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Trial registered on ANZCTR


Registration number
ACTRN12617000657325
Ethics application status
Approved
Date submitted
10/04/2017
Date registered
8/05/2017
Date last updated
22/04/2020
Date data sharing statement initially provided
18/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Lisdexamfetamine for the treatment of methamphetamine addiction
Scientific title
A randomised double blind placebo controlled study of lisdexamfetamine for the treatment of methamphetamine dependence
Secondary ID [1] 291650 0
None
Universal Trial Number (UTN)
U1111-1195-2142
Trial acronym
LiMA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Addiction 302802 0
Methamphetamine dependence 302804 0
Condition category
Condition code
Mental Health 302299 302299 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Week 1 (Induction): 150mg lisdexamfetamine capsules taken orally, daily
Weeks 2-13 (Maintenance phase): 250mg lisdexamfetamine capsules taken orally, daily
Weeks 14-15 (Reduction): 150mg lisdexamfetamine capsules taken orally, daily for 1 week, then 50mg lisdexamfetamine capsules daily taken orally,daily for a further week

Oral lisdexamfetamine dimesylate 50 mg capsules and placebo capsules will be used to make up the prescribed study dose. Trial medications will be obtained, prepacked in child resistant blister packs, stored and shipped 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.
The GMP facility shall package and label the study medication in boxes and ship to the relevant pharmacy departments.
Each box shall include the name and strength of the drug along with all other warnings and instructions necessary to fulfil the requirements of the Poisons and Therapeutic Goods Act 1966 and the Poisons and Therapeutic Goods Regulation 2008
Each box shall be dispended by a pharmacist and provided to an appropriately qualified nurse, who will supervise the administration of the medication to the participant. The participant will take home the box containing the remainder of the medication.
At initial research interview, participants will be counselled on strategies to promote medication adherence using a modified version of the COMBINE to draw up an initial medication adherence plan check which will be conducted at subsequent research assessments. Adherence will be assessed through self-report and pill counts and conduct counselling to promote adherence using the brief medication adherence check session worksheet.
Intervention code [1] 297736 0
Treatment: Drugs
Comparator / control treatment
Daily placebo for the 15 week duration of the trial treatment. Size zero placebo capsules containing microcrystalline cellulose (to mimic that of the active capsule) will be used

The routine 4-session manualised Cognitive Behaviour Therapy (CBT) program developed by Baker et al will be provided by trained therapists to all participants in the trial.
For the purpose of this study, therapists are defined as staff with graduate qualifications in a relevant health discipline (such as counselling, nursing, social work, psychology, psychiatry), including trainees with adequate skills, that have undergone training on the use of the manual.
For patients that meet the eligibility criteria of the study, a copy of the trial documentation completed at screening will be provided to the therapist for the purpose of an initial assessment.
Therapists will co-ordinate four 1 hour sessions to occur at least one week apart, between weeks 2 and 13 (i.e. during the maintenance dose treatment period)


Control group
Placebo

Outcomes
Primary outcome [1] 301706 0
To examine the efficacy of oral lisdexamfetamine in reducing methamphetamine use compared to placebo in people who are dependent on methamphetamine.
This outcome will be assessed using the Timeline Follow back Questionnaire (patient reported drug use) self reports. In addition, urine samples will be collected and analysed for methamphetamine.
Timepoint [1] 301706 0
Weeks 5, 9, 13, and 19.
Primary outcome [2] 301707 0
To examine the safety of oral lisdexamfetamine in people who are dependent on methamphetamine.
Safety will be assessed using a number of measures as follows:
Vitals signs (Blood pressure, pulse, temperature, respiratory rate)
Electrocardiogram
Physical assessments
Brief Psychiatric Rating Scale (Psychosis & hostility items)
21-item Depression and Anxiety Scale
Adverse Events: Any spontaneously reported adverse events will be recorded after the subject signs the informed consent form. In addition, adverse events will be elicited using
a non-leading question each time the subject visits the clinic.
Many of the side effects that have been associated with lisdexamfetamine are also seen in methamphetamine use and include:
* loss of appetite (25 out of 100 people)
* dry mouth (23 out of 100 people)
* headache (20 out of 100 people)
* trouble sleeping (16 out of100 people)
* diarrhoea (6 out of 100 people)
* agitation, anxiety, aggression, irritability, feeling jittery, feeling tired, feeling sleepy, dizziness, and restlessness (5 out of 100 people)
* nausea (5 out of 100 people)
* weight loss (4 out of 100 people)
* upper stomach area pain (1 out of 100 people)
* vomiting (less than 1 out of 100 people)
Medications in this drug class can also cause:
* rash and fever
* shortness of breath, excessive sweating, and excessive widening of the pupil
* decreased sex drive and erectile dysfunction
* excessive motor activity with or without feelings of restlessness
* tic, tremor
* rapid heartbeat (tachycardia), palpitations, increased blood pressure
Timepoint [2] 301707 0
Weeks 5, 9, 13, and 19.
Secondary outcome [1] 333626 0
To examine the abuse liability profile of oral lisdexamfetamine in people who are dependent on methamphetamine.
This outcome will be assessed using the Abuse Liability modified DEQ-5 questionnaire.
Timepoint [1] 333626 0
Weeks 5, 9, 13, and 19.
Secondary outcome [2] 333627 0
To examine changes in physical health, mental health and wellbeing in the study population between those taking oral lisdexamfetamine compared to placebo.
This is a composite endpoint and will be assessed using the Patient Health Questionnaire – 15 (PHQ-15) and the Short Form-12 Health Survey (SF-12)
Timepoint [2] 333627 0
Weeks 5, 9, 13, and 19.
Secondary outcome [3] 333628 0
To examine differences in retention rates in the study population between those taking oral lisdexamfetamine compared to placebo.
Retention rates of participants between arms will be examined by the number of patients that completed treatment (i.e. number of patients that completed week 13)
Timepoint [3] 333628 0
Week 13
Secondary outcome [4] 333629 0
To examine differences in amphetamine cravings in the study population between those taking oral lisdexamfetamine compared to placebo
This outcome will be assessed using a Visual Analogue Scale for cravings
Timepoint [4] 333629 0
Weeks 5, 9, 13, and 19.
Secondary outcome [5] 333630 0
To examine differences in use of other drugs of abuse (alcohol, cocaine, opioids, cannabis and benzodiazepines) in the study populations between those taking oral lisdexamfetamine compared to placebo.
This is a composite secondary outcomes and will be assessed using the Timeline Follow back Questionnaire (patient reported drug use) self reports and urine drug screens.
Timepoint [5] 333630 0
Weeks 5, 9, 13, and 19.
Secondary outcome [6] 333631 0
To examine differences in blood borne virus transmission risk behaviour in the study population between those taking oral lisdexamfetamine compared to placebo
This outcome will be assessed using the Opioid Treatment Index Injecting (OTI-I) Section III: HIV Risk-Taking Behaviour.
Timepoint [6] 333631 0
Weeks 5, 9, 13, and 19.
Secondary outcome [7] 333632 0
To examine difference in criminality in the study population between those taking oral lisdexamfetamine compared to placebo.
This outcome will be assessed using the Treatment Index Crime (OTI-C)
Timepoint [7] 333632 0
Weeks 5, 9, 13, and 19.
Secondary outcome [8] 333633 0
To assess the cost effectiveness of lisdexamfetamine relative to the placebo control.
This outcome will be assessed using a number of methods as follows:
Additional questions will be included on the OTI-C to determine related costs of any criminal offense committed during the timeframe of the study, and any relevant criminal justice costs.
The EQ-5D-5L will contribute to the estimation of quality-adjusted life years
A Health Services Utilisation questionnaire will be used to assess work time lost to attend treatment and any changes /differences in productivity due to having undertaken treatment.
Travel time and costs for participants will be collected at a single time point (week 5) and averaged across their number of attendances
Timepoint [8] 333633 0
Weeks 5, 9, 13, and 19.
Secondary outcome [9] 333706 0
To examine differences in amphetamine withdrawal in the study population between those taking oral lisdexamfetamine compared to placebo
This outcome will be assessed using the Amphetamine Withdrawal Questionnaire (AWQ)
Timepoint [9] 333706 0
Weeks 5, 9, 13, and 19.
Secondary outcome [10] 333707 0
To examine differences in amphetamine severity of dependence in the study population between those taking oral lisdexamfetamine compared to placebo
This outcome will be assessed using the Severity of Dependence Scale (SDS)
Timepoint [10] 333707 0
Weeks 5, 9, 13, and 19.
Secondary outcome [11] 333708 0
To examine changes in cognitive and psychosocial functioning in the study population between those taking oral lisdexamfetamine compared to placebo.
This outcome will be measured by the following battery of neurocognitive tests and validated patient surveys:
Wechsler test of adult reading (WTAR)
Montreal Cognitive Assessment (MOCA)
Trail-making test
Rey Auditory Verbal Learning Task (RAVLT)
Flankers task
Rapid Visual Information Processing (RVIP)
Digit-Symbol
N-Back
Timepoint [11] 333708 0
Weeks 1, 5, 9, 13 and 19

Eligibility
Key inclusion criteria
1. Provide written, informed consent to participate in the study.
2. Aged 18 to 65 years
3. Be treatment seeking for methamphetamine use
4. Meet ICD-10 criteria for methamphetamine dependence for at least twelve months
5. Self-report methamphetamine use of at least 14 days out of the previous 28
6. Have one urine drug screen (UDS) positive for methamphetamine within 7 days prior to registration
7. Participants must have the ability to store study medication securely
8. Be willing and able to comply with requirements of study
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
9. Current effective counselling based treatment for methamphetamine dependence
10. Current pharmacotherapy treatment for opioid dependence
11. Use of prescribed dexamphetamine or modafinil in the previous four weeks
12. Current dependent use of alcohol or non-prescribed substances other than amphetamines, diagnosed by specialist clinical assessment against ICD-10 criteria, which in the opinion of the investigator would interfere with participation in the study.
13. Currently lactating or pregnant, or of childbearing potential and not willing to avoid becoming pregnant during the study
14. Sensitivity or previous adverse reaction to lisdexamfetamine
15. Current, severe medical disorder (e.g. Cardiovascular disease, uncontrolled hypertension, peripheral vascular disease, assessed by study medical officer)
16. Current, severe psychiatric disorder (e.g. Acute psychosis, severe anxiety and/or mood disorder, intent to harm self or others assessed by study medical officer and/or psychiatrist)
17. History of glaucoma, hyperthyroidism, pheochromocytoma, motor tics, vocal tics or Tourette’s syndrome
18. Use of monoamine oxidase inhibitors in previous 14 days; or use of other medications that could interact with study medication on assessment by the investigator.
19. Exposure to any investigational drug within the 4 weeks prior to screening
Note: Co-enrolment in another study not involving an investigational drug is not an exclusion criterion, provided it does not cause undue burden on the participant or effect the ethical, safety, statistical, or practical requirements of this study as determined by the PI
20. Not available for follow-up (e.g. Likely travel or imprisonment)
21. Undergoing child protection service/court/work ordered drug testing

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be performed by a computer-generated randomisation schedule which has been developed by an independent statistician and uploaded to the REDCap study database.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised in a 1:1 ratio between groups using variable block randomisation stratified by treatment site. Randomisation will be performed by the trial site
pharmacist within the REDCap database.

The randomisation component of the database has been safe guarded with specific user rights allowing only the trial site pharmacist and statisticians to access the randomisation form and view the subsequent allocations. As a further security measure, the randomisation allocation will be displayed in the databased as ‘A’ or ‘B’ with only the study statistician and the trial site pharmacist knowing which allocation is related to Lisdexamfetamine and which is related to Placebo.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Mixed Models for Repeated Measures will compare groups on changes in outcome variables (days of methamphetamine use derived from self report interview data) in the maintenance medication phase (weeks 2 - 13). All analyses will use intention-to-treat analyses. Missing data will be imputed using multiple imputation procedures. These primary analyses will also be controlled for any significant between-groups differences in baseline demographic and methamphetamine use between groups. Bivariate comparisons at each time point (weeks 5, 9, 13, 19) will be conducted controlling for familywise Type I error rates.
Analysis of urine drug screen results (UDS) will follow established techniques for similar drug trials, whereby missing UDS results assigned as positive, such that each participant will have a proportion (%) of methamphetamine positive UDS between 0-12 out of 12 possible weekly UDS

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 7812 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 7813 0
Cumberland Hospital - Westmead
Recruitment hospital [3] 13172 0
Turning Point Drug and Alcohol Centre - Richmond
Recruitment hospital [4] 13173 0
Drug and Alcohol Clinical Services, Hunter New England Local Health District - Newcastle
Recruitment hospital [5] 13174 0
Drug & Alcohol Services South Australia (DASSA) - Stepney
Recruitment postcode(s) [1] 15745 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 15746 0
2145 - Westmead
Recruitment postcode(s) [3] 15908 0
5069 - Stepney
Recruitment postcode(s) [4] 25727 0
3121 - Richmond
Recruitment postcode(s) [5] 25728 0
2300 - Newcastle

