Background
Study objectives
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Primary Objective 1: To examine the effects of nabiximols vs. placebo on a range of cannabis treatment efficacy outcomes, primarily, changes in illicit cannabis use during treatment and effects on retention in treatment.
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Primary Objective 2: To examine the adverse event profile and abuse liability of nabiximols as a take home treatment for cannabis use disorder.
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Primary Objective 3: To assess the costs and health related quality of life (HRQoL) associated with nabiximols treatment and the potential societal savings (decreased health care, improved productivity, and decreased criminal behaviours).
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Secondary objectives: To examine changes in health related outcomes during outpatient treatment with nabiximols, including a range of mental and physical health dimensions, cognitive function, and psychosocial functioning.
Methods
Study design
Study period | ||||||||||||||||
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Screen | Enrol | Post-allocation | Follow up | |||||||||||||
Timepoint* | -t1 | 0 | Wk 1 | Wk2 | Wk3 | Wk4 | Wk5 | Wk6 | Wk7 | Wk8 | Wk9 | Wk 10 | Wk 11 | Wk 12 | Wk 13 | Wk 24 |
Enrolment | ||||||||||||||||
Phone screen (Eligibility) | X | |||||||||||||||
Informed consent for medical screen | X | |||||||||||||||
Medical screen/assessment (Eligibility) | X | |||||||||||||||
Informed consent for main study participation | X | |||||||||||||||
Allocation | X | |||||||||||||||
Intervention | ||||||||||||||||
Medication [Nabiximols or placebo] dispensed | X | X | X | X | X | X | X | X | X | X | X | X | X | |||
Nursing clinical reviews | X | X | X | X | X | X | X | X | X | X | X | X | X | |||
Medical clinical reviews | X | X | X | X | X | |||||||||||
CBT sessions | X | X | X | X | X | X | ||||||||||
Urine drug screen | X | X | X | X | X | X | X | X | X | X | X | X | X | X | ||
Assessments | ||||||||||||||||
Research Interviews. Variables include: Cannabis & other substance use (TLFB), CWS, AEs, Aberrant medication behaviour (mod ORBIT), SF-6D (QOL), WHO Health and Performance Questionnaire: CT version, SF-36 (Physical and Mental health), DASS-21, PHQ-15, OTI: BPI, Crime, Satisfaction, Test blind (week 12 only) | X | X | X | X | X | |||||||||||
Clinical (Nursing/medical) Review variables: AEs, Aberrant medication behaviour (weigh bottles), ratings dose adequacy, ATOP & BPRS at 4 week intervals, reason for study termination Wk 24. | X | X | X | X | X | X | X | X | X | X | X | X | ||||
Cognitive assessment. Variables include Blood samples (pre/post cognitive testing), Cognitive testing, Abuse liability (subjective liking, strength, Physiological response) | X | X | X |
Regulatory and funding
Sites
Participants
Sample size
Eligibility criteria
Exclusion criteria
Early termination criteria
Recruitment
Randomisation and blinding
Clinical intervention
Study medications
Clinical reviews
Psychosocial intervention
Outcome and treatment process measures
Domain | Name | Description of measure | How and when administered |
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Basic | Demographics | 10 Questions: basic demographics including; age, gender, employment, relationship status, education level, living situation and Aboriginal and Torres Strait Islander background. | Research Interview: Week 0 (baseline) day 1 |
Cannabis Use | Cannabis Use | 4 semi-structured questions: exploring frequency, amount and method of cannabis use in the last 4-weeks | Research Interview: Weeks 0, 4, 8, 12, 24 |
Cannabis Withdrawal Scale (CWS) [35] | 19 items on a 10-point Likert Scale, with 0 = Not at all to 10 = Extremely. The CWS is used as a diagnostic instrument in clinical and research settings to assess cannabis withdrawal symptoms. Participants are asked how they feel over the last 24 h in 8 domains; irritability, depression, anxiety, cannabis cravings, physical symptoms, sleep difficulty, restlessness and appetite. | Research Interview and Clinical Reviews: Weekly | |
Marijuana Craving Questionnaire-short form (MCQ) [66] | 12 items on a 7-point Likert scale, with 1 = strongly disagree to 7 = strongly agree. The MCQ is a self-report instrument that assesses marijuana craving along 4 dimensions; compulsivity, emotionality, expectancy and purposefulness. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Cannabis Problems Questionnaire (Adult revised- CPQ-R) [67] | 27 items on a 11-point Likert scale, with 0 = doesn’t apply to me to 10 = strongly apply to me. The CPQ-R measures acute and physical consequences, psychological consequences, and social consequences of cannabis use. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Self-coping and efficacy for quitting cannabis questionnaire [68] | 20 items on a 7-point Likert scale, with 1 = not at all confident to 7 = very confident. Participants are asked to indicated their confidence in their ability to resist the temptation to use cannabis in a variety of interpersonal and intrapersonal situations. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Modified Time Line Follow Back (adapted) [40] | Using a modified Time Line Follow Back approach examining cannabis use in preceding 4 week period. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Other Substance Use | Australian Treatment Outcome Profile (ATOP) [36] | 3 Part Questionnaire: | Research Interview: Weeks 0, 4, 8, 12, 24 |
1. Substance use; items refer to substance use over the last 4-weeks, in particular: alcohol, amphetamines, benzodiazepines, heroin, other opioids, cocaine, other substances and tobacco. | |||
2. Injecting risk behaviour; 2-items exploring injecting behaