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Trial registered on ANZCTR


Registration number
ACTRN12623000866606
Ethics application status
Approved
Date submitted
18/07/2023
Date registered
11/08/2023
Date last updated
17/09/2023
Date data sharing statement initially provided
11/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Naltrexone and bupropion for the treatment of methamphetamine use disorder
Scientific title
An open-label safety and feasibility pilot trial of oral naltrexone-bupropion combination pharmacotherapy for methamphetamine use disorder
Secondary ID [1] 309112 0
None
Universal Trial Number (UTN)
U1111-1289-1728
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Addiction 329200 0
Methamphetamine use disorder 329201 0
Condition category
Condition code
Mental Health 326158 326158 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Commercially available oral tablets containing naltrexone hydrochloride 8 mg and bupropion hydrochloride 90 mg (branded Contrave 8/90).

Week 1 – 12: Medication Period and Primary Endpoint (days 1 – 84)
Participants will receive an increasing dose regimen as follows:
• Day 1: 1 tablet morning (total 1 tablet per day)
• Day 2: 1 tablet morning & 1 tablet evening (total 2 tablets per day)
• Day 3: 2 tablets morning & 1 tablet evening (total 3 tablets per day)
• Day 4: 2 tablets morning & 2 tablets evening (total 4 tablets per day)
• Day 5: 3 tablets morning & 2 tablets evening (total 5 tablets per day)

From day 5 onwards the dose will remain at 5 tablets daily (3 morning, 2 evening) for the remainder of the 12 week medication period (to day 84 inclusive). In Week 13 (day 85 to 88), the dose will be gradually decreased then ceased, as follows:

Week 13: Taper-down Period (days 85 – 88)
• Day 85: 2 tablets morning & 2 tablets evening (4 tablets per day)
• Day 86: 2 tablets morning & 1 tablets evening (3 tablets per day)
• Day 87: 1 tablet morning & 1 tablet evening (2 tablets per day)
• Day 88: 1 tablet morning FINAL DOSE (1 tablet per day)

Adherence will be assessed by two means:
• Self-reported medication adherence (via brief smartphone survey) sent daily
• Simplified Medication Adherence Questionnaire (SMAQ) administered at each weekly clinic visit
Intervention code [1] 325574 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334051 0
Safety
Safety will be monitored by study staff conducting weekly clinic visits, with oversite from the site PI. Safety data will be collected through Adverse Event and Serious Adverse Event reporting, and a Data Safety and Monitoring Board (DSMB) will be convened to review accumulating data. The incidence of adverse events (AEs) will be recorded across the duration of the study, by system organ class (SOC), including the number of participants with AEs of vital signs recorded outside expected limits. The primary safety measure is the number of treatment-emergent AEs by SOC, described by seriousness, severity, causality and expectedness (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Annotated with TGA Comments, 2016; National Health and Medical Research Council, 2016). Adverse events will be documented during weekly clinic visit assessments. Subjective descriptions of AEs provided by participants will be transcribed verbatim and reported in accordance with the Medical Dictionary for Regulatory Activities (MedDRA) terminology, developed under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Severity will be graded from Grade 1 (mild) to Grade 5 (death) by the site principal investigator (U.S. Department of Health and Human Services, 2017). Causality will be determined by the site principal investigator, and expectedness in accordance with international guidelines and the Australian product label for Contrave 8/90. Any known reaction listed on the product label will be considered potentially causally related.

Adverse events associated with combined naltrexone–bupropion (Contrave) are mostly mild or moderate in severity. The most commonly reported side effects are nausea, constipation, vomiting (greater than or equal to 1/10 people), dizziness, dry mouth, and headache (greater than or equal to 1/100 to less than 1/10 people). Gastrointestinal symptoms are generally self-limited and self-resolving within 4 weeks (iNova Pharmaceuticals, 2022). Contrave can cause an increase in systolic and/or diastolic blood pressure as well as an increase in resting heart rate. Blood pressure and pulse should be measured prior to initiation of therapy and should be regularly assessed in accordance with standard clinical practice.

Naltrexone has the capacity to cause hepatocellular injury (liver damage) when given in excessive doses (4 to 6 times the weekly dose of this study). It does not appear to be damaging to the liver at the recommended doses (Generic Health, 2021) however as a precaution, any patients with indications of acute hepatitis or liver failure will be excluded from participating in this study.

