week 2 is Days 9 to 15, Week 3 is Days 16 to 22, Week 4 is Days 23 to 29, Week 5 is Days 30 to 36, and Week 6 is Days 37 to 43. The days in the on-study period will be partitioned into 1-week intervals likewise, counting backward from the end date.

For non-interval-based endpoints, nominal visits and nominal timepoints (when applicable) will be used.

3.8.3. Selection of Data in the Event of Multiple Records in a Window

Not applicable



4. SUBJECT DISPOSITION

4.1. Subject Enrollment

The number and percentage of subjects randomized in each country and by each investigator within a country will be summarized overall and by treatment group. The denominator for this calculation will be the number of randomized subjects.

Similarly, the number and percentage of subjects enrolled in each randomization stratum will be summarized. If there is a discrepancy between IVRS/IWRS and eCRF data with respect to randomization stratum values, eCRF data will be used in statistical analyses, and discrepancies between IVRS/IWRS data and eCRF data will be listed.

4.2. Disposition of Subjects

A summary of subject disposition will be provided by treatment group. This summary will present the number of subjects screened, randomized, included in the safety analysis set, and the number and percentage of subjects meeting the following criteria:

• Completed the study drug treatment,

• Did not complete the study drug treatment (with summary of reasons for not completing the study treatment),

• Completed the study (includes the study treatment period and any post treatment follow up period), and

• Did not complete the study (with summary of reasons for not completing the study).

The denominator for the percentages of subjects in each category will be the number of subjects in the safety analysis set.

No inferential statistics will be generated. A data listing of reasons for premature study treatment/study discontinuation will be provided.

4.3. Extent of Exposure

4.3.1. Duration of Exposure to Study Drug

Duration of exposure to study drug will be defined as (last dose date – first dose date of double-blind treatment phase + 1), regardless of temporary interruptions in study drug administration, and will be expressed in weeks (shown to one decimal place, eg, 4.5 weeks). Duration of exposure to study drug will be summarized using descriptive statistics (sample size, mean, standard deviation, median, first quartile (Q1), third quartile (Q3), minimum, and maximum).



Summaries will be provided by treatment group for the safety analysis set.

4.3.2. Adherence with Study Drug

Unreturned bottles will be excluded from adherence calculations.

The actual number of tablets ingested will be calculated using the Study Drug Accountability Log eCRF: total number of tablets ingested = total number of tablets dispensed - total number of tablets returned.

The expected number of tablets ingested will be calculated based on the Study Drug Administration eCRF.

Expected number of tablets ingested = sum across dosing intervals of ([stop date - start date + 1] × dose [1 or 2 tablets] × frequency [1 or 2])

Adherence rate = 100 (total number of tablets ingested)/(expected number of tablets ingested).

Adherence will be calculated for the single-blind placebo run-in period and for the double-blind treatment period separately. Adherence will be capped at 100% for summarization.

Descriptive statistics for adherence (sample size, mean, standard deviation, median, Q1, Q3, minimum, and maximum) along with the number and percentage of subjects belonging to adherence categories will be provided by treatment group and overall for the safety analysis set.

4.4. Protocol Deviations and Major Eligibility Violations

Prior to database lock, clinical research, biostatistics, and clinical operations representatives will review a list of major eligibility violations prepared by the clinical operations group and identify any that warrant excluding subjects from the mITT analysis set. Also prior to database lock, they will review a list of major protocol deviations prepared by the clinical operations group and identify any affecting efficacy-evaluability that warrant excluding subjects from the PP analysis set.



5. BASELINE DATA

5.1. Demographics and Baseline Characteristics

Subject demographic data including age, sex, race, and ethnicity and baseline characteristics including body weight, BMI, waist circumference, and HbA1c will be summarized by treatment group and overall using descriptive statistics (sample size, mean, standard deviation, median, Q1, Q3, minimum and maximum) for continuous data and by the number and percentage of subjects for categorical data. Risk factors including dyslipidemia, smoking, and alcohol use will be summarized similarly. These summaries will be provided for the safety analysis set. Chi-squared test p-values for categorical variables and ANOVA p-values for continuous variables may be presented as an aid to assessing comparability of the ranolazine and placebo groups.

5.2. Medical History

Cardiovascular and diabetes history, including duration of diabetes, will be summarized by treatment group and overall by the number and percentage of subjects with each condition. Summaries will be provided for the safety analysis set. P-values for assessing comparability of treatment groups will be shown as above.

Other medical history and surgical history data will be listed only. Other medical history and surgical history data will not be coded.



6. EFFICACY ANALYSES

6.1. Definition of the Primary Efficacy Endpoint

The primary efficacy endpoint is average weekly angina frequency over the last 6 weeks on treatment. To perform the primary analysis, the following two variables will be defined: total number of episodes over the last 6 weeks on treatment and duration (total number of days with data) corresponding to the last 6 weeks on treatment. The response variable for the primary analysis, which is to be performed by fitting a generalized linear model with negative binomial error distribution and log link, is the total number of episodes over the last 6 weeks on treatment. Duration enters into the model as log person days, where person days is the number of days for which data were obtained. Model estimates will be re-expressed in terms of angina frequency in attacks per week.

Days with missing diary information on angina frequency will be excluded from these calculations. For example, if during the 6-week look back, 2 out of 42 days were missing angina diary information, 40 instead of 42 would be the applicable number of person days that would be equal to the total person time in the GLM. Total number of episodes would be the total number of angina episodes reported for those 40 days.

6.2. Statistical Hypothesis for the Primary Efficacy Endpoint

The null and alternative hypotheses for the primary efficacy endpoint will be:

H0: θ = 1 Ha: θ ≠ 1

where θ is the incidence density ratio of weekly average angina frequency over the last 6 weeks on treatment (Ranolazine/Placebo).

6.3. Analysis of the Primary Efficacy Endpoint

The primary analysis will be performed by fitting a GLM with negative binomial distribution, log link, and log person time as the offset {17875}. The primary efficacy analysis includes the period of time corresponding to the last 42 days of on-treatment diary data (defined in Section 3.8.2). The model will include treatment, log weekly baseline angina frequency, and the baseline stratification factors number of concomitant antianginal medications (1 or 2) and geographic region (Russia, Ukraine, and Belarus; or Other). See Section 3.7 for the definition of baseline angina frequency. Treatment difference will be expressed as an incidence density ratio. Sample SAS code is available in the document GS-US-259-0133 Programming Specs.

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Key sensitivity analyses for the primary endpoint will also be based on the same GLM as for the primary analysis, but will explore different ways of defining the population and the data to be used for the analysis. Specifically, the following analyses will be conducted:

A) FASon-study: Includes only subjects whose last dose is taken on or after study Day 14 and includes all on-study diary data after discontinuing study drug. For the purpose of this analysis, the last 6 weeks on study as defined in Section 3.8.2 will be used to estimate weekly angina frequency.

B) modified Intent-to-Treat on treatment (mITTon-treatment): Includes all on-treatment diary data for subjects in the mITT analysis set (no requirement for at least 14 days of treatment). For this analysis, the last 6 weeks on treatment as defined in Section 3.8.2 will be used.

C) mITTon-study: Includes all on-study diary data for subjects in the mITT analysis set (no requirement for at least 14 days of treatment, diary data after discontinuing study drug are included). For the purpose of this analysis, the last 6 weeks on study as defined in Section 3.8.2 will be used to estimate weekly angina frequency.

Additional sensitivity analysis of the primary endpoint using the PP analysis set will be performed.

Table 6-1 depicts the proposed primary and key sensitivity analyses.

Table 6-1. Proposed Primary and Key Sensitivity Analyses

Analysis Population

Include only subjects whose last dose is taken on or after

study Day 14

Exclude data after discontinuing study drug (Yes=on-treat,

No=on-study) Analysis

Method –GLM

FASon-treatment Yes Yes Primary Analysis

FASon-study Yes No Sensitivity Analysis A

mITTon-treatment No* Yes Sensitivity Analysis B

mITTon-study No* No Sensitivity Analysis C

* Includes all diary data available for subjects in the mITT analysis set, without excluding any data from the first 14 days.

In addition to the GLM model mentioned above for primary and key sensitivity efficacy analyses, angina frequency will also be assessed based on a generalized estimating equations (GEE) repeated measures analysis with negative binomial distribution, using a log link and exchangeable covariance structure. The repeated measures will be the angina frequency for



each week of the treatment period, and will be performed for the FAS or mITT populations as described in Table 6-1. Weekly diary data may be pooled if the GEE model results in non-convergence due to sparse data. Details of the data pooling method will be fully described in the clinical study report (CSR).

The repeated measures model will include time and its interactions with treatment and log baseline weekly angina frequency, in addition to the stratification factors included in the primary negative binomial model. The average treatment difference that corresponds to the last 6 weeks of the treatment period (ie, Weeks 3 through 8), expressed as an incidence density ratio, will be estimated using this GEE repeated measures model.

Depending upon the amount and type of missing data, and the relationship between missingness, treatment, and outcome data, a broader range of sensitivity analyses that give greater reassurance on the robustness of the trial results will be considered. Additional sensitivity analyses may include primary endpoint analyses based upon one or more conservative imputation scenarios, or a responder analysis, for evaluation of missing data with respect to the estimated treatment difference, to mitigate the bias concerns resulting from the missing data. Additional sensitivity analyses will include the following pair of resampling analyses.

Resampling analyses: An equal-slopes ANCOVA model will be fitted to log angina frequency in attacks per week. The covariate will be log baseline angina frequency in attacks per week. Terms for treatment effect (ranolazine vs placebo), no. of concomitant antianginal medications (1 vs 2), and geographic region (Russia, Ukraine, and Belarus vs Other) will be included. With a model of this kind, the effect of treatment is estimated as a multiplier, eg, a ranolazine:placebo angina frequency ratio of 0.8 (20% reduction) or 1.1 (10% increase). Before database lock and unblinding, the model may be modified as appears appropriate, eg, by adding interaction terms. The SAP will be revised to reflect any such changes. Inferences about the effect of ranolazine treatment will be based on bootstrap and permutation methods.

These resampling analyses will be FAS analyses over the last 6 weeks on treatment. If any subject has no reported attacks during the response period, the number of attacks will be set to 1 to calculate angina frequency in attacks per week.

The permutation test will proceed as follows. First, a p-value is obtained by fitting the ANCOVA model. This is the “observed p-value.” Next, we randomly permute the treatment codes and calculate a p-value for each permuted sample. From this set of calculated p-values we obtain the p-value distribution under the null hypothesis that a subject’s treatment assignment has no effect on their response. The permutation-based p-value is the proportion of p-values that are less than or equal to the observed p-value. In a randomized trial, the permutation procedure strictly controls the type 1 error rate of between-treatments tests {22512}.

1



For practical reasons, rather than generating all possible permutations of the treatment codes, we will generate 20,000 permutations and obtain an approximate permutation p-value. For reproducibility, we will use a SAS random number seed of 1908022650.

The bootstrap confidence interval for the effect of treatment will be calculated as follows. First we take the original data set, and make a new sample that is of the same size. The new sample is taken from the original using sampling with replacement. We repeat this 20,000 times, and for each of these bootstrap samples we compute the estimated treatment effect using the ANCOVA model specified above. For reproducibility, we will use a seed of 576155286 to generate the bootstrap samples. We then compute the bootstrap confidence interval using the bias-corrected accelerated, or BCa, confidence interval {22513}. The basic ideas and procedures of this approach are detailed in Bootstrap Confidence Intervals: An Introduction to the Bootstrap {22532}. Compared with the standard method for confidence intervals based on standard errors, the BCa confidence interval created this way has the advantage that it is second-order accurate, is transformation-respecting, and is range-preserving {22513}.

6.4. Secondary Efficacy Endpoints

6.4.1. Definition of Secondary Efficacy Endpoints

Secondary efficacy endpoints include:

• Average weekly frequency of SL NTG use over the last 6 weeks on treatment

This endpoint is defined in a similar way to the primary endpoint of average weekly angina frequency. See Section 3.8.2 for details in definition of last 6 weeks on treatment. Days with missing diary information on SL NTG use will be excluded from the calculation.

• Angina-free days over the last 6 weeks on treatment

For the purpose of summarizing the proportion of angina-free days over the last 6 weeks on treatment, the following two variables will be defined: total number of angina-free days over last 6 weeks on treatment and duration corresponding to last 6 weeks on treatment. See Section 3.8.2 for details in definition of last 6 weeks on treatment. Days with missing diary information on angina frequency will be excluded from the calculation. The proportion of angina-free days will be calculated as (total number of angina-free days)/(total number of days with diary information on angina frequency). For analysis, as described in the next section, weekly numerator and denominator counts are calculated and the ranolazine:placebo ratio of the geometric means across weeks of the odds of having an angina-free day is estimated.

• Proportion of subjects achieving at least a 50% reduction in the average weekly angina frequency



For purposes of summarization, a subject will be considered to have at least a 50% reduction in average weekly angina frequency if (average weekly angina frequency during last 6 weeks on treatment)/(baseline angina frequency) is less than or equal to 0.5.

Average weekly angina frequency is defined as (total number of angina episodes during last 6 weeks on treatment)/(corresponding duration in weeks). See Section 3.8.1 for details in definition of last 6 weeks on treatment. Days with missing diary information on angina frequency will be excluded from this calculation.

