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BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email
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LiMA: A study protocol for a randomised, double blind,
placebo controlled trial of lisdexamfetamine for the
treatment of methamphetamine dependence
Journal: BMJ Open
Manuscript ID bmjopen-2017-020723
Article Type: Protocol
Date Submitted by the Author: 15-Mar-2018
Complete List of Authors: Ezard, Nadine; St Vincents Hospital; University of New South Wales - Randwick Campus Dunlop, Adrian; Hunter New England Local Health District, Drug and
Alcohol Clinical Services; University of Newcastle Hall, Michelle; Hunter New England Local Health District, Drug and Alcohol Clinical Services Ali, Robert; University of Adelaide McKetin, Rebecca; Curtin University Australia-Asia-Pacific Institute Bruno, Raimondo; University of Tasmania Nghi, Phung; Western Sydney Local Health District Carr, Andrew; St. Vincent's Hospital White, Jason; University of South Australia Clifford, Brendan; St. Vincent's Hospital; University of Sydney Liu, Zhixin; University of New South Wales - Randwick Campus Shanahan , Marian Shanahan ; National Drug and Alcohol Research Centre
Dolan, Kate; National Drug and Alcohol Research Centre Baker, Amanda; University of Newcastle, Lintzeris, Nicholas; South East Sydney Local Health District, The Langton Centre; University of Sydney
Keywords: Methamphetamine, Study protocol, Lisdexamfetamine, Pharmacotherapy, Stimulant use disorder
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TITLE PAGE
Title of article
LiMA: a study protocol for a randomised, double blind, placebo controlled trial of lisdexamfetamine for the
treatment of methamphetamine dependence
Corresponding author
Michelle Hall
Newcastle Community Health Centre
Drug and Alcohol Clinical Services
Level 3, 670 Hunter St
Newcastle, 2300, NSW
T: + 61 2 40164781
Co-authors
Nadine Ezard1,2
, Adrian Dunlop3,4
, Michelle Hall3, Robert Ali
6,2 , Rebecca McKetin
5, Raimondo Bruno
8, , Nghi
Phung7, Andrew Carr
1,2, Jason White
8, Brendan Clifford
1,11, Zhixin Liu
2 Marian Shanahan
10, Kate Dolan
10,
Amanda Baker4, Nicholas Lintzeris11,12
1St. Vincent's Hospital, Sydney, NSW, Australia
2UNSW, Sydney, NSW, Australia
3Hunter New England Drug and Alcohol Clinical Services, Newcastle, NSW, Australia
4 School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
5Curtin University, Perth, WA, Australia
6University of Adelaide, Adelaide, SA, Australia
7Western Sydney Local Health District, Sydney, NSW, Australia
8University of South Australia, Adelaide, SA, Australia
9University of Tasmania, Hobart, TAS, Australia
10National Drug and Alcohol Research Centre, UNSW Sydney, NSW, Australia
11University of Sydney, Sydney, NSW and
12South East Sydney Local Health District, Sydney, NSW, Australia
Key Words
Methamphetamine, Study protocol, Lisdexamphetamine, Pharmacotherapy, Stimulant use disorder
Word count
4100 (excluding title page, abstract, references, figures and tables)
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ABSTRACT
Introduction
Methamphetamine dependence is a growing public health concern. There is currently no pharmacotherapy
approved for methamphetamine dependence. Lisdexamfetamine dimesylate, used in the treatment of
Attention-Deficit Hyperactivity Disorder (ADHD) and binge eating disorder, has potential as an agonist
therapy for methamphetamine dependence, and possible benefits of reduced risk of aberrant use due to its
novel formulation.
Methods and analysis
A double-blind randomised controlled trial will be used to evaluate the efficacy of lisdexamfetamine in
reducing methamphetamine use. The target sample is 180 participants with methamphetamine
dependence of ≥ 2 years, using ≥ 14 days out of the previous 28, who have previously attempted but not
responded to treatment for methamphetamine use. Participants will be randomly assigned to receive either
a 15-week intervention consisting of induction (1 week of 150mg lisdexamfetamine (LDX) or placebo),
maintenance (12 weeks of 250mg LDX or placebo) and reduction (1 week of 150mg LDX or placebo and 1
week of 50mg LDX or placebo). All participants will be given access to 4 sessions of CBT as treatment-as-
usual and receive a 4-week follow up appointment. The primary outcomes are efficacy (change from
baseline in days of methamphetamine use by self-report for the last 28 days at week 13, and urinalyses
confirmation of methamphetamine use) and safety (treatment related adverse events). Secondary outcomes
are total number of days of self-report MA use over the 12 week active treatment, longest period of
abstinence during treatment period, percentage of achieving >= 21 days abstinence, craving, withdrawal,
dependence, retention, blood borne virus transmission risk behaviour, criminal behaviour, as well measures
of abuse liability, physical and mental health, other substance use, cognitive performance, psychosocial
functioning, treatment retention and satisfaction. Additionally, the study will assess the cost effectiveness of
lisdexamfetamine relative to the placebo control.
Discussion
This will be the first Phase III trial of lisdexamfetamine for methamphetamine dependence. If successful the
intervention will provide a much needed therapeutic adjunct for people who are dependent on
methamphetamine.
Ethics and Dissemination
The study has been approved by the Human Research Ethics Committee of St. Vincent’s Hospital, Sydney,
Australia (HREC/16/SVH/222). Contact the corresponding author for the full trial protocol.
ARTICLE SUMMARY
Strengths and limitations of this study
• First Phase III trial of lisdexamfetamine for methamphetamine dependence.
• If successful the intervention will provide a much needed therapeutic adjunct for people who are
dependent on methamphetamine.
• The design is for a fixed dose (with option for one dose decrease): if efficacious, further dose-response
relationship studies may be indicated
• The duration of active treatment is limited to 12 weeks, if efficacious further studies will be needed to
explore optimum duration of treatment and a reducing regimen
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BACKGROUND
Methamphetamine is a synthetic stimulant of growing global public health importance and an important
contributor to the global burden of disease (1). There are an estimated 34 million people worldwide who use
the drug, and an estimated 17 million who are dependent on methamphetamine (2).
Australia has one of the highest documented rates of methamphetamine dependence in the world, with
160,000 people estimated to be dependent during 2013/14 (1). Methamphetamine dependence is
estimated to cost Australia around $5 billion a year, an economic impact which could be reduced by effective
treatments (3, 4). Methamphetamine dependence is associated with a range of negative health outcomes
including psychosis, depression, anxiety, blood-borne virus transmission, sexually transmissible infections,
and cardiovascular and cerebrovascular events (5). These problems are most prevalent among people who
use methamphetamine on a heavy or regular basis (6), highlighting the need for effective treatments for this
group.
There is no approved medication for the treatment of methamphetamine dependence. The current
standard treatment for methamphetamine dependence relies on psychosocial interventions, primarily
Cognitive Behaviour Therapy (CBT)-based approaches (7). Such approaches produce small to medium
reductions in methamphetamine use in controlled studies (d = 0.53 (8)). However, CBT approaches require a
substantial investment by trained therapists, there is often poor engagement with counselling by
methamphetamine users, and cognitive impairment associated with severe methamphetamine dependence
may limit CBT effectiveness (7). Poorer treatment outcomes are seen in methamphetamine users who use
frequently (those using methamphetamine at least 15 days out of the previous 30 days at treatment entry),
than in less frequent users (9), highlighting the need for more effective treatment approaches for such
individuals.
Many authors have highlighted the potential role of substitution agonist treatment for methamphetamine
dependence (10). The theoretical base for agonist prescription is consistent with the rationale for existing
agonist substitution for nicotine and opioid dependence. Agonist substitution therapies aim to replace
harmful drug use with safer alternatives in terms of dose, route of administration and adverse effects. Long-
acting agonists can reduce amphetamine withdrawal (11), craving (12), and decrease the euphoriant and
reinforcing effects of extra (illicit) stimulant use due to cross-tolerance (13). Agonist treatment also provides
a framework for regular ongoing healthcare and psychosocial interventions with this high-risk population,
enabling patients to distance themselves from illicit drug networks and related crime.
Agonist therapies for methamphetamine dependence show promise. A number of ‘weak’ stimulant agonist
therapies have been studied, including methylphenidate and modafinil (14). A recent systematic review
showed no benefit over placebo for any of these medications, noting limitations in retention and power of
published studies (15). Dexamphetamine, a more direct monoamine agonist that more closely mimics the
effects of methamphetamine, has been used clinically for amphetamine and methamphetamine dependence
in the United Kingdom (in doses ranging from 20mg to 200mg) for some time (16, 17), and in New South
Wales, Australia, since 2006, at doses up to 80mg (18). This experience suggests dexamphetamine
substitution treatment may be useful in retaining a difficult to engage group of severely dependent
methamphetamine users who do not respond to stand-alone psychosocial interventions. Previous studies
from methamphetamine dependent (19-21) subjects found no serious consequences of dexamphetamine in
doses from 30 - 110mg/day (22).