Funding & Sponsors
Funding source category [1] 296148 0
Government body
Name [1] 296148 0
National Health and Medical Research Council
Address [1] 296148 0
GOP Box 1421
Canberra ACT 2601
Country [1] 296148 0
Australia
Funding source category [2] 296149 0
Charities/Societies/Foundations
Name [2] 296149 0
Curran Foundation
Address [2] 296149 0
Level 3, de Lacy Building
390 Victoria Street
Darlinghurst NSW 2010
Country [2] 296149 0
Australia
Primary sponsor type
Individual
Name
Associate Professor Nadine Ezard
Address
St Vincent's Hospital Sydney
390 Victoria Street
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 295063 0
None
Name [1] 295063 0
Address [1] 295063 0
Country [1] 295063 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297395 0
St Vincents Hospital Human Research Ethics Committee
Ethics committee address [1] 297395 0
390 Victoria Street
Darlinghurst, NSW, 2010
Ethics committee country [1] 297395 0
Australia
Date submitted for ethics approval [1] 297395 0
01/08/2016
Approval date [1] 297395 0
26/10/2016
Ethics approval number [1] 297395 0
HREC/16/ SVH/222
Ethics committee name [2] 300146 0
Aboriginal Health & Medical Research Council Ethics Committee
Ethics committee address [2] 300146 0
Level 3, 66 Wentowrth Avenue
Surry Hills NSW 2010
Ethics committee country [2] 300146 0
Australia
Date submitted for ethics approval [2] 300146 0
21/07/2017
Approval date [2] 300146 0
20/09/2017
Ethics approval number [2] 300146 0
1290/17
Ethics committee name [3] 302682 0
ACON Research Ethics Review Committee
Ethics committee address [3] 302682 0
414 Elizabeth St
Surrey Hills, NSW, 2010
Ethics committee country [3] 302682 0
Australia
Date submitted for ethics approval [3] 302682 0
06/11/2018
Approval date [3] 302682 0
27/11/2018
Ethics approval number [3] 302682 0
2018/27

Summary
Brief summary
Australia has one of the highest rates of methamphetamine dependence in the world. While counselling is effective for many people with less severe dependence, there is no proven medication treatment for severe dependence.

Lisdexamfetamine is a stimulant of the brain and is approved in Australia for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). It is a once-daily oral medication converted to dexamphetamine in the blood.

The aim of the LiMA study is to test if lisdexamfetamine is effective in reducing methamphetamine use, cravings and withdrawal symptoms in people who are dependent on methamphetamine.

This will be a randomised double-blind placebo-controlled study which means that one group will receive lisdexamfetamine and another will receive a placebo (a medication with no active ingredients), in addition to counselling. Participants, clinicians and researchers involved in the study will not know to which group they have been allocated. The two groups will be compared and the findings will contribute to evidence for the future use of lisdexamfetamine in the treatment of methamphetamine dependence.

180 people will be recruited to the LiMA study which will be conducted in specialist treatment centres in Sydney, Newcastle and Adelaide. It is anticipated that recruitment will start in early 2017.
Trial website
https://limastudy.info/
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 73914 0
A/Prof Nadine Ezard
Address 73914 0
Alcohol & Drug Service, St. Vincent’s Hospital
Level 4 O’Brien Centre,
Victoria & Burton Streets,
Darlinghurst NSW 2010
Country 73914 0
Australia
Phone 73914 0
+ 61 2 8382 1036
Fax 73914 0
Email 73914 0
nadine.ezard@svha.org.au
Contact person for public queries
Name 73915 0
Ms Shikha Agrawal
Address 73915 0
St Vincent's Health Network Sydney
The O’Brien Centre
390 Victoria Street, Darlinghurst NSW 2010
Country 73915 0
Australia
Phone 73915 0
+61 02 8382 4974
Fax 73915 0
Email 73915 0
shikha.agrawal@svha.org.au
Contact person for scientific queries
Name 73916 0
A/Prof Nadine Ezard
Address 73916 0
Alcohol & Drug Service, St. Vincent’s Hospital
Level 4 O’Brien Centre,
Victoria & Burton Streets,
Darlinghurst NSW 2010
Country 73916 0
Australia
Phone 73916 0
+ 61 2 8382 1036
Fax 73916 0
Email 73916 0
nadine.ezard@svha.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The Participant Information Sheet and Consent Form indicates that the participants information will only be disclosed with their permission, except as required by law.
What supporting documents are/will be available?
No other documents available
Summary results
No Results