See Section 3.7 for definition of baseline angina frequency. For analysis, as described in the next section, whether a subject had at least a 50% reduction from baseline is determined for each of the last 6 weeks on treatment and the ranolazine:placebo ratio of the geometric means across weeks of the odds of having at least a 50% reduction is estimated.

• Change from baseline in the SF-36 Mental Component Score {17872}

See Appendix 2 for calculation of SF-36 Mental Component Score.

• Change from baseline in SF-36 Physical Component Score {17872}

See Appendix 2 for calculation of SF-36 Physical Component Score.

• PGIC scale score {17829}

The PGIC score as entered into the eCRF will be used. This score will range from 1 to 7.

6.4.2. Analysis Methods for Secondary Efficacy Endpoints

Average weekly SL-NTG use will be analyzed using the same methodology as described above for primary analysis of weekly angina frequency. The primary analysis will be performed by fitting a GLM with negative binomial distribution, log link, and log person time as the offset. Secondary analysis will be performed using a GEE repeated measures analysis with negative binomial distribution, using a log link and exchangeable covariance structure.

Angina-free days will be assessed based on a GEE logistic regression analysis with binomial distribution, using a logit link and an unstructured covariance matrix. If computations using an unstructured covariance structure are not feasible due to departures from positive definiteness, then exchangeable covariance structure will be used. The repeated measures will be number of angina-free days for each week of the treatment period, and will be performed for the FAS using on-treatment data. The repeated measures model will include time and its interactions with treatment, in addition to the stratification factors included in the primary negative binomial model. The average treatment difference that corresponds to the last 6 weeks of the treatment period, expressed as an odds ratio, will be estimated using this GEE logistic regression model.



Proportion of subjects achieving at least a 50% reduction in the average weekly angina frequency will be analyzed using the GEE logistic regression analysis as described above for angina-free days. The repeated measures will be angina response, defined as a ≥ 50% reduction in weekly angina frequency from baseline, for each week of the treatment period. This model will include time and its interaction with treatment, in addition to the stratification factors included in the primary negative binomial model. The average treatment difference that corresponds to the last 6 weeks of the treatment period, expressed as an odds ratio, will be estimated using this GEE logistic regression model.

Change from baseline at Last Visit in SF-36 scores will be analyzed using an analysis of covariance model with baseline value as covariate, and number of concomitant antianginal medications (1 or 2), baseline angina frequency (< 3 or ≥ 3), geographic region (Russia, Ukraine, and Belarus; or Other), and treatment as factors. Subjects who discontinued treatment early will have their assessment at the early termination visit used for this analysis. Adequacy of model assumptions and interactions will be investigated and methods and data presentations will be modified as warranted.

PGIC will be analyzed using an analysis of variance model with number of concomitant antianginal medications (1 or 2), baseline angina frequency (< 3 or ≥ 3), geographic region (Russia, Ukraine, and Belarus; or Other), and treatment as factors. Subjects who discontinued treatment early will have their assessment at the early termination visit carried forward for this analysis. Adequacy of model assumptions and interactions will be investigated and methods and data presentations will be modified as warranted.

Primary analysis for all secondary endpoints will be performed on the FAS, using on-treatment data for diary-based endpoints (eg, SL NTG use) and the last assessment obtained after study Day 1 for questionnaire-based endpoints. Provided that more than 20 mITT subjects are excluded from the FAS, sensitivity analysis for all secondary endpoints will be performed on the mITT set using on-study data.

6.5. Exploratory Efficacy Endpoints

6.5.1. Definition of Exploratory Efficacy Endpoints

Exploratory efficacy endpoints include:

• Change from baseline in the Rose Dyspnea Scale {15682}

See Appendix 2 for calculation of Rose Dyspnea Scale.

• Change from baseline in average daily dyspnea score {17833}

Average daily dyspnea score is defined as the average score over the on-treatment period, ie, (sum of scores reported during the interval)/(number of days during the interval for which a score was reported).

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• Change from baseline in each domain of the SAQ {15681}

See Appendix 2 for calculation of SAQ domain scores. The 5 domains will be analyzed separately:

— Physical limitations

— Angina stability

— Angina frequency

— Treatment satisfaction

— Disease perception (quality of life)

• Change from baseline in Physician’s Global Assessment (PGA) Visual Analog Scale (VAS)

The PGA-VAS score as entered into the eCRF will be used.

6.5.2. Analysis Methods for Exploratory Efficacy Endpoints

All exploratory endpoints except Rose Dyspnea score will be analyzed by fitting an analysis of covariance model with baseline value as covariate, and number of concomitant antianginal medications (1 or 2), baseline angina frequency (< 3 or ≥ 3), geographic region (Russia, Ukraine, and Belarus; or Other), and treatment as factors. Because Rose Dyspnea score has only 5 possible values (0, 1, 2, 3, or 4) and blinded preliminary analysis found no change from baseline to end of treatment in approximately 60% of subjects, ANCOVA methods are considered unsuitable. The placebo-corrected effect of ranolazine treatment on Rose Dyspnea score will be tested using a Cochran-Mantel-Haenszel test of equality of mean scores, stratifying by number of concomitant antianginal medications (1 or 2), baseline angina frequency (< 3 or ≥ 3), geographic region (Russia, Ukraine, and Belarus; or Other), and baseline score.

Subjects who discontinued treatment early will have their assessment at the early termination visit carried forward. Interactions and adequacy of model assumptions will be investigated and methods and data presentations will be modified as warranted.

Primary analysis for all exploratory endpoints will be performed on the FAS using on-treatment data for diary-based endpoints (ie, daily dyspnea score) and the last assessment obtained after study Day 1 for questionnaire-based endpoints.

6.6. Changes From Protocol-Specified Efficacy Analyses

In the protocol, mITT analyses were described as using randomized treatment, regardless of actual treatment received. This has been changed to actual treatment. Also, mITT analyses



were specified as supportive analyses, with the FAS as the primary analysis set. Preliminary data indicate that fewer than 20 subjects in the mITT set will be excluded from the FAS, and that there are no discrepancies between randomized and actual treatments received. Hence, a statement has been added that if there are no treatment discrepancies and 20 or fewer subjects are not in the FAS, supportive mITT analysis will be limited to a replication of the primary efficacy analysis.

The model for the primary analysis of angina frequency was described as including terms for treatment, log baseline angina frequency, and all 3 baseline stratification factors. This has been changed to omit baseline angina frequency category (< 3 or ≥ 3 attacks/week), as baseline angina frequency is already included as a continuous covariate. Sensitivity analyses of angina frequency for which baseline AF was included both as a continuous covariate and as a stratification factor indicator variable have been changed likewise.

ANCOVA analyses were specified for all exploratory endpoints; for the Rose Dyspnea Scale, this has been amended to a Cochran-Mantel-Haenszel analysis.



7. SAFETY ANALYSES

7.1. Adverse Events and Deaths

7.1.1. Adverse Event Dictionary

Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 15.1. System organ class (SOC), high level group term (HLGT), high level term (HLT), preferred term (PT), and lower level term (LLT) will be attached to the clinical database.

7.1.2. Adverse Event Severity

AEs are assessed by the investigator as mild, moderate, or severe according to criteria specified in the study protocol. Events with severity not recorded will be counted as severe.

7.1.3. Relationship of Adverse Events to Study Drug

Related AEs are those for which the investigator answers “Yes” to the question “Related to Study Drug?”. Events with relationship not recorded will be counted as related.

Also, adverse events are assessed by the investigator as related or unrelated to study procedures (eg, venipuncture or lead placement), according to criteria given in the protocol. Relationship to study procedures will be listed.

7.1.4. Serious Adverse Events

Serious adverse events (SAEs) are those identified as serious in the clinical database. The clinical database will be reconciled with the SAE database from the Gilead Drug Safety and Public Health Department before database finalization.

7.1.5. Treatment-Emergent Adverse Events

7.1.5.1. Definition of Treatment-Emergent

Treatment-emergent AEs are events that meet one of the following criteria:

• Began on or after the date of the first dose of double-blind study drug and on or before the date of the last dose of study drug plus 14 days.

• Had no recorded start date and the stop date is on or after the first dose of double-blind study drug.



Exception: An event with an onset on the same or next calendar day that a previous non-treatment-emergent event resolves is not treatment emergent if all of the following criteria are met:

• The events have the same MedDRA LLT

• The later event has the same or lower severity

• The later event is not related to study drug

7.1.5.2. Incomplete Dates

If the date of onset is incomplete, then the month and year (or year alone if month is not recorded) of onset determine treatment emergence as follows. The event is treatment emergent if the month and year of onset (or year of onset) of the event meets both of the following criteria:

• The same as or after the month and year (or year) of the first dose of double-blind study drug

• The same as or before the month and year (or year) of the 14th day after the date of the last dose of study drug

If date of onset is completely missing, the event will be counted as treatment emergent.

7.1.6. Summaries of Adverse Events and Deaths

A brief summary of AEs will show, by treatment group, the number and percentage of subjects who (1) had any treatment-emergent AE, (2) had any treatment-emergent treatment-related AE, (3) had any treatment-emergent SAE, (4) had any treatment-emergent treatment-related SAE, (5) permanently discontinued from study drug due to an AE, and (6) died during study.

Summaries (number and percentage of subjects) of adverse events (by SOC, HLT, and PT) will be provided by treatment group using the safety analysis set as follows:

• All treatment-emergent AEs

• All treatment-emergent AEs by severity

• All treatment-emergent treatment-related AEs

• All treatment-emergent SAEs

• All treatment-emergent treatment-related SAEs



• All treatment-emergent AEs that caused permanent discontinuation from study drug

• All treatment-emergent AEs with frequency ≥ 1% in either treatment group

• All treatment-emergent non-serious AEs with frequency ≥ 1% in either treatment group

• Deaths

• All AEs recorded on or after screening visit and prior to first dose of placebo run-in period

• All AEs recorded on or after first dose of placebo-run in period and prior to first dose of double-blind study medication

Summaries of AEs with frequency ≥ 1% in either treatment group will be provided by PT, by treatment group and overall, with PTs listed in descending order of overall frequency. They will not include AEs with frequencies that are less than 1% but that round to 1%.

Multiple events will be counted once only per subject in each summary. For data presentation, SOC and HLT will be ordered alphabetically, with PT ordered by decreasing total frequency, breaking ties alphabetically. For summaries by severity, the most severe event will be selected. In addition to the presentation by SOC and HLT, each summary will also be presented by preferred term only, ordered by decreasing ranolazine group frequency.

In addition to the by-treatment summaries, data listings will be provided for the following:

• All AEs (with a column indicating whether the event is treatment-emergent)

• SAEs

• Deaths

• AEs leading to permanent discontinuation of study drug

7.1.7. Additional Analysis of Adverse Events

Treatment-emergent AEs in each treatment group will be summarized by age group (< 65 years of age at screening, 65 to 74, 75 and over), by sex, and by renal function category, as follows:

• Severe renal impairment as defined by MDRD equation-estimated glomerular filtration rate (GFR) < 30 mL/min

• Moderate renal impairment: GFR ≥ 30 and < 60 mL/min



• Mild renal impairment: GFR ≥ 60 and < 90 mL/min

• Normal renal function: GFR ≥ 90 mL/min

7.2. Laboratory Evaluations

Laboratory data will be presented in data listings.

7.3. Body Weight and Vital Signs

Body weight, heart rate, and systolic and diastolic blood pressure, both sitting and standing, at each visit and change from baseline will be summarized for the safety analysis set using descriptive statistics (sample size, mean, standard deviation, median, Q1, Q3, minimum and maximum) by treatment group for each postbaseline nominal visit.

7.4. Medications

Prior and concomitant medications will be coded using the World Health Organization (WHO) Drug Dictionary. The WHO preferred name and drug code will be attached to the clinical database.

7.4.1. Prior Medications

Antianginal medications used prior to the first dose of double-blind study drug will be summarized (number and percentage of subjects) by WHO preferred name, for each treatment group and overall. Entries coded to the same preferred name will be counted once per subject. The summary will be ordered by decreasing overall frequency of use. Prior diabetic medications and all other medications will be summarized similarly.

If whether a medication was started prior to or after the first dose of double-blind study drug is unclear, it will be counted as both a prior medication and as a concomitant medication. For instance, if a subject was randomized on 12 April 2012 and started atenolol in “April 2012,” atenolol would be counted as both a prior antianginal and a concomitant medication.

Summaries of prior medication use will be provided for the safety analysis set.

7.4.2. Concomitant Medications

Medication use during the interval beginning on the date of the first dose of double-blind study drug and ending on the date of the last dose plus 14 days will be summarized (number and percentage of subjects) by WHO drug class and preferred name, for each treatment group and overall. Entries coded to the same preferred name will be counted once per subject. The summary will be ordered alphabetically by drug class and then by decreasing overall frequency within a class.

Summaries of concomitant medications will be provided for the safety analysis set.



7.5. Electrocardiogram Results

ECG results, including QTcF and QTcB, will be presented in a data listing.

7.6. Other Safety Measures

A data listing will be provided for subjects experiencing pregnancy during the study.

7.7. Changes From Protocol-Specified Safety Analyses

There will be no summary of safety laboratory data as specified in the protocol, since no postbaseline data is planned to be collected, except in Germany. Summaries of AEs by age group (< 65, 65 to 74, and 75 and over), sex, and renal function category (severe, moderate, and mild renal impairment and normal renal function) have been added.



8. PHARMACOKINETIC ANALYSES

Not applicable



9. REFERENCES

15681 Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol 1995;25 (2):333-41.