While a statistically significant benefit on methamphetamine use has not been established with
dexamphetamine pharmacotherapy, feasibility has been demonstrated with 60mg dexamphetamine/day
(equivalent to 150mg lisdexamfetamine) (19). Studies with sustained-release dexamphetamine (SR-DXA)
formulations have shown increased retention in treatment at up to 110mg SR-DXA/daily (mean dose of
80mg SR-DXA daily) (20), and decreased craving and withdrawal symptoms in a study using 60mg SR-DXA
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(21). This latter study (n=60) with a treatment duration of 8 weeks concluded that further studies should
test a longer treatment duration, that higher doses of dexamphetamine could be warranted due to possible
physiological tolerance, and that larger sample sizes are required (21).
Lisdexamfetamine, a pharmacologically inactive prodrug, is absorbed after oral administration and is
hydrolysed to inactive l-lysine and active dexamphetamine by red blood cells (23). It has a slower onset,
lower peak concentration, and longer duration of action than dexamphetamine (24). It is metabolised
rapidly to dexamphetamine: the peak plasma concentration occurs 3 hours after dosing. The plasma half-life
(t½) of dexamphetamine is 10 hours (25), with plasma dexamphetamine concentrations reaching steady
state at day 5 of once-daily lisdexamfetamine dosing (24). There is no plasma accumulation of
lisdexamfetamine (26). The conversion time from lisdexamfetamine to dexamphetamine results in a more
blunted effect on brain dopamine than immediate release dexamphetamine (27) and, as a consequence, it
has a more moderate reinforcing effect in self-administration studies due to the slower onset of peak effects
than other stimulant drugs (28).
Abuse liability studies of lisdexamfetamine with doses of up to 150mg indicate it has significantly less
propensity for abuse-related ‘liking’ when compared to dexamphetamine or diethylpropion (29). The lower
abuse liability of lisdexamfetamine, due to its rate-limited hydrolysis, attenuated onset and intensity of
amphetamine-like effects, and more moderate reinforcing properties thus reduce the need for supervised
dosing.
There have been no published randomised controlled trials of lisdexamfetamine for methamphetamine
dependence. Mooney et al (30) were unable to show a significant change in cocaine use, though the study
used a lower dose of 70mg lisdexamfetamine, and failed to reach its planned sample size. The maintenance
dose of 250mg lisdexamfetamine represents equivalence to current dexamphetamine regimes for
methamphetamine dependence (31). This dose has also been tolerated by non-methamphetamine
dependent volunteers in a pharmacokinetic study (32), as well as in a study in participants with
schizophrenia receiving anti-psychotic pharmacotherapy (33). A recent safety dose-escalating trial of
methamphetamine dependent participants with high frequency of use (34) successfully escalated 14 out of
16 participants to 250mg lisdexamfetamine (35)].
OBJECTIVES
The objective of the current trial was to test the efficacy of lisdexamfetamine for reducing
methamphetamine use among people with methamphetamine dependence, who had not previously
responded to psychosocial treatments.
We hypothesise that treatment with oral lisdexamfetamine will result in significantly reduced
methamphetamine use at 13 weeks compared to placebo in people who are dependent on
methamphetamine. The primary objectives of the study are efficacy and safety of 250mg of
lisdexamfetamine in reducing methamphetamine use after 13 weeks of treatment. Secondary objectives are
to examine the changes in physical and mental health, cognitive and psychosocial functioning and well-being
between lisdexamfetamine and placebo groups, as well as differences in retention rates, craving and
withdrawal symptoms, and severity of dependence. Other secondary objectives are to examine differences
in blood borne virus transmission risk behaviour, criminality, and in use of alcohol and other drugs between
groups, as well as the abuse liability profile of lisdexamfetamine and the cost effectiveness of
lisdexamfetamine relative to the placebo control.
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METHODS
Trial Design
This project is a randomised double-blind placebo controlled fixed dose parallel design comparing a 12-week
maintenance course of 250mg lisdexamfetamine daily to placebo.
Sample Size
The sample size calculation is based on data from the existing NSW Stimulant Treatment Program clients (31)
who meet inclusion criteria. Such clients showed a reduction from a mean of 19 day of use out of 28 days at
pre-treatment to a mean of 9 days /28 days with standard deviation (SD) of 9 days at 12 weeks post-
treatment. To detect a mean difference of 4.5 days (9 days in control vs. 4.5 days in the lisdexamfetamine
group out of 28 days) at week 13 (12 weeks post treatment), assuming a pooled SD of 9 days (i.e. d=0.5, a
median clinically relevant effect size), with over 80% power at two-sided significance level of 0.05, a sample
size of 126 (63 per group) is required (10). Conservatively estimating a 30% attrition from research follow-up
(previous trials have achieved follow-up of 81% at 12 weeks (27), 90 participants per group will be recruited
– 180 in total.
Participants
The study population is treatment seeking adults with long-standing (≥12 months) methamphetamine
dependence who have failed to respond to previous methamphetamine treatment attempts. Participants
will be aged 18 to 65 years, meet ICD-10 criteria for methamphetamine dependence and self-report
methamphetamine use of ≥14 days out of the previous 28. Prior use of methamphetamine will be verified
by urinalysis. Failure to respond to previous treatment is defined as relapse to dependent use within one
month of completing treatment. Participants must be willing and able to comply with study requirements,
be able to store study medications securely, and be able to provide written, informed consent.
Exclusion criteria are sensitivity or previous adverse reaction to lisdexamfetamine, concurrent use or use
within the previous 14 days of medications with possible interaction with lisdexamfetamine. Known
contraindications for lisdexamfetamine are also exclusion criteria. Individuals with severe medical disorders,
including cardiovascular disease, untreated hypertension and peripheral vascular disease, will be ineligible,
as will those with severe psychiatric disorders. Those currently in counselling for methamphetamine
dependence or who have been prescribed dexamphetamine or modafinil (in the four weeks prior to
assessment) will be ineligible. Other exclusion criteria are dependent use of alcohol or other drugs,
exposure to another investigational drug within the 4 weeks prior to screening, unavailability for follow-up,
pregnant or lactating women and receipt of current pharmacotherapy treatment for opioid dependence.
Four specialist outpatient stimulant treatment centres in New South Wales and South Australia will recruit
participants. Potential participants will be pre-screened in person or by telephone by a researcher, and if
potentially eligible invited to attend for a formal eligibility assessment by a specialist in addiction medicine.
The assessment schedule, including eligibility assessments, is outlined in Table 1.
Table 1. Assessments and procedures: Eligible participants will be required to attend the clinic daily for the
first five days of treatment. On day 5 they will be provided with 2 days’ supply of study medication to take at
home.
For the remainder of the treatment period participants will attend the clinic twice a week for supervised
dosing, safety assessments, provision of urine sample and collection of take home dioses. Research visits will
occur every four weeks until week 19.
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Demographics and Baseline Assessments
Demographics Screening
Medical Screening Screening
Substance Use History and Treatment Screening
Columbia Suicide Severity Rating Scale – Screening (CSSRS) (36) Screening
Enriched Social Support Inventory (ESSI) Week 1
Wender-Utah Rating Scale (WURS)(37) Week 1
Intervention and counselling
Lisdexamfetamine or Placebo Weeks 1 to 15
Baker et al. 4 session CBT (38) Weeks 2 to 13 (4 sessions at least 2 weeks apart)
Efficacy and Safety Measures
Time Line Follow Back (All drugs - Past 28 days) (39) Screening and Weeks 1, 5, 9, 13, 19
Time Line Follow Back (Methamphetamine only - Past 7 days) Weeks 2, 3, 4, 6, 7, 8, 10, 11, 12, 14, 15
Medication Adherence (40) Weeks 1 to 15 (twice weekly)
Treatment Satisfaction Questionnaire (TSQM) (41) plus testing blind Weeks 5, 9, 13, 19
Adverse Events Weeks 1 to 15 (twice weekly) and Week 19
Urine Drug Screen Screening and Weeks 1 to 15 (twice weekly)
Vital signs (temperature, blood pressure, heart rate, respiratory rate) Screening and Weeks 1 to 15 (twice weekly)
Concomitant Medications Screening and Weeks 1 to 15 (twice weekly)
Electrocardiogram Screening and Weeks 5, 9, 13
Pregnancy testing (if applicable) Screening and Weeks 1, 5, 9, 13
Medical Assessment – Since last visit Screening and Weeks 1, 5, 9, 13, 19
Columbia Suicide Severity Rating Scale – Since last visit (CSSRS)(36) Screening and Weeks 1, 5, 9, 13, 19
Brief Psychiatric Rating Scale – 4 items (BPRS) (42) Screening and Weeks 1, 5, 9, 13, 19
Review by study doctor Weeks 1, 5, 9, 13 and last day of treatment
Measures of physical and mental health and cognitive and psychosocial functioning
Patient Health Questionnaire – 15 (PHQ15)(43) Weeks 1, 5, 9, 13, 19
Depression & Anxiety Survey Scale (DASS21)(44) Weeks 1, 5, 9, 13, 19
World Health Organization Quality of Life (WHOQOL-BREF) Weeks 1, 5, 9, 13, 19
Insomnia Severity Index (ISI) (45) Weeks 1, 5, 9, 13, 19
Neurocognitive testing batteries (combinations of the following):
(MOCA) (46), (WTAR) (47), RAVLT (48-50) RVIP (50, 51), N-Back (52), Trail
making test (53-56), Flankers (51, 57), Digit-Symbol (58, 59)
Screening and Weeks 1, 5, 9, 13, 19
Measures of cravings, withdrawal and severity of dependence
Amphetamine Withdrawal Questionnaire (AWQ) (60) Weeks 1, 5, 9, 13, 19
Visual Analogue Scale for Cravings (61) Weeks 1, 5, 9, 13, 19
Severity of Dependence Scale (SDS) (62) Weeks 1, 5, 9, 13, 19
Measures of abuse liability, other drug use, risk behaviour and crime
Drug Evaluation Questionnaire (DEQ5) Weeks 1, 5, 9, 13, 19
Time Line Follow Back (All drugs - Past 28 days) (39) Screening and Weeks 1, 5, 9, 13, 19
Urine Drug Screen Weeks 1 to 15 (twice weekly)
Opiate Treatment Index - Injecting Practices (OTI-I) Weeks 1, 5, 9, 13, 19
Opiate Treatment Index - Crime (OTI-C) Weeks 1, 5, 9, 13, 19
Substance Use and Sex Index (SUSI) Weeks 1, 5, 9, 13, 19
Measures for the Cost Effectiveness Analysis
EuroQol- 5D (EQ5D) (63) Weeks 1, 5, 9, 13, 19
Health Service Utilisation Weeks 1, 5, 9, 13, 19
Work Productivity Questionnaire (64) Weeks 1, 5, 9, 13, 19
Opiate Treatment Index – Crime (OTI-C) – additional questions Weeks 1, 5, 9, 13, 19
Travel Time and Costs Week 5
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Randomisation
Eligible participants will be randomised to receive either the lisdexamfetamine or a placebo medication (see
Figure 1). A computer-generated randomisation schedule has been developed by an independent statistician
and uploaded to the study database. Randomisation will be performed by the trial site pharmacist within the
study database. The randomisation component of the database has been safe guarded with specific user
rights allowing only the trial site pharmacist, the statistician and the chair of the Independent Data Safety
Monitoring Committee (IDSMC) to access randomisation allocations. Study participants, investigators, clinical
and research staff will be blinded to the treatment condition allocated to reduce the risk of bias. Emergency
unbinding will be permitted if required for safety of a participant, ongoing safe conduct of the trial or in the
case of pregnancy.
Intervention
Oral lisdexamfetamine dimesylate 50 mg capsules will be used to make up the prescribed study dose. Trial
medications will be obtained, prepacked in child resistant blister packs, stored and transported to
participating sites by a contracted Good Manufacturing Practice registered facility in accordance with the
Poisons and Therapeutic Goods Act 1966 and the Poisons and Therapeutic Goods Regulation 2008.
The active drug (lisdexamfetamine dimesylate) and the placebo shall be provided in identical capsules to
ensure the study blind.
Eligible participants enrolled in the study will commence with 7 days of 150mg lisdexamfetamine or placebo
daily (the induction phase) (34, 35). They will attend the clinic for the first five days for supervised
administration of the study medication, recording of blood pressure, pulse and temperature, monitoring of
adverse events and medication adherence counselling. On the fifth day the participant will be provided with
two additional doses self-administer orally once a day. If the induction phase is tolerated, the participant
will progress to the 250mg lisdexamfetamine/placebo 12-week maintenance phase.
During the maintenance phase, participants will visit the clinic twice per week for a nursing review where
vital signs will be recorded, adverse events monitored and medication adherence counselling undertaken.
On the visit days, the administration of the dose for that day will be observed by the study nurse and
participants will be provided with two or three days’ supply of the lisdexamfetamine/placebo to take home
for self-administration until the next clinic visit. Participants will be required to return study medication
packs for pill counts. A urine sample will be provided at each of the twice-weekly visits, one of which will be
randomly selected according to a predetermined randomised schedule and sent for testing at the end of the
study for the presence of methamphetamine, and the other stored for future use. Once each week study
personnel will collect self-reported methamphetamine use for the previous week.
Participants will undergo a medical review every four weeks during the maintenance phase (weeks 5, 9 and
13), as well as neurocognitive testing and questionnaire completion as outlined in Table 1.
If the participant experiences a grade 2 or 3 adverse event at any time that is considered to be related to the
study drug, the study doctor shall consult with the Trial Chairperson about the option of withholding one
dose. If a dose is withheld the participant will be reviewed by the study doctor the following day, or sooner
as clinically indicated. If the adverse event is resolved the following day, the dose can be recommenced and
the participant will be reviewed the subsequent day. If the adverse event is not resolved or recurs after
recommencing, the study doctor will then consult with the Trial Chairperson with regards to ceasing the
medication and withdrawing the participant from the treatment component of the study.
During the reduction phase the dose will be tapered so as to minimise any drug discontinuation effects. The
dose will be reduced to 150mg lisdexamfetamine or placebo daily for 1 week, then 50mg lisdexamfetamine
or placebo daily for one week and then ceased.
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Lisdexamfetamine will not be available for the management of methamphetamine dependence following
completion of the study. However, ongoing treatment will be individualised to the participant and outlined
in a treatment plan which will be developed at Week 13 by the study doctor.
Subjects will have a follow-up visit 4 weeks after cessation of the reduction phase (week 19).
Participants will be reimbursed with a supermarket voucher (that cannot be spent on alcohol or cigarettes)
at weeks 1, 5, 9, 13 and 19. Reimbursements will start at $20 and increase by $10 each month until the
follow-up visit.
All participants will be offered counselling representing best practice treatment as usual. This will consist of
four sessions of CBT of up to one hour per session (38), specially designed for and validated in the study
population and delivered by trained therapist who will receive supervision monthly.
In addition to safety concerns (including acute psychosis, suicidal or homicidal ideation) or pregnancy,
participants may be withdrawn from the study if they are absent from study treatment for more than 2
consecutive weeks. They will also be withdrawn from the study if they become subject to drug testing for
legal or occupational reasons (due to the risk of unblinding to group allocation).
Statistical Methods
All efficacy analyses will use an intention-to-treat (ITT) approach. ITT will be defined as all randomized
patients who received at least one dose of the prescribed medication. The primary efficacy measure is the
change from baseline in days of methamphetamine use self-reported for the last 28 days at week 13. A
likelihood-based mixed model repeated measures (MMRM) approach will be used for the primary efficacy
analysis. The difference between two groups at week 13 will be the primary comparison, and differences at
week 5, 9 and 19 will also be examined. No imputation of missing data will be performed under MMRM
approach, the MMRM analysis makes use of all available data and is reliable for effect and standard error
estimates under missing at random (MAR) assumption(65). Sensitivity analysis including baseline observation
carried forward imputation will be performed to investigate the robustness of results to the departure from
MAR assumption.
Secondary measures of the intervention effect will include total number of days of self-report MA use over
the 12 week active treatment period; longest period of abstinence during treatment period; percentage of
achieving >= 21 days abstinence; percentage of MA negative urines 4 weeks prior to week 12; craving,
withdrawal, dependence, retention, blood borne virus transmission risk behaviour, criminal behaviour, as
well measures of abuse liability, physical and mental health, other substance use, cognitive performance,
psychosocial functioning, and treatment satisfaction. Statistical analysis strategies (t-test, Mann–Whitney U
test, Chi-square test, linear/generalised linear regression, and mixed model analysis) will be used for
secondary outcomes based on the type and distribution of the outcome measures. Kaplan-Merrier curve, log
rank test and Cox proportional hazard model will be applied in the time to event data analysis.
Analysis of urine drug screen (UDS) results will follow established techniques for similar drug trials
(Treatment Effectiveness Score (66)), calculated as a proportion (%) of UDS negative for methamphetamine
out of total of 12 possible UDS (with missing tests counted as positive).
All patients enrolled in the study will be evaluated with respect to safety-related outcomes. Safety data will
be analysed according to the treatment that the patients actually received. Safety analyses will include
summaries of the incidence of all adverse events that are possibly or probably treatment related, that occur
during the study treatment period or within 30 days of the last dose of study treatment.
Additionally, the study will assess the cost effectiveness of lisdexamfetamine relative to the placebo control.
The primary outcome will be Quality Adjusted Life Years measured by the EQ-5D-5L. Costs will include
clinical resources, other health care, crime, productivity and personal costs. The costs will be summed and
combined with the outcome measure, and the incremental cost-effectiveness ratio calculated.
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All tests of the treatment effect will be conducted at a two-sided alpha level of 0.05.
Interim analyses will be performed when the 50th patient has completed treatment or 6 months after the
commencement of recruitment, whichever comes first.
An Independent Data Safety Monitoring Committee (IDSMC) will monitor the progress of the study with the
aim of safeguarding trial participants by assessing the safety and efficacy of the drug being investigated in
the trial. The IDSMC may recommend stopping the trial if the number and/or severity of adverse events
justify discontinuation of the study; on the basis of a positive efficacy result only when the primary endpoint
(methamphetamine use) data are truly compelling and the risk of a false positive conclusion is acceptably
low (p<0.001 for primary endpoint); if accrual rates are too low and/or that noncompliance is too great to
provide adequate power for identifying the specified benefit; it becomes clear that successful completion of
the study is not feasible.
Data Statement
Study data will be collected and managed using REDCap electronic data capture tools hosted at Hunter New
England Local Health District]. REDCap (67)1
(Research Electronic Data Capture) is a secure, web-based
application designed to support data capture for research studies, providing: 1) an intuitive interface for
validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated
export procedures for seamless data downloads to common statistical packages; and 4) procedures for
importing data from external sources.
Ethics and Dissemination
Prior to an individual’s participation in the trial, he/she shall be fully informed about the research and given
ample time and opportunity to inquire about details and decide whether or not to participate. If they agree
to participate they will be asked to sign the study specific consent form. Participants will also be invited to
consent for their urine samples to be stored for future research
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at the time of
randomisation. Results arising from the main study will be published in peer-reviewed journals, and
disseminated at international conferences. Results will be reported in such a manner that participants will
not be identifiable in any way.
All data will be considered the property of the Trial Chairperson who, in consultation with the Trial
Management Committee, will be responsible for presentations and publications arising from this trial.
Discussion
This is the first Phase III trial of lisdexamfetamine for methamphetamine dependence. The strength of this
study is in its proposed sample size, powered to detect a medium effect size in between group differences in
the primary outcome (days of methamphetamine use), using a higher dose of agonist medication (more than
triple) used typically for the treatment of ADHD. Participants will be closely monitored with twice weekly
clinic visits and nursing reviews and monthly medical reviews. Twice weekly dispensing will promote
retention in the study, and prevent high drop-out rates experienced in other studies (68). The study protocol
proposes to deliver the medication in an outpatient setting allowing participants take-home dosing to more
closely mimic the service delivery situations in which the medication may be used and provide some
indication. Limitations of the study include the fixed dose design, active treatment restricted to 12 weeks
and twice weekly observed dosing. If efficacious further dose-response relationship studies may be indicated
to explore optimum duration of treatment and a reducing regimen. If successful the intervention will provide
a much needed therapeutic adjunct for people who are dependent on methamphetamine.
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OTHER INFORMATION
Patient involvement
The initial concept of investigating the use of lisdexamfetamine in reducing methamphetamine use in
people who are dependent on methamphetamine was proposed by a patient who prefers to be unnamed.
No other patients were involved in setting the research question or the outcome measures, nor have they
been involved in developing plans for design or implementation of the study.
Author Contributions
The study was conceived and designed by NL, AD, NE and RA. Significant contributions to the development
and conceptualisation of the protocol was made by NE, AD, NL, RA, MH, BC, RM, RB, NP, AC, JW, ZL, MS and
AB. KD contributed to the design of the protocol. BC and MH wrote the first draft of the article with
significant input from NE. RM, ZL, MS and AB critically revised the article for intellectual content.
Acknowledgments
We thank Andrew Dawson (Royal Prince Alfred Hospital), Anthony Gill and Craig Rodgers (St. Vincent’s
Hospital Sydney, Australia), James Ward and Michael Farrell (UNSW Sydney, Australia), Mark Montebello
(Northern Sydney Local Health District Drug and Alcohol Service, St Leonards, Australia) and Ian Richards
and Will Liaw (Drug and Alcohol Services South Australia) for insightful comments on the protocol of the
study.
Funding
This study is funded largely by the National Health and Medical Research Council (NHMRC), Australia
(APP1109466) and the St Vincent’s Curran Foundation, Australia. The contents of the published material
are solely the responsibility of the individual authors and do not reflect the views of the NHMRC nor the
Curran Foundation.
Conflicts of Interests
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf.
(available on request from the corresponding author) and have the following declarations: AC reports
grants, personal fees and non-financial support from Gilead Sciences, grants, personal fees and nonfinancial
support from ViiV Healthcare, grants and personal fees from MSD and personal fees from Mayne
Healthcare, outside the submitted work; RB has received investigator-initiated untied educational grants
from Reckitt Benckiser/Indivior for the development of an opioid-related behavior scale and a study of
opioid substitution therapy uptake among chronic non-cancer pain patients and has received an untied
educational grant from Mundipharma for a post-market study of oxycodone. NL reports personal fees from
Indivior, personal fees from Mundipharma, grants from Braeburn Pharmaceuticals outside the submitted
work. AD reports grants from Braeburn Pharmaceuticals during the conduct of the study. All remaining
authors have nothing to declare and have no support from any organisation or any other relationships or
activities that could appear to have influenced the submitted work.
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Trial Registration number
Australian New Zealand Clinical Trials Registry: ACTRN12617000657325 (registered 08 May 2017)
Figure legend
Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the
eligibility criteria and provide written informed consent to participate will be randomised to
lisdexamfetamine or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post
treatment.
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Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the eligibility criteria and provide written informed consent to participate will be randomised to lisdexamfetamine
or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post treatment.
297x420mm (300 x 300 DPI)
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CONSORT 2010 checklist Page 1
CONSORT 2010 checklist of information to include when reporting a randomised trial*
Section/Topic Item No Checklist item
Reported on page No
Title and abstract
1a Identification as a randomised trial in the title 1
1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2
Introduction
Background and
objectives
2a Scientific background and explanation of rationale 3, 4
2b Specific objectives or hypotheses 4
Methods
Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 4
3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons n/a
Participants 4a Eligibility criteria for participants 5
4b Settings and locations where the data were collected 5
Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were
actually administered
7
Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they
were assessed
8
6b Any changes to trial outcomes after the trial commenced, with reasons n/a
Sample size 7a How sample size was determined 5
7b When applicable, explanation of any interim analyses and stopping guidelines 9
Randomisation:
Sequence
generation
8a Method used to generate the random allocation sequence 7
8b Type of randomisation; details of any restriction (such as blocking and block size) 7
Allocation
concealment
mechanism
9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),
describing any steps taken to conceal the sequence until interventions were assigned
7
Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to
interventions
7
Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 7
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CONSORT 2010 checklist Page 2
assessing outcomes) and how
11b If relevant, description of the similarity of interventions n/a
Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 8
12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 8
Results
Participant flow (a
diagram is strongly
recommended)
13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and
were analysed for the primary outcome
n/a
13b For each group, losses and exclusions after randomisation, together with reasons n/a
Recruitment 14a Dates defining the periods of recruitment and follow-up n/a
14b Why the trial ended or was stopped n/a
Baseline data 15 A table showing baseline demographic and clinical characteristics for each group n/a
Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was
by original assigned groups
n/a
Outcomes and
estimation
17a For each primary and secondary outcome, results for each group, and the estimated effect size and its
precision (such as 95% confidence interval)
n/a
17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended n/a
Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing
pre-specified from exploratory
n/a
Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) n/a
Discussion
Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 9
Generalisability 21 Generalisability (external validity, applicability) of the trial findings n/a
Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence n/a
Other information
Registration 23 Registration number and name of trial registry 10
Protocol 24 Where the full trial protocol can be accessed, if available 10
Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 10
*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also
recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.
Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.