Bupropion is associated with an increased risk of seizures. This risk is dose dependent, meaning that the risk increases as the dose increases. At a daily dose of 450 mg, there is an approximately 4 in 1,000 chance (0.4% chance) of experiencing a seizure. Individuals with a pre-existing increased risk of seizure (including history of epilepsy or seizure disorder, or an acute eating disorder, or are currently undergoing acute alcohol withdrawal) will be excluded from participating in this study.
The use of bupropion has been associated with an increased risk of suicidal thinking and behaviour. Symptoms of depression and suicidal thoughts will be assessed at each weekly clinic visit throughout the study.
Timepoint [1] 334051 0
Assessments will be conducted weekly during Weeks 1-12. The primary endpoint is the end of Week 12 (day 84 post-baseline).
Primary outcome [2] 334052 0
Feasibility:
• Time taken to recruit entire sample (number of weeks between recruitment of participant 1 to recruitment of participant 20)
• Proportion of ineligible participants at pre-screening and screening (assessed at study end through audit of pre-screening and screening logs)
• Retention rate over the full duration of the study (assessed at study end through audit of study records - number of participants attending each weekly clinic visit)
• Daily self-reported medication adherence (assessed via very brief smartphone delivered survey prompting participants to respond if they have taken their daily medication)
• Weekly medication adherence assessment (assessed weekly using the Simplified Medication Adherence Questionnaire - SMAQ)
Timepoint [2] 334052 0
Upon conclusion of the study (i.e. the end of Week 16 - day 112 post-baseline)
Secondary outcome [1] 419196 0
Changes in psychological wellbeing (level of psychological distress) assessed using the Depression Anxiety Stress Scales - short form (DASS-21). This will be assessed as a composite outcome (DASS-21 total score) and as three separate outcomes (DASS-21 subscale scores - Depression, Anxiety, Stress) - see below.
Timepoint [1] 419196 0
Assessed weekly from baseline to Week 16 post-baseline.
Secondary outcome [2] 419197 0
Acceptability of the intervention, assessed by:

- Qualitative interviews conducted between weeks 13-16. Interviews will be semi-structured, one-on-one interviews of approximately 30 minutes, examining the themes of expectation and expectation management, experience of participating in the trial, thoughts on how the trial could be improved in the future and any general concerns around orally administered naltrexone-bupropion combination therapy, and how the potential addition of a placebo may change their perspectives.

- Treatment Satisfaction Questionnaire for Medication Version II (TSQM v. II).
Timepoint [2] 419197 0
Qualitative interviews: Once per participant, between weeks 13-16 post-baseline.
TSQM v. II: Weekly from week 1 to week 16 post-baseline.
Secondary outcome [3] 419198 0
Change in methamphetamine use, assessed by presence of methamphetamine in urine assessed through dipstick urine drug screen (UDS).
Timepoint [3] 419198 0
Baseline, weeks 5-6 and weeks 11-12 post-baseline.
Secondary outcome [4] 424765 0
Quality of life, assessed by the Personal Wellbeing Index (PWI).
Timepoint [4] 424765 0
Baseline, week 12, week 16 post-baseline.
Secondary outcome [5] 424773 0
Social support, assessed by the ENRICHD Social Support Inventory (ESSI)
Timepoint [5] 424773 0
Baseline, week 12, week 16 post-baseline.
Secondary outcome [6] 424778 0
Physical health symptoms, assessed by the Patient Health Questionnaire 15 (PHQ-15)
Timepoint [6] 424778 0
Weekly, from baseline to week 16 post-baseline.
Secondary outcome [7] 424779 0
Suicidality, assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).
Timepoint [7] 424779 0
Weekly, from baseline to week 16 post-baseline.
Secondary outcome [8] 424781 0
Subjective severity of dependence, assessed by the Severity of Dependence Scale (SDS) for methamphetamine use.
Timepoint [8] 424781 0
Baseline, week 12, week 16 post-baseline.
Secondary outcome [9] 425112 0
DASS-21 depression subscale score.
Timepoint [9] 425112 0
Assessed weekly from baseline to Week 16 post-baseline.
Secondary outcome [10] 425113 0
DASS-21 anxiety subscale score.
Timepoint [10] 425113 0
Assessed weekly from baseline to Week 16 post-baseline.
Secondary outcome [11] 425114 0
DASS-21 stress subscale score.
Timepoint [11] 425114 0
Assessed weekly from baseline to Week 16 post-baseline.
Secondary outcome [12] 425115 0
Change in methamphetamine use, assessed by Timeline Follow-Back (28 days) assessed at Baseline, week 4, week 8, week 12, week 16 post-baseline.
Timepoint [12] 425115 0
Baseline, week 4, week 8, week 12, week 16 post-baseline.
Secondary outcome [13] 425116 0
Subjective severity of dependence, assessed by the Craving Visual Analogue Scale (CVAS).
Timepoint [13] 425116 0
Weekly, from baseline to week 16 post-baseline.

Eligibility
Key inclusion criteria
Greater than or equal to 18 years of age

Able to provide informed consent

Interested in managing, reducing, or stopping methamphetamine use

Meet DSM-5-TR diagnostic criteria for Stimulant Use Disorder – Amphetamine-Type Substance assessed at enrolment

Self-report methamphetamine use at least 14 days out of the previous 28 at baseline using the Timeline Follow-back (TLFB) method, assessed within 24 hours of first scheduled study dose

Opioid free for at least 7 concurrent days (self-report), assessed within 24 hours of first scheduled study dose

Provide a urine sample positive for methamphetamine and negative for opioids within 24 hours of first scheduled study dose

If person of childbearing potential, willingness to undergo a pregnancy test within 24 hours of first scheduled study dose and avoid pregnancy during the entire study duration

Meet subjective and objective measures of being opioid-free prior to naltrexone induction, according to the determination of the PI at enrolment

Willing and able to comply with all study requirements, including ability to store study medications securely

Agree to use a smartphone to self-report daily adherence to the study medication
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Currently pregnant or breastfeeding, or planning on becoming pregnant during the course of the study

Presence of any psychiatric or physical comorbidity that would interfere with study participation as assessed by the PI

Presence of any factors that increase risk of seizure, including a history of epilepsy, seizure disorder, or head trauma with associated loss of consciousness that required hospitalisation, current anorexia nervosa or bulimia, or any other conditions that increase seizure risk in the opinion of the study’s medical monitor

Coexisting dependence on alcohol, benzodiazepines, GHB, or opiates, or undergoing treatment for any other substance use disorder

Expected need for opioid-containing medications at any point during the study (e.g. planned surgery)

Current use of medications associated with serotonin syndrome, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)

Liver function tests (LFT) indicating elevated levels as follows: AST/ALT results > 5 times ULN, total bilirubin > 2 times ULN, or platelets below 75 x 103/µL

Contraindications for naltrexone hydrochloride as per the Australian Product Information Sheet:
o Patients receiving opioid analgesics.
o Patients currently dependent on opioids since an acute withdrawal syndrome may ensue.
o Patients in acute opioid withdrawal.
o Any individual with a history of sensitivity to naltrexone or any other components of this product. It is not known if there is any cross-sensitivity with naloxone or the phenanthrene containing opioids.
o Any individual with acute hepatitis or liver failure. Naltrexone GH should not be given to patients with acute hepatitis or liver failure.

Contraindications for bupropion hydrochloride sustained release tablets as per the Australian Product Information Sheet:
o Patients with hypersensitivity to bupropion or any of the other components of the preparation.
o Patients with a current seizure disorder or any history of seizures.
o Patients with a known central nervous system (CNS) tumour.
o Patients undergoing abrupt withdrawal from alcohol or benzodiazepines.
o Patients currently being treated with any other preparation containing bupropion as the incidence of seizures is dose dependent.
o Patients with a current or previous diagnosis of bulimia or anorexia nervosa.
o Concomitant use of bupropion hydrochloride and monoamine oxidase inhibitors (MAOIs). At least 14 days should elapse between discontinuation of MAOIs and initiation of treatment with bupropion hydrochloride tablets.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 4
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/10/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 24197 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 39729 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 313313 0
Government body
Name [1] 313313 0
Australian Government Department of Health and Aged Care
Country [1] 313313 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Sydney
Address
390 Victoria Street
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 315056 0
None
Name [1] 315056 0
Address [1] 315056 0
Country [1] 315056 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312537 0
St Vincents Hospital Human Research Ethics Committee
Ethics committee address [1] 312537 0
Ethics committee country [1] 312537 0
Australia
Date submitted for ethics approval [1] 312537 0
24/04/2023
Approval date [1] 312537 0
07/06/2023
Ethics approval number [1] 312537 0
2023/ETH00549

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125018 0
Prof Nadine Ezard
Address 125018 0
St Vincent’s Hospital Sydney
Alcohol and Drug Service
390 Victoria Street
Darlinghurst NSW 2010
Country 125018 0
Australia
Phone 125018 0
+61 2 8382 1014
Fax 125018 0
Email 125018 0
Nadine.Ezard@svha.org.au
Contact person for public queries
Name 125019 0
Carl Moller
Address 125019 0
St Vincent’s Hospital Sydney
Alcohol and Drug Service
390 Victoria Street
Darlinghurst NSW 2010
Country 125019 0
Australia
Phone 125019 0
+61 2 9348 0225
Fax 125019 0
Email 125019 0
carl.moller@unsw.edu.au
Contact person for scientific queries
Name 125020 0
Carl Moller
Address 125020 0
St Vincent’s Hospital Sydney
Alcohol and Drug Service
390 Victoria Street
Darlinghurst NSW 2010
Country 125020 0
Australia
Phone 125020 0
+61 2 9348 0225
Fax 125020 0
Email 125020 0
carl.moller@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Current supporting documents:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19724Study protocol  carl.moller@unsw.edu.au
19725Informed consent form  carl.moller@unsw.edu.au
19726Ethical approval  carl.moller@unsw.edu.au


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19724Study protocol  nadine.ezard@svha.org.au
19725Informed consent form  nadine.ezard@svha.org.au
19726Ethical approval  nadine.ezard@svha.org.au

Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.