15682 Rose GA, Blackburn H. Cardiovascular survey methods. Monograph series 1968;56:1-188.

17829 Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. Journal of manipulative and physiological therapeutics 2004;27 (1):26-35.

17833 Stenton C. The MRC breathlessness scale. Occupational medicine (Oxford, England) 2008;58 (3):226-7.

17872 McHorney CA, Ware JE, Jr., Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Medical care 1993;31 (3):247-63.

17875 Keene ON, Jones MR, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study. Pharm Stat 2007;6 (2):89-97.

17876 Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75 (4):800-2.

21226 SAS Institute Inc. 2009. SAS/STAT® 9.2 User’s Guide, Second Edition. Cary, NC: SAS Institute Inc.

22512 Berger VW. Pros and cons of permutation tests in clinical trials. Stat Med 2000;19 (10):1319-28.

22513 Efron B. Better Bootstrap Confidence Intervals. J Am Stat Assoc 1987;82 (397):171-85.

22532 Efron B, Tibshirani RJ. Better Bootstrap Confidence Intervals. An Introduction to the Bootstrap. New York, NY: Chapman & Hall; 1993: 184-8.



10. SOFTWARE

All analyses will be performed using the same SAS version (Version 9.2 or higher).

SAS® Software Version 9.2. SAS Institute Inc., Cary, NC, USA. {21226}



11. STATISTICAL ANALYSIS PLAN REVISIONS

Revision Date (dd month yyyy) Section Summary of Revisions Reason for Revisions

31 Oct 2012 3.1 Analysis Sets

The sequence of analysis set definitions was changed to mITT,

FAS, PP, SS, with the required text rearrangements. The phrase “did not have any major eligibility violations”

was changed to “did not have any egregious eligibility violations.”

Dosing and diary compliance requirements for the PP were specified. A minimum diary

compliance requirement for the FAS (at least 7 days during the primary analysis period, ie, last 6 weeks on

treatment) was specified.

Clarify nesting relationship of analysis sets for statistical

programmers, that is, SS ⊇ mITT ⊇ FAS ⊇ PP, by moving mITT

definition before FAS definition. Clarify relationship between mITT and FAS, ie, FAS is mITT further restricted to subjects who did not

discontinue study drug prior to Day 14 and meet the minimum diary compliance requirement. Clarify

nature of eligibility violations considered as warranting exclusion from the mITT and its FAS and PP

subsets. Clarify the programming

requirements for the PP, namely, both dosing and diary compliance

must be calculated. Ensure stability of primary analysis by requiring at least 7 days of diary

data.

31 Oct 2012 3.2 Subject Groups

A statement that mITT analysis will be limited to repeating the primary efficacy analysis if the difference

between the mITT and FAS sets is 20 or fewer subjects was added.

Preliminary data indicate very few (approximately 15) mITT subjects

discontinued randomized study drug prior to Day 14. The additional

information provided by repeating FAS analyses for the mITT set as supporting analyses appears likely

to be minimal. Hence, it was decided to repeat only the primary

efficacy analysis if 20 or fewer mITT subjects are excluded from

the FAS.




31 Oct 2012 3.3 Strata and

Covariates

A parenthetical note that baseline angina frequency stratum (< 3 or ≥ 3

attacks/week) is included only in efficacy analysis models that do not

already include baseline angina frequency as a continuous covariate was added. The paragraph stating that stratum membership will be determined for analysis using the applicable e-diary or eCRF data,

rather than data reported by sites to the IXRS, was revised for clarity.

Avoid redundancy. Increase clarity.

31 Oct 2012 3.4 Examination

of Subject Subsets

The following sentence was deleted: Stratification factors will not be included in the model for these

subset analyses.

The intention was to indicate that a subset defined by a level of a stratification factor would not

include that factor in the model, but the deleted sentence can be read as

meaning that none of the subset analyses will include stratification

factors.

31 Oct 2012 3.6 Missing Data

The following sentence: “For questionnaire data (including SF-36, PGIC, Rose Dyspnea, and

Seattle Angina Questionnaire [SAQ]), scores of subjects who

terminate early will be imputed by carrying the last obtained score

forward (last observation carried forward [LOCF] imputation).”

was changed to: For questionnaire data (comprising

PGA-VAS, SF-36, PGIC, Rose Dyspnea Scale, and Seattle Angina Questionnaire [SAQ]), postbaseline

scores of subjects with no postbaseline assessment will not be

imputed.

Clarify that baseline scores will not be carried forward. Per protocol,

each questionnaire was to be administered twice, first at the

Randomization visit and again at the final (Week 8 or Early Termination) visit. The original wording had been

misinterpreted to apply to scores obtained at the Randomization,

rather than Early Termination, visit.

31 Oct 2012 3.7 Definitions,

Data Handling

Conventions, and

Transformations

A definition of day of study drug discontinuation was added: day of

last dose of study drug.

Clarify meaning of FAS restriction to subjects who did not discontinue

study drug prior to Day 14, ie, a subject taking the last dose on Day

13 is considered to have discontinued on Day 13 and is

therefore not in the FAS.





Data Handling

Conventions, and

Transformations

Definition of baseline value: scope was expanded from “quality of life and safety assessments” to “quality

of life, safety, and other assessments,” and to subjects who did not receive double-blind study drug, and an example was added

(baseline body weight). The definition of baseline Daily Dyspnea Score was moved to this section and

modified to match the baseline definitions for the other 2 daily diary-

based variables.

Clarify baseline value programming requirements.


Data Handling

Conventions, and

Transformations

Three minor changes to the definition of type 2 diabetes mellitus duration

were made: ‘Diabetes’ changed to ‘type 2

diabetes mellitus’ Duration in days calculated as

(Screening visit date – diagnosis date) rather than as (Screening visit

date – diagnosis date + 1) Rule for partial dates of diagnosis modified to set imputed dates later

than the date of the Screening visit to the date of the Screening visit

Make type 2 diabetes mellitus duration formula consistent with age formula. Avoid imputing dates that might result in negative calculated durations (at least 1 subject has a

year-only diagnosis date where year = year of Screening visit).


Data Handling

Conventions, and

Transformations

A table showing the TFL convention for display of p-values was added.

Clarify programming requirements.

14 Nov 2012 3.8.1 Definition of Study Day 1

The definition of Study Day -1 was removed.

Not needed.




31 Oct 2012 3.8.2 Analysis Windows

Operational definitions were added for the following analysis windows

and relevant dates: last 21 days of single-blind placebo

run-in period last 6 weeks on treatment

last 6 weeks on study date of first dose of double-blind

study drug date of last dose of double-blind

study drug

Clarify programming requirements and analysis definitions.

31 Oct 2012 5.1 Demographi

cs and Baseline

Characteristics

Age definition removed. Presentation of baseline comparability p-values

made optional by changing “will be presented” to “may be presented.”