Page 18 of 18
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LiMA: A study protocol for a randomised, double blind,
placebo controlled trial of lisdexamfetamine for the
treatment of methamphetamine dependence
Journal: BMJ Open
Manuscript ID bmjopen-2017-020723.R1
Article Type: Protocol
Date Submitted by the Author: 25-May-2018
Complete List of Authors: Ezard, Nadine; St Vincents Hospital; University of New South Wales - Randwick Campus Dunlop, Adrian; Hunter New England Local Health District, Drug and
Alcohol Clinical Services; University of Newcastle Hall, Michelle; Hunter New England Local Health District, Drug and Alcohol Clinical Services Ali, Robert; University of Adelaide McKetin, Rebecca; Curtin University Australia-Asia-Pacific Institute Bruno, Raimondo; University of Tasmania Nghi, Phung; Western Sydney Local Health District Carr, Andrew; St. Vincent's Hospital White, Jason; University of South Australia Clifford, Brendan; St. Vincent's Hospital; University of Sydney Liu, Zhixin; University of New South Wales - Randwick Campus Shanahan , Marian Shanahan ; National Drug and Alcohol Research Centre
Dolan, Kate; National Drug and Alcohol Research Centre Baker, Amanda; University of Newcastle, Lintzeris, Nicholas; South East Sydney Local Health District, The Langton Centre; University of Sydney
<b>Primary Subject Heading</b>:
Addiction
Secondary Subject Heading: Addiction
Keywords: Methamphetamine, Study protocol, Lisdexamfetamine, Pharmacotherapy, Stimulant use disorder
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TITLE PAGE
Title of article
LiMA: a study protocol for a randomised, double blind, placebo controlled trial of lisdexamfetamine for the
treatment of methamphetamine dependence
Corresponding author
Michelle Hall
Newcastle Community Health Centre
Drug and Alcohol Clinical Services
Level 3, 670 Hunter St
Newcastle, 2300, NSW
T: + 61 2 40164781
Co-authors
Nadine Ezard1,2, Adrian Dunlop3,4, Michelle Hall3, Robert Ali6,2 , Rebecca McKetin5, Raimondo Bruno8, , Nghi
Phung7, Andrew Carr1,2, Jason White8, Brendan Clifford1,11, Zhixin Liu2 Marian Shanahan10, Kate Dolan10,
Amanda Baker4, Nicholas Lintzeris
11,12
1St. Vincent's Hospital, Sydney, NSW, Australia
2UNSW, Sydney, NSW, Australia
3Hunter New England Drug and Alcohol Clinical Services, Newcastle, NSW, Australia
4 School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
5Curtin University, Perth, WA, Australia
6University of Adelaide, Adelaide, SA, Australia
7Western Sydney Local Health District, Sydney, NSW, Australia
8University of South Australia, Adelaide, SA, Australia
9University of Tasmania, Hobart, TAS, Australia
10National Drug and Alcohol Research Centre, UNSW Sydney, NSW, Australia
11University of Sydney, Sydney, NSW and
12South East Sydney Local Health District, Sydney, NSW, Australia
Key Words
Methamphetamine, Study protocol, Lisdexamphetamine, Pharmacotherapy, Stimulant use disorder
Word count
4474 (excluding title page, abstract, references, figures and tables)
ABSTRACT
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Introduction
Methamphetamine dependence is a growing public health concern. There is currently no pharmacotherapy
approved for methamphetamine dependence. Lisdexamfetamine dimesylate, used in the treatment of
Attention-Deficit Hyperactivity Disorder (ADHD) and binge eating disorder, has potential as an agonist
therapy for methamphetamine dependence, and possible benefits of reduced risk of aberrant use due to its
novel formulation.
Methods and analysis
A double-blind randomised controlled trial will be used to evaluate the efficacy of lisdexamfetamine in
reducing methamphetamine use. The target sample is 180 participants with methamphetamine
dependence of ≥ 2 years, using ≥ 14 days out of the previous 28, who have previously attempted but not
responded to treatment for methamphetamine use. Participants will be randomly assigned to receive
either a 15-week intervention consisting of induction (1 week of 150mg lisdexamfetamine (LDX) or
placebo), maintenance (12 weeks of 250mg LDX or placebo) and reduction (1 week of 150mg LDX or
placebo and 1 week of 50mg LDX or placebo). All participants will be given access to 4 sessions of CBT as
treatment-as-usual and receive a 4-week follow up appointment. The primary outcomes are efficacy
(change from baseline in days of methamphetamine use by self-report for the last 28 days at week 13, and
urinalyses confirmation of methamphetamine use) and safety (treatment related adverse events).
Secondary outcomes are total number of days of self-report MA use over the 12 week active treatment,
longest period of abstinence during treatment period, percentage of achieving >= 21 days abstinence,
craving, withdrawal, dependence, retention, blood borne virus transmission risk behaviour, criminal
behaviour, as well measures of abuse liability, physical and mental health, other substance use, cognitive
performance, psychosocial functioning, treatment retention and satisfaction. Additionally, the study will
assess the cost effectiveness of lisdexamfetamine relative to the placebo control.
Ethics and Dissemination
The study has been approved by the Human Research Ethics Committee of St. Vincent’s Hospital, Sydney,
Australia (HREC/16/SVH/222). Contact the corresponding author for the full trial protocol.
Results arising from the main study will be published in peer-reviewed journals, and disseminated at
international conferences. Results will be reported in such a manner that participants will not be
identifiable in any way.
ARTICLE SUMMARY
Strengths and limitations of this study
• The study design is a prospective, randomised controlled trial
• Strength in methods include allocation concealment, blinding, compliance measuring, dropout
measuring and analyses of results by intention to treat.
• The fixed dose design is a limitation; if efficacious, further dose-response relationship studies may
be indicated
• The duration of active treatment is limited to 12 weeks, if efficacious further studies will be needed
to explore optimum duration of treatment and a reducing regimen
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BACKGROUND
Methamphetamine is a synthetic stimulant of growing global public health importance and an important
contributor to the global burden of disease (1). There are an estimated 34 million people worldwide who
use the drug, and an estimated 17 million who are dependent on methamphetamine (2).
Australia has one of the highest documented rates of methamphetamine dependence in the world, with
160,000 people estimated to be dependent during 2013/14 (1). Methamphetamine dependence is
estimated to cost Australia around $5 billion a year, an economic impact which could be reduced by
effective treatments (3, 4). Methamphetamine dependence is associated with a range of negative health
outcomes including psychosis, depression, anxiety, blood-borne virus transmission, sexually transmissible
infections, and cardiovascular and cerebrovascular events (5). These problems are most prevalent among
people who use methamphetamine on a heavy or regular basis (6), highlighting the need for effective
treatments for this group.
There is no approved medication for the treatment of methamphetamine dependence. The current
standard treatment for methamphetamine dependence relies on psychosocial interventions, primarily
Cognitive Behaviour Therapy (CBT)-based approaches (7). Such approaches produce small to medium
reductions in methamphetamine use in controlled studies (d = 0.53 (8)). However, CBT approaches require
a substantial investment by trained therapists, there is often poor engagement with counselling by
methamphetamine users, and cognitive impairment associated with severe methamphetamine
dependence may limit CBT effectiveness (7). Poorer treatment outcomes are seen in methamphetamine
users who use frequently (those using methamphetamine at least 15 days out of the previous 30 days at
treatment entry), than in less frequent users (9), highlighting the need for more effective treatment
approaches for such individuals.
Many authors have highlighted the potential role of substitution agonist treatment for methamphetamine
dependence (10). The theoretical base for agonist prescription is consistent with the rationale for existing
agonist substitution for nicotine and opioid dependence. Agonist substitution therapies aim to replace
harmful drug use with safer alternatives in terms of dose, route of administration and adverse effects.
Long-acting agonists can reduce amphetamine withdrawal (11), craving (12), and decrease the euphoriant
and reinforcing effects of extra (illicit) stimulant use due to cross-tolerance (13). Agonist treatment also
provides a framework for regular ongoing healthcare and psychosocial interventions with this high-risk
population, enabling patients to distance themselves from illicit drug networks and related crime.
Agonist therapies for methamphetamine dependence show promise. A number of ‘weak’ stimulant agonist
therapies have been studied, including methylphenidate and modafinil (14). A recent systematic review
showed no benefit over placebo for any of these medications, noting limitations in retention and power of
published studies (15). Dexamphetamine, a more direct monoamine agonist that more closely mimics the
effects of methamphetamine, has been used clinically for amphetamine and methamphetamine
dependence in the United Kingdom (in doses ranging from 20mg to 200mg) for some time (16, 17), and in
New South Wales, Australia, since 2006, at doses up to 80mg (18). This experience suggests
dexamphetamine substitution treatment may be useful in retaining a difficult to engage group of severely
dependent methamphetamine users who do not respond to stand-alone psychosocial interventions.
Previous studies from methamphetamine dependent (19-21) subjects found no serious consequences of
dexamphetamine in doses from 30 - 110mg/day (22).
While a statistically significant benefit on methamphetamine use has not been established with
dexamphetamine pharmacotherapy, feasibility has been demonstrated with 60mg dexamphetamine/day
(equivalent to 150mg lisdexamfetamine) (19). Studies with sustained-release dexamphetamine (SR-DXA)
formulations have shown increased retention in treatment at up to 110mg SR-DXA/daily (mean dose of
80mg SR-DXA daily) (20), and decreased craving and withdrawal symptoms in a study using 60mg SR-DXA
(21). This latter study (n=60) with a treatment duration of 8 weeks concluded that further studies should
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test a longer treatment duration, that higher doses of dexamphetamine could be warranted due to possible
physiological tolerance, and that larger sample sizes are required (21).