Age is defined in Section 3.7. Following a review of blinded

preliminary data, it was decided that certain of the numerous baseline comparability p-values presented were of little value and should be

omitted.

31 Oct 2012 6.1 Definition of the Primary

Efficacy Endpoint

No substantive changes; computational detail and examples

added.

Clarify programming requirements for primary efficacy analysis.

31 Oct 2012 6.3 Analysis of the

Primary Efficacy Endpoint

Consistent with the note added in Section 3.3 (Strata and Covariates), baseline angina frequency is omitted

from the model because baseline angina frequency is already included as a covariate. The description of the GEE supporting analysis was revised to state that a log (rather than logit) link will be used, and exchangeable

covariance structure.

Avoid redundancy; provide a full and correct specification of the GEE

supporting analysis.

31 Oct 2012 6.3 Analysis of the

Primary Efficacy Endpoint

Two resampling analyses added as supporting analyses, with full

computational details. SAS code note updated to reflect transfer of code examples from Appendix 2 to a

separate document, “GS-US-259-0133 Programming Specs.”

The original text stated “Resampling methods … may be used” but did not specify them. Details added to clarify programming requirements.




31 Oct 2012 6.4.1 Definition of Secondary Efficacy

Endpoints

For angina-free days and 50% or greater reduction from baseline

angina frequency, both the endpoint as defined for purposes of

summarization and the measure of treatment effect are described.

Clarify how the effect of treatment will be assessed.

31 Oct 2012 6.4.2 Analysis

Methods for Secondary Efficacy

Endpoints

Primary analysis for all secondary endpoints will be performed on the

FAS using on-treatment data for diary-based endpoints (eg, SL NTG

use) and the last assessment obtained after study Day 1 for questionnaire-

based endpoints.

The italicized text was added because some subjects had delayed

Week 8 visits and were no longer on treatment by the time of the visit, to clarify that data from questionnaires

completed at such visits are not excluded.

14 Nov 2012 6.4.2 Analysis

Methods for Secondary Efficacy

Endpoints

A note was added that the on-study mITT sensitivity analyses will not be

performed if 20 or fewer mITT subjects are excluded from the FAS.

It was decided to repeat only the primary efficacy analysis if 20 or fewer mITT subjects are excluded

from the FAS. See Section 3.2 revision summary.

31 Oct 2012 6.5.2 Analysis

Methods for Exploratory

Efficacy Endpoints

The analysis method for Rose Dyspnea Scale score (0, 1, 2, 3, or 4) was changed from ANCOVA with baseline score as a covariate to a

Cochran-Mantel-Haenszel analysis stratified by baseline score.

Concerns about interpretability of ANCOVA-based treatment effect

estimates.

31 Oct 2012 7.1.1 Adverse

Event Dictionary

MedDRA version (15.1) specified. Version decision was reached 10/31.

31 Oct 2012 7.1.6 Summaries of Adverse Events and

Deaths

Frequency cutoff for AE summaries by preferred term was changed from

5% to 1%.

Review of blinded preliminary data indicated that no preferred terms

had been reported at a frequency of ≥ 5%.

31 Oct 2012 7.1.7 Additional Analysis of

Adverse Events

Adverse event summaries by age group, sex, and renal function

category were added.

Better describe adverse event profiles in subgroups of interest.

31 Oct 2012 7.4.1 Prior Medications

A summary of other prior medications was added to the

summaries of prior antianginal medications and prior diabetic

medications.

Better characterize medication use in the study subjects.




31 Oct 2012 Appendix 1 Table of

Contents for Statistical

Tables, Figures, and

Listings

“Diabetes History” table renamed “Type 2 Diabetes Mellitus History.” Frequency cutoff changed from 5% to 1% for adverse event summaries

by preferred term. Analysis set changed from SS to none for Deaths

table to indicate inclusion of all reported deaths; additional changes

as appropriate to reflect analysis revisions.

Reflect analysis changes described above, improve clarity.




Listings

Figures added. Figures had been omitted.




Listings

Pregnancy Report listing removed. Death Report analysis set changed from SS to none to include deaths prior to and during the single-blind

placebo run-in period. Editorial changes: “Diabetes History”

listing renamed “Type 2 Diabetes Mellitus History.” Seattle Angina Questionnaire listing split into a

listing of item responses and a listing of domain scores.

Follow-up was completed for all subjects and no pregnancy reports

were received.

14 Nov 2012 Appendix 2 Questionnair

e Scoring

Summary of SF-36 Health Survey scoring procedure revised to correct a

typo in an example, correct the handling of missing item responses to

match the rule given in the user’s guide referenced, and state that

derived scores will be rounded to 1 decimal place in analysis datasets.

Clarify and correct SF-36 Health Survey scoring procedure; facilitate

data transfer and validation.



12. APPENDICES

Appendix 1. Table of Contents for Statistical Tables, Figures, and Listings Appendix 2. Questionnaire Scoring



Appendix 1. Table of Contents for Statistical Tables, Figures, and Listings

Tables

Title Analysis Set

Enrollment by Region, Country, and Investigator Randomized Analysis Set

Enrollment by Randomization Stratum Randomized Analysis Set

Subject Disposition Randomized Analysis Set

Demographics and Baseline Characteristics Safety Analysis Set

Cardiovascular History Safety Analysis Set

Type 2 Diabetes Mellitus History Safety Analysis Set

Risk Factors Safety Analysis Set

Adherence to Study Medication Safety Analysis Set

Analysis Sets

Duration of Exposure to Study Medication Safety Analysis Set

Time to Premature Discontinuation of Study Drug Safety Analysis Set

Angina Frequency Diary Compliance Full Analysis Set

Weekly Angina Frequency -- Generalized Negative Binomial Log-Linear Model (Last 42 Days of ON-TREATMENT Data)

Full Analysis Set

Weekly Angina Frequency -- Generalized Negative Binomial Log-Linear Model (Last 42 Days of ON-STUDY Data)

Full Analysis Set


Modified Intent-to-Treat Analysis Set

Weekly Angina Frequency -- Generalized Negative Binomial Log-Linear Model (Last 42 Days of ON-STUDY Data)


Weekly Angina Frequency -- Resampling Methods Based on ANCOVA Model (Last 42 Days of ON-TREATMENT Data)

Full Analysis Set

Weekly Angina Frequency -- Repeated Measures Analysis using GEE (All ON-TREATMENT Data)

Full Analysis Set

Weekly Angina Frequency -- Repeated Measures Analysis using GEE (All ON-STUDY Data)

Full Analysis Set

Weekly Angina Frequency -- Repeated Measures Analysis using GEE (All ON-TREATMENT Data)

Modified Intent-to-Treat Analysis Set*

Weekly Angina Frequency -- Repeated Measures Analysis using GEE (All ON-STUDY Data)



Per Protocol Analysis Set

Weekly Angina Frequency -- Generalized Linear Model (Last 42 Days of ON-TREATMENT Data) by Age Group

Full Analysis Set



Title Analysis Set

Weekly Angina Frequency -- Generalized Linear Model (Last 42 Days of ON-TREATMENT Data) by Sex

Full Analysis Set

Weekly Angina Frequency -- Generalized Linear Model (Last 42 Days of ON-TREATMENT Data) by Weekly Angina Frequency at Baseline

Full Analysis Set

Weekly Angina Frequency -- Generalized Linear Model (Last 42 Days of ON-TREATMENT Data) by Number of Antianginal Medications

Full Analysis Set

Weekly Angina Frequency -- Generalized Linear Model (Last 42 Days of ON-TREATMENT Data) by Geographic Region

Full Analysis Set

Weekly SL NTG Frequency -- Generalized Negative Binomial Log-Linear Model (Last 42 Days of ON-TREATMENT Data)

Full Analysis Set

Weekly SL NTG Frequency -- Repeated Measures Analysis using GEE (All ON-STUDY Data)


Proportion of Subjects with >= 50% Reduction in Weekly Angina Frequency – Repeated Measures Analysis using GEE (ON-TREATMENT Data)

Full Analysis Set

Proportion of Subjects with >= 50% Reduction in Weekly Angina Frequency – Repeated Measures Analysis using GEE (ON-STUDY Data)


Angina-Free Days – Repeated Measures Analysis using GEE (ON-TREATMENT Data)

Full Analysis Set

Angina-Free Days – Repeated Measures Analysis using GEE (ON-STUDY Data)


Weekly Angina Frequency by Patient Subgroup using GEE (All ON-TREATMENT Data)

Full Analysis Set

Questionnaire Data: Overall Summary Full Analysis Set

SF-36 Mental Component Summary Score -- Analysis of Covariance

Full Analysis Set

SF-36 Mental Component Summary Score -- Analysis of Covariance


SF-36 Physical Component Summary Score -- Analysis of Covariance

Full Analysis Set

SF-36 Physical Component Summary Score -- Analysis of Covariance


Patient's Global Impression of Change (PGIC) Score -- Analysis of Variance

Full Analysis Set

Patient's Global Impression of Change (PGIC) Score -- Analysis of Variance


Rose Dyspnea Score -- Cochran-Mantel-Haenszel Analysis Full Analysis Set



Title Analysis Set

Daily Dyspnea Score -- Analysis of Covariance (ON-TREATMENT Data)

Full Analysis Set

SAQ -- Analysis of Covariance Full Analysis Set

Physician's Global Assessment (VAS) -- Analysis of Covariance Full Analysis Set

Treatment-Emergent Adverse Events: Overall Summary Safety Analysis Set

Treatment-Emergent Adverse Events Safety Analysis Set

Treatment-Emergent Adverse Events by Severity Safety Analysis Set

Treatment-Emergent Adverse Events Related to Study Drug Safety Analysis Set

Treatment-Emergent Serious Adverse Events Safety Analysis Set

Treatment-Emergent Serious Adverse Events Related to Study Drug

Safety Analysis Set

Treatment-Emergent Adverse Events Leading to Permanent Study Drug Discontinuation

Safety Analysis Set

Adverse Events Recorded Between Screening and First Dose of Study Drug in Qualifying Period

Safety Analysis Set

Adverse Events with Onset during Qualifying Period and Prior to First Dose of Study Drug in Treatment Period

Safety Analysis Set

Treatment-Emergent Adverse Events by Preferred Term with Frequency >= 1% in Any Treatment Group

Safety Analysis Set

Treatment-Emergent Serious Adverse Events by Preferred Term with Frequency >= 1% in Any Treatment Group

Safety Analysis Set

Treatment-Emergent Non-serious Adverse Events by Preferred Term with Frequency >= 1% in Any Treatment Group

Safety Analysis Set

Treatment-Emergent Adverse Events by Age Group Safety Analysis Set

Treatment-Emergent Adverse Events by Sex Safety Analysis Set

Treatment-Emergent Adverse Events by Renal Function Group Safety Analysis Set

Prior Antianginal Medications Safety Analysis Set

Prior Diabetic Medications Safety Analysis Set

Other Prior Medications Safety Analysis Set

Concomitant Medications Safety Analysis Set

Summary of Body Weight and Vital Signs Safety Analysis Set

Summary of Deaths During Study

* Table will be generated only if more than 20 mITT subjects are not in the FAS. See Section 3.2.



Figures

Title Analysis Set

Adherence to Study Medication by Treatment Group Full Analysis Set

Angina Frequency Diary Compliance by Treatment Group Full Analysis Set

Angina Frequency by Study Week and Treatment Group Full Analysis Set

Sublingual Nitroglycerin Use by Study Week and Treatment Group

Full Analysis Set

Questionnaire Data: Overall Summary of Baseline Values Full Analysis Set

Questionnaire Data: Overall Summary of End of Treatment / Last Visit Values

Full Analysis Set

Questionnaire Data: Overall Summary of Treatment Differences at End of Treatment / Last Visit

Full Analysis Set



Listings

Title Analysis Set

Enrollment Randomized Analysis Set

Follow-up and Study Completion Randomized Analysis Set

Inclusion and Exclusion Criteria Randomized Analysis Set

Stratification Discrepancies Randomized Analysis Set

Demographics and Baseline Characteristics Safety Analysis Set

Medical History (Other) Safety Analysis Set

Cardiovascular History Safety Analysis Set

Type 2 Diabetes Mellitus History Safety Analysis Set

Risk Factors Safety Analysis Set

Surgical History Safety Analysis Set

Study Drug Administration Safety Analysis Set

Study Drug Accountability Safety Analysis Set

Study Drug Exposure and Adherence Safety Analysis Set

Death Report

Angina Frequency, SL NTG Frequency, and Daily Dyspnea Score


Angina Frequency Analysis Variables Modified Intent-to-Treat Analysis Set

Patient's Global Impression of Change (PGIC) Modified Intent-to-Treat Analysis Set

SF-36 Modified Intent-to-Treat Analysis Set

Seattle Angina Questionnaire Item Responses Modified Intent-to-Treat Analysis Set

Seattle Angina Questionnaire Raw and Rescaled Domain Scores Modified Intent-to-Treat Analysis Set

Rose Dyspnea Score Modified Intent-to-Treat Analysis Set

Physician's Global Assessment (PGA) Visual Analog Scale Modified Intent-to-Treat Analysis Set

Body Weight and Vital Signs Safety Analysis Set

12-Lead ECG Safety Analysis Set

Antianginal Medications Safety Analysis Set

Diabetic Medications Safety Analysis Set

Other Medications Safety Analysis Set

Adverse Events Safety Analysis Set

Serious Adverse Events Safety Analysis Set

Adverse Events Leading to Permanent Study Drug Discontinuation

Safety Analysis Set



Title Analysis Set

Laboratory Data -- Hematology Safety Analysis Set

Laboratory Data -- Chemistry Safety Analysis Set

Laboratory Data -- HbA1c and Fasting Lipid Panel Safety Analysis Set



Appendix 2. Questionnaire Scoring

Rose Dyspnea Scale

The Rose dyspnea score is defined as the summary score of the 4 items where each question answered ‘Yes’ is assigned a score of 1 and each question answered ‘No’ is assigned a score of 0. This score should range from 0 to 4.