Lisdexamfetamine, a pharmacologically inactive prodrug, is absorbed after oral administration and is
hydrolysed to inactive l-lysine and active dexamphetamine by red blood cells (23). It has a slower onset,
lower peak concentration, and longer duration of action than dexamphetamine (24). It is metabolised
rapidly to dexamphetamine: the peak plasma concentration occurs 3 hours after dosing. The plasma half-
life (t½) of dexamphetamine is 10 hours (25), with plasma dexamphetamine concentrations reaching steady
state at day 5 of once-daily lisdexamfetamine dosing (24). There is no plasma accumulation of
lisdexamfetamine (26). The conversion time from lisdexamfetamine to dexamphetamine results in a more
blunted effect on brain dopamine than immediate release dexamphetamine (27) and, as a consequence, it
has a more moderate reinforcing effect in self-administration studies due to the slower onset of peak
effects than other stimulant drugs (28).
Abuse liability studies of lisdexamfetamine with doses of up to 150mg indicate it has significantly less
propensity for abuse-related ‘liking’ when compared to dexamphetamine or diethylpropion (29). The lower
abuse liability of lisdexamfetamine, due to its rate-limited hydrolysis, attenuated onset and intensity of
amphetamine-like effects, and more moderate reinforcing properties thus reduce the need for supervised
dosing.
There have been no published randomised controlled trials of lisdexamfetamine for methamphetamine
dependence. Mooney et al (30) were unable to show a significant change in cocaine use, though the study
used a lower dose of 70mg lisdexamfetamine, and failed to reach its planned sample size. The
maintenance dose of 250mg lisdexamfetamine represents equivalence to current dexamphetamine
regimes for methamphetamine dependence (31). This dose has also been tolerated by non-
methamphetamine dependent volunteers in a pharmacokinetic study (32), as well as in a study in
participants with schizophrenia receiving anti-psychotic pharmacotherapy (33). A recent safety dose-
escalating trial of methamphetamine dependent participants with high frequency of use (34) successfully
escalated 14 out of 16 participants to 250mg lisdexamfetamine (35)].
OBJECTIVES
The objective of the current trial was to test the efficacy of lisdexamfetamine for reducing
methamphetamine use among people with methamphetamine dependence, who had not previously
responded to psychosocial treatments.
We hypothesise that treatment with oral lisdexamfetamine will result in significantly reduced
methamphetamine use at 13 weeks compared to placebo in people who are dependent on
methamphetamine. The primary objectives of the study are efficacy and safety of 250mg of
lisdexamfetamine in reducing methamphetamine use after 13 weeks of treatment. Secondary objectives
are to examine the changes in physical and mental health, cognitive and psychosocial functioning and well-
being between lisdexamfetamine and placebo groups, as well as differences in retention rates, craving and
withdrawal symptoms, and severity of dependence. Other secondary objectives are to examine differences
in blood borne virus transmission risk behaviour, criminality, and in use of alcohol and other drugs between
groups, as well as the abuse liability profile of lisdexamfetamine and the cost effectiveness of
lisdexamfetamine relative to the placebo control.
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METHODS
Trial Design
This project is a randomised double-blind placebo controlled fixed dose parallel design comparing a 12-
week maintenance course of 250mg lisdexamfetamine daily to placebo.
Sample Size
The sample size calculation is based on data from the existing NSW Stimulant Treatment Program clients
(31) who meet inclusion criteria. Such clients showed a reduction from a mean of 19 day of use out of 28
days at pre-treatment to a mean of 9 days /28 days with standard deviation (SD) of 9 days at 12 weeks
post-treatment. To detect a mean difference of 4.5 days (9 days in control vs. 4.5 days in the
lisdexamfetamine group out of 28 days) at week 13 (12 weeks post treatment), assuming a pooled SD of 9
days (i.e. d=0.5, a median clinically relevant effect size), with over 80% power at two-sided significance level
of 0.05, a sample size of 126 (63 per group) is required (10). Conservatively estimating a 30% attrition from
research follow-up (previous trials have achieved follow-up of 81% at 12 weeks (27), 90 participants per
group will be recruited – 180 in total.
Participants
This study is being conducted in sites experienced in delivering and evaluating interventions in people who
are dependent on methamphetamine. The participating sites are located in New South Wales (NSW) and
South Australia (SA).
The study population is treatment seeking adults with long-standing (≥12 months) methamphetamine
dependence who have failed to respond to previous methamphetamine treatment attempts. Participants
will be aged 18 to 65 years, meet ICD-10 criteria for methamphetamine dependence and self-report
methamphetamine use of ≥14 days out of the previous 28. Prior use of methamphetamine will be verified
by urinalysis. Failure to respond to previous treatment is defined as relapse to dependent use within one
month of completing treatment. Participants must be willing and able to comply with study requirements,
be able to store study medications securely, and be able to provide written, informed consent.
Exclusion criteria are sensitivity or previous adverse reaction to lisdexamfetamine, concurrent use or use
within the previous 14 days of medications with possible interaction with lisdexamfetamine. Known
contraindications for lisdexamfetamine are also exclusion criteria. Individuals with severe medical
disorders, including cardiovascular disease, untreated hypertension and peripheral vascular disease, will be
ineligible, as will those with severe psychiatric disorders. Those currently in counselling for
methamphetamine dependence or who have been prescribed dexamphetamine or modafinil (in the four
weeks prior to assessment) will be ineligible. Other exclusion criteria are dependent use of alcohol or other
drugs, exposure to another investigational drug within the 4 weeks prior to screening, unavailability for
follow-up, pregnant or lactating women and receipt of current pharmacotherapy treatment for opioid
dependence.
Four specialist outpatient stimulant treatment centres in New South Wales and South Australia will recruit
participants. Potential participants will be pre-screened in person or by telephone by a researcher, and if
potentially eligible invited to attend for a formal eligibility assessment by a specialist in addiction medicine.
The assessment schedule, including eligibility assessments, is outlined in Table 1.
Table 1. Assessments and procedures: Eligible participants will be required to attend the clinic daily for the
first five days of treatment. On day 5 they will be provided with 2 days’ supply of study medication to take
at home.
For the remainder of the treatment period participants will attend the clinic twice a week for supervised
dosing, safety assessments, provision of urine sample and collection of take home doses. Research visits
will occur every four weeks until week 19.
Demographics and Baseline Assessments
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Demographics Screening
Medical Screening Screening
Substance Use History and Treatment Screening
Columbia Suicide Severity Rating Scale – Screening (CSSRS) (36) Screening
Enriched Social Support Inventory (ESSI) Week 1
Wender-Utah Rating Scale (WURS)(37) Week 1
Intervention and counselling
Lisdexamfetamine or Placebo Weeks 1 to 15
Baker et al. 4 session CBT (38) Weeks 2 to 13 (4 sessions at least 2 weeks apart)
Efficacy and Safety Measures
Time Line Follow Back (All drugs - Past 28 days) (39) Screening and Weeks 1, 5, 9, 13, 19
Time Line Follow Back (Methamphetamine only - Past 7 days) Weeks 2, 3, 4, 6, 7, 8, 10, 11, 12, 14, 15
Medication Adherence (40) Weeks 1 to 15 (twice weekly)
Treatment Satisfaction Questionnaire (TSQM) (41) plus testing blind Weeks 5, 9, 13, 19
Adverse Events Weeks 1 to 15 (twice weekly) and Week 19
Urine Drug Screen Screening and Weeks 1 to 15 (twice weekly)
Vital signs (temperature, blood pressure, heart rate, respiratory rate) Screening and Weeks 1 to 15 (twice weekly)
Concomitant Medications Screening and Weeks 1 to 15 (twice weekly)
Electrocardiogram Screening and Weeks 5, 9, 13
Pregnancy testing (if applicable) Screening and Weeks 1, 5, 9, 13
Medical Assessment – Since last visit Screening and Weeks 1, 5, 9, 13, 19
Columbia Suicide Severity Rating Scale – Since last visit (CSSRS)(36) Screening and Weeks 1, 5, 9, 13, 19
Brief Psychiatric Rating Scale – 4 items (BPRS) (42) Screening and Weeks 1, 5, 9, 13, 19
Review by study doctor Weeks 1, 5, 9, 13 and last day of treatment
Measures of physical and mental health and cognitive and psychosocial functioning
Patient Health Questionnaire – 15 (PHQ15)(43) Weeks 1, 5, 9, 13, 19
Depression & Anxiety Survey Scale (DASS21)(44) Weeks 1, 5, 9, 13, 19
World Health Organization Quality of Life (WHOQOL-BREF) Weeks 1, 5, 9, 13, 19
Insomnia Severity Index (ISI) (45) Weeks 1, 5, 9, 13, 19
Neurocognitive testing batteries (combinations of the following):
(MOCA) (46), (WTAR) (47), RAVLT (48-50) RVIP (50, 51), N-Back (52), Trail
making test (53-56), Flankers (51, 57), Digit-Symbol (58, 59)
Screening and Weeks 1, 5, 9, 13, 19
Measures of cravings, withdrawal and severity of dependence
Amphetamine Withdrawal Questionnaire (AWQ) (60) Weeks 1, 5, 9, 13, 19
Visual Analogue Scale for Cravings (61) Weeks 1, 5, 9, 13, 19
Severity of Dependence Scale (SDS) (62) Weeks 1, 5, 9, 13, 19
Measures of abuse liability, other drug use, risk behaviour and crime
Drug Evaluation Questionnaire (DEQ5) Weeks 1, 5, 9, 13, 19
Time Line Follow Back (All drugs - Past 28 days) (39) Screening and Weeks 1, 5, 9, 13, 19
Urine Drug Screen Weeks 1 to 15 (twice weekly)
Opiate Treatment Index - Injecting Practices (OTI-I) Weeks 1, 5, 9, 13, 19
Opiate Treatment Index - Crime (OTI-C) Weeks 1, 5, 9, 13, 19
Substance Use and Sex Index (SUSI) Weeks 1, 5, 9, 13, 19
Measures for the Cost Effectiveness Analysis
EuroQol- 5D (EQ5D) (63) Weeks 1, 5, 9, 13, 19
Health Service Utilisation Weeks 1, 5, 9, 13, 19
Work Productivity Questionnaire (64) Weeks 1, 5, 9, 13, 19
Opiate Treatment Index – Crime (OTI-C) – additional questions Weeks 1, 5, 9, 13, 19
Travel Time and Costs Week 5
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Randomisation
Eligible participants will be randomised to receive either the lisdexamfetamine or a placebo medication
(see Figure 1). A computer-generated randomisation schedule has been developed by an independent
statistician and uploaded to the study database. Randomisation will be performed by the trial site
pharmacist within the study database. The randomisation component of the database has been safe
guarded with specific user rights allowing only the trial site pharmacist, the statistician and the chair of the
Independent Data Safety Monitoring Committee (IDSMC) to access randomisation allocations. Study
participants, investigators, clinical and research staff will be blinded to the treatment condition allocated to
reduce the risk of bias. Emergency unbinding will be permitted if required for safety of a participant,
ongoing safe conduct of the trial or in the case of pregnancy.