Summarized from the SF-36 Health Survey scoring instructions (Ware JE, Kosinski M, Dewey JE. How to Score Version 2 of the SF-36® Health Survey. Lincoln, RI: QualityMetric Incorporated, 2000):

SF-36 physical and mental component scores calculation (PCS and MCS)

The SF-36 is a self-reported health survey. Higher scores indicate better health-related quality of life (eg, more freedom from pain). Ten items (1, 6, 7, 8, 9e, 9a, 9d, 9h, 11b, 11d) require recoding so that higher item values are better . Eight scales make up the PCS and the MCS. All but 1 of the 36 items are used to score the eight SF-36 scales (item 2 is not used). The items making up each scale are given below:



Physical Functioning (PF) items 3a through 3j

Role-Physical (RP) items 4a through 4d

Bodily Pain (BP) items 7 and 8

General Health (GH) items 1, 11a through 11d

Vitality (VT) items 9a, 9e, 9g, 9i

Social Functioning (SF) items 6 and 10

Role-Emotional (RE) items 5a through 5c

Mental Health (MH) items 9b, 9c, 9d, 9f, 9h

Step 1 Recodes No Recode Items 2, 3a to 3j, 4a to 4d, 5a to 5c, 9b, 9c, 9f, 9g, 9i, 10, 11a, 11c Item 1 Recode In general, would you say your health is: Response Raw Item Value Recode Excellent 1 5.0 Very good 2 4.4 Good 3 3.4 Fair 4 2.0 Poor 5 1.0 Item 6 Recode During the past 4 weeks, to what extent has your physical health or emotional problems interfered with your normal social activities with family, friends, neighbors, or groups? Response Raw Item Value Recode Not at all 1 5 Slightly 2 4 Moderately 3 3 Quite a bit 4 2 Extremely 5 1



Item 7 Recode How much bodily pain have you had during the past 4 weeks? Response Raw Item Value Recode None 1 6.0 Very mild 2 5.4 Mild 3 4.2 Moderate 4 3.1 Severe 5 2.2 Very severe 6 1.0 Item 8 Recode (if Item 7 is not missing) During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)?

Response Raw Item 8 Value

Raw Item 7 Value Recode

Not at all 1 1 6 Not at all 1 2 to 6 5 A little bit 2 1 to 6 4 Moderately 3 1 to 6 3 Quite a bit 4 1 to 6 2 Extremely 5 1 to 6 1 Item 8 Recode (if Item 7 is missing) During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)? Response Raw Item Value Recode Not at all 1 6.0 Slightly 2 4.75 Moderately 3 3.5 Quite a bit 4 2.25 Extremely 5 1.0 Item 9a, 9d, 9e, 9h Recode 9a: Did you feel full of life? 9d: Have you felt calm and peaceful? 9e: Did you have a lot of energy? 9h: Have you been happy? Response Raw Item Value Recode All of the time 1 5 Most of the time 2 4 Some of the time 3 3 A little of the time 4 2 None of the time 5 1



Item 11b and 11d Recode 11b: I am as healthy as anybody I know 11d: My health is excellent Response Raw Item Value Recode Definitely True 1 5 Mostly True 2 4 Don’t Know 3 3 Mostly False 4 2 Definitely False 5 1 Step 2 Sum, Transformation, z-score standardization

(a) Sum the item values for each scale, using the recode values for those items that were recoded. This is the “actual raw score” for the scale. If there are missing item values, but the subject answered at least half of the items in the scale (eg, 2 out of 3 in a 3-item scale), calculate the actual raw score as the average of the item values for the completed items times the number of items in the scale. Otherwise, set the actual raw score to missing.

(b) Calculate the transformed scale score: 100(Actual raw score - lowest possible raw score)/(Possible raw score range) =

transformed scale score For example, a raw PF score of 21 would be transformed as follows:

100(21-10)/20 = 55

where the lowest possible raw score = 10 and the possible raw score range = 20.

Scale Lowest and Highest Possible Raw Scores

Possible Raw Score Range

Transformed Score Mean

Transformed Score SD

PF 10, 30 20 83.29094 23.75883 RP 4, 20 16 82.50964 25.52028 BP 2, 12 10 71.32527 23.66224 GH 5, 25 20 70.84570 20.97821 VT 4, 20 16 58.31411 20.01923 SF 2, 10 8 84.30250 22.91921 RE 3, 15 12 87.39733 21.43778 MH 5, 25 20 74.98685 17.75604

(c) Subtract the 1998 general US population mean as shown above for each transformed scale, and divide by the SD.

For example, PF_Z = (PF – 83.29094) / 23.75883.



Step 3 Norm-based Transformation of the Individual Scale Scores (this step is not applicable to this study)

Transform each z-score to the norm-based (50, 10) scoring. This is accomplished by multiplying each scale score by 10 and adding 50.

For example, Norm-Based PF = 50 + (PF_Z * 10).

Step 4 Physical and Mental Summary Measures

Using the z-scale standardization from step 2, and showing negative coefficients in bold type,

AGG_PHYS = (PF_Z * 0.42402) + (RP_Z * 0.35119) + (BP_Z * 0.31574) + (GH_Z * 0.24954) + (VT_Z * 0.02877) + (SF_Z * -0.00753) + (RE_Z * -0.19206) + (MH_Z * -0.22069)

AGG_MENT = (PF_Z * -0.22999) + (RP_Z * -0.12329) + (BP_Z * -0.09731) + (GH_Z * -0.01571) + (VT_Z * 0.23534) + (SF_Z * 0.26876) + (RE_Z * 0.43407) + (MH_Z * 0.48581)

Step 5 Transformation of Summary Scores

Transformed Physical (PCS) = 50 + AGG_PHYS * 10

Transformed Mental (MCS) = 50 + AGG_MENT * 10

The transformed scores have the following interpretation: scores above and below 50 are above and below the average for the 1998 general US population, and a 1-point difference in score corresponds to a difference of one-tenth of the 1998 general US population SD. In analysis datasets, to facilitate validation and data transfer, the transformed physical and mental component scores will be rounded to 1 decimal place.

statistical analysis plan · 1 or 2 of the allowed antianginal medications with at least 50% of...

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