Intervention
Oral lisdexamfetamine dimesylate 50 mg capsules will be used to make up the prescribed study dose. Trial
medications will be obtained, prepacked in child resistant blister packs, stored and transported to
participating sites by a contracted Good Manufacturing Practice registered facility in accordance with the
Poisons and Therapeutic Goods Act 1966 and the Poisons and Therapeutic Goods Regulation 2008.
The active drug (lisdexamfetamine dimesylate) and the placebo shall be provided in identical capsules to
ensure the study blind.
Eligible participants enrolled in the study will commence with 7 days of 150mg lisdexamfetamine or
placebo daily (the induction phase) (34, 35). They will attend the clinic for the first five days for supervised
administration of the study medication, recording of blood pressure, pulse and temperature, monitoring of
adverse events and medication adherence counselling. On the fifth day the participant will be provided
with two additional doses self-administer orally once a day. If the induction phase is tolerated, the
participant will progress to the 250mg lisdexamfetamine/placebo 12-week maintenance phase.
During the maintenance phase, participants will visit the clinic twice per week for a nursing review where
vital signs will be recorded, adverse events monitored and medication adherence counselling undertaken.
On the visit days, the administration of the dose for that day will be observed by the study nurse and
participants will be provided with two or three days’ supply of the lisdexamfetamine/placebo to take home
for self-administration until the next clinic visit. Participants will be required to return study medication
packs for pill counts. A urine sample will be provided at each of the twice-weekly visits, one of which will
be randomly selected according to a predetermined randomised schedule and sent for testing at the end of
the study for the presence of methamphetamine, and the other stored for future use. Once each week
study personnel will collect self-reported methamphetamine use for the previous week.
Participants will undergo a medical review every four weeks during the maintenance phase (weeks 5, 9 and
13), as well as neurocognitive testing and questionnaire completion as outlined in Table 1.
If the participant experiences a grade 2 or 3 adverse event at any time that is considered to be related to
the study drug, the study doctor shall consult with the Trial Chairperson about the option of withholding
one dose. If a dose is withheld the participant will be reviewed by the study doctor the following day, or
sooner as clinically indicated. If the adverse event is resolved the following day, the dose can be
recommenced and the participant will be reviewed the subsequent day. If the adverse event is not
resolved or recurs after recommencing, the study doctor will then consult with the Trial Chairperson with
regards to ceasing the medication and withdrawing the participant from the treatment component of the
study.
During the reduction phase the dose will be tapered so as to minimise any drug discontinuation effects. The
dose will be reduced to 150mg lisdexamfetamine or placebo daily for 1 week, then 50mg lisdexamfetamine
or placebo daily for one week and then ceased.
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Lisdexamfetamine will not be available for the management of methamphetamine dependence following
completion of the study. However, ongoing treatment will be individualised to the participant and outlined
in a treatment plan which will be developed at Week 13 by the study doctor.
Subjects will have a follow-up visit 4 weeks after cessation of the reduction phase (week 19).
Participants will be reimbursed with a supermarket voucher (that cannot be spent on alcohol or cigarettes)
at weeks 1, 5, 9, 13 and 19. Reimbursements will start at $20 and increase by $10 each month until the
follow-up visit.
All participants will be offered counselling representing best practice treatment as usual. This will consist of
four sessions of CBT of up to one hour per session (38), specially designed for and validated in the study
population and delivered by trained therapist who will receive supervision monthly.
In addition to safety concerns (including acute psychosis, suicidal or homicidal ideation) or pregnancy,
participants may be withdrawn from the study if they are absent from study treatment for more than 2
consecutive weeks. They will also be withdrawn from the study if they become subject to drug testing for
legal or occupational reasons (due to the risk of unblinding to group allocation).
Participants that have discontinued protocol treatment will be offered the opportunity continue to
participate in all remaining research interviews and assessments. For those participants that revoke their
consent for the entire study, no further data will be collected from the participant.
Statistical Methods
All efficacy analyses will use an intention-to-treat (ITT) approach. ITT will be defined as all randomized
patients who received at least one dose of the prescribed medication. The primary efficacy measure is the
change from baseline in days of methamphetamine use self-reported for the last 28 days at week 13. A
likelihood-based mixed model repeated measures (MMRM) approach will be used for the primary efficacy
analysis. The difference between two groups at week 13 will be the primary comparison, and differences at
week 5, 9 and 19 will also be examined. No imputation of missing data will be performed under MMRM
approach, the MMRM analysis makes use of all available data and is reliable for effect and standard error
estimates under missing at random (MAR) assumption(65). Sensitivity analysis including baseline
observation carried forward imputation will be performed to investigate the robustness of results to the
departure from MAR assumption.
Secondary measures of the intervention effect will include total number of days of self-report MA use over
the 12 week active treatment period; longest period of abstinence during treatment period; percentage of
achieving >= 21 days abstinence; percentage of MA negative urines 4 weeks prior to week 12; craving,
withdrawal, dependence, retention, blood borne virus transmission risk behaviour, criminal behaviour, as
well measures of abuse liability, physical and mental health, other substance use, cognitive performance,
psychosocial functioning, and treatment satisfaction. Statistical analysis strategies (t-test, Mann–Whitney U
test, Chi-square test, linear/generalised linear regression, and mixed model analysis) will be used for
secondary outcomes based on the type and distribution of the outcome measures. Kaplan-Merrier curve,
log rank test and Cox proportional hazard model will be applied in the time to event data analysis.
Analysis of urine drug screen (UDS) results will follow established techniques for similar drug trials
(Treatment Effectiveness Score (66)), calculated as a proportion (%) of UDS negative for methamphetamine
out of total of 12 possible UDS (with missing tests counted as positive).
All patients enrolled in the study will be evaluated with respect to safety-related outcomes. Safety data will
be analysed according to the treatment that the patients actually received. Safety analyses will include
summaries of the incidence of all adverse events that are possibly or probably treatment related, that occur
during the study treatment period or within 30 days of the last dose of study treatment.
Additionally, the study will assess the cost effectiveness of lisdexamfetamine relative to the placebo
control. The primary outcome will be Quality Adjusted Life Years measured by the EQ-5D-5L. Costs will
include clinical resources, other health care, crime, productivity and personal costs. The costs will be
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summed and combined with the outcome measure, and the incremental cost-effectiveness ratio
calculated.
All tests of the treatment effect will be conducted at a two-sided alpha level of 0.05.
Interim analyses will be performed when the 50th patient has completed treatment or 6 months after the
commencement of recruitment, whichever comes first.
An Independent Data Safety Monitoring Committee (IDSMC) will monitor the progress of the study with the
aim of safeguarding trial participants by assessing the safety and efficacy of the drug being investigated in
the trial. The IDSMC may recommend stopping the trial if the number and/or severity of adverse events
justify discontinuation of the study; on the basis of a positive efficacy result only when the primary
endpoint (methamphetamine use) data are truly compelling and the risk of a false positive conclusion is
acceptably low (p<0.001 for primary endpoint); if accrual rates are too low and/or that noncompliance is
too great to provide adequate power for identifying the specified benefit; it becomes clear that successful
completion of the study is not feasible.
Data Statement
Study data will be collected and managed using REDCap electronic data capture tools hosted at Hunter New
England Local Health District]. REDCap (67)1
(Research Electronic Data Capture) is a secure, web-based
application designed to support data capture for research studies, providing: 1) an intuitive interface for
validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated
export procedures for seamless data downloads to common statistical packages; and 4) procedures for
importing data from external sources.
Ethics and Dissemination
The study has been approved by the Human Research Ethics Committee of St. Vincent’s Hospital, Sydney,
Australia (HREC/16/SVH/222). Contact the corresponding author for the full trial protocol.
Prior to an individual’s participation in the trial, he/she shall be fully informed about the research and given
ample time and opportunity to inquire about details and decide whether or not to participate. If they agree
to participate they will be asked to sign the study specific consent form. Participants will also be invited to
consent for their urine samples to be stored for future research
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at the time of
randomisation. Results arising from the main study will be published in peer-reviewed journals, and
disseminated at international conferences. Results will be reported in such a manner that participants will
not be identifiable in any way.
All data will be considered the property of the Trial Chairperson who, in consultation with the Trial
Management Committee, will be responsible for presentations and publications arising from this trial.
Patient involvement
The initial concept of investigating the use of lisdexamfetamine in reducing methamphetamine use in
people who are dependent on methamphetamine was proposed by a patient who prefers to be unnamed.
No other patients were involved in setting the research question or the outcome measures, nor have they
been involved in developing plans for design or implementation of the study.
Discussion
This is the first Phase III trial of lisdexamfetamine for methamphetamine dependence. The strength of this
study is in its proposed sample size, powered to detect a medium effect size in between group differences
in the primary outcome (days of methamphetamine use), using a higher dose of agonist medication (more
than triple) used typically for the treatment of ADHD. Participants will be closely monitored with twice
weekly clinic visits and nursing reviews and monthly medical reviews. Twice weekly dispensing will promote
retention in the study, and prevent high drop-out rates experienced in other studies (68). The study
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protocol proposes to deliver the medication in an outpatient setting allowing participants take-home
dosing to more closely mimic the service delivery situations in which the medication may be used and
provide some indication. Limitations of the study include the fixed dose design, active treatment restricted
to 12 weeks and twice weekly observed dosing. If efficacious further dose-response relationship studies
may be indicated to explore optimum duration of treatment and a reducing regimen. If successful the
intervention will provide a much needed therapeutic adjunct for people who are dependent on
methamphetamine.
OTHER INFORMATION
Author Contributions
The study was conceived and designed by NL, AD, NE and RA. Significant contributions to the development
and conceptualisation of the protocol was made by NE, AD, NL, RA, MH, BC, RM, RB, NP, AC, JW, ZL, MS and
AB. KD contributed to the design of the protocol. BC and MH wrote the first draft of the article with
significant input from NE. RM, ZL, MS and AB critically revised the article for intellectual content.
Acknowledgments
We thank Andrew Dawson (Royal Prince Alfred Hospital), Anthony Gill and Craig Rodgers (St. Vincent’s
Hospital Sydney, Australia), James Ward and Michael Farrell (UNSW Sydney, Australia), Mark Montebello
(Northern Sydney Local Health District Drug and Alcohol Service, St Leonards, Australia) and Ian Richards
and Will Liaw (Drug and Alcohol Services South Australia) for insightful comments on the protocol of the
study.
Funding
This study is funded largely by the National Health and Medical Research Council (NHMRC), Australia
(APP1109466) and the St Vincent’s Curran Foundation, Australia. The contents of the published material
are solely the responsibility of the individual authors and do not reflect the views of the NHMRC nor the
Curran Foundation.
Conflicts of Interests
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf.
(available on request from the corresponding author) and have the following declarations: AC reports
grants, personal fees and non-financial support from Gilead Sciences, grants, personal fees and nonfinancial
support from ViiV Healthcare, grants and personal fees from MSD and personal fees from Mayne
Healthcare, outside the submitted work; RB has received investigator-initiated untied educational grants
from Reckitt Benckiser/Indivior for the development of an opioid-related behavior scale and a study of
opioid substitution therapy uptake among chronic non-cancer pain patients and has received an untied
educational grant from Mundipharma for a post-market study of oxycodone. NL reports personal fees from
Indivior, personal fees from Mundipharma, grants from Braeburn Pharmaceuticals outside the submitted
work. AD reports grants from Braeburn Pharmaceuticals during the conduct of the study. All remaining
authors have nothing to declare and have no support from any organisation or any other relationships or
activities that could appear to have influenced the submitted work.
Trial Registration number
Australian New Zealand Clinical Trials Registry: ACTRN12617000657325 (registered 08 May 2017)
Figure legend
Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the
eligibility criteria and provide written informed consent to participate will be randomised to
lisdexamfetamine or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post
treatment.
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Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the eligibility criteria and provide written informed consent to participate will be randomised to lisdexamfetamine
or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post treatment.
297x420mm (300 x 300 DPI)
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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*
Section/item Item No
Description Addressed on page number
Administrative information
Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym __1__(Pg1 Manuscript)
Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry __6__(Pg10 Manuscript)
2b All items from the World Health Organization Trial Registration Data Set __6,7__(N/A Manuscript)
Protocol version 3 Date and version identifier __All__(N/A Manuscript)
Funding 4 Sources and types of financial, material, and other support __6_(Pg13 Manuscript)
Roles and responsibilities
5a Names, affiliations, and roles of protocol contributors __6_( Pgs1,11 Manuscript)
5b Name and contact information for the trial sponsor __6__(N/A Manuscript)
5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities
__N/A (Included in CTRA_
5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)
__38__(N/A Manuscript)
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Introduction
Background and rationale
6a Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention
_9 - 11_ Pgs3,4 Manuscript)
6b Explanation for choice of comparators __11__(Pg4 Manuscript)
Objectives 7 Specific objectives or hypotheses __12__(Pg4 Manuscript)
Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
__13__(Pg5 Manuscript)
Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained
__13__(Pg5 Manuscript)
Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)
_13 - 14_(Pg5 Manuscript)
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered
27 - 28_(Pgs7,8 Manuscript)
11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease)
29 - 31_ (Pgs7,8 Manuscript)
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)
__24__(Pg7 Manuscript)
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _13 - 14_(Pg5 Manuscript)
Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended
_29 - 31_ (Pg6 Manuscript)
Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure)
_20 - 22_ (Pg6 Manuscript)
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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations
__35__(Pg5 Manuscript)
Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size __14__(N/A Manuscript)
Methods: Assignment of interventions (for controlled trials)
Allocation:
Sequence generation
16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions
__16__(Pg7 Manuscript)
Allocation concealment mechanism
16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned
__16__(Pg7 Manuscript)
Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions
__16__(Pg7 Manuscript)
Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how
__36__(Pg7 Manuscript)
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial
__36__(Pg7 Manuscript)
Methods: Data collection, management, and analysis
Data collection methods
18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol
23 - 26 (Pgs6,9 Manuscript)
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols
_24,31_(Pg8 Manuscript)
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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol
__34__(Pg9 Manuscript)
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol
35 - 36 (Pgs8,9 Manuscript)
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ____N/A_______
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation)
__35__(Pg8 Manuscript)
Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed
__38__(Pg9 Manuscript)
21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial
__37__(Pg9 Manuscript)
Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct
31 - 33 (Pgs6,7 Manuscript)
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor
__35__(N/A Manuscript)
Ethics and dissemination
Research ethics approval
24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _38_ (Pg9 Manuscript)
Protocol amendments
25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)
_38_(N/A Manuscript)
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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32)
__15__(Pg9 Manuscript)
26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable
_43,46_(N/A Manuscript)
Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial
_38_ (Pg9 Manuscript)
Declaration of interests
28 Financial and other competing interests for principal investigators for the overall trial and each study site _N/A_ (Pg10 Manuscript)
Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators
_38_ (Pg10 Manuscript)
Ancillary and post-trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation
_38_(N/A Manuscript)
Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions
_38_ (Pg9 Manuscript)
31b Authorship eligibility guidelines and any intended use of professional writers _38_(N/A Manuscript)
31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ____N/A_______
Appendices
Informed consent materials
32 Model consent form and other related documentation given to participants and authorised surrogates _Separate document_
Biological specimens
33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable
_23_(Pg7 Manuscript)
*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license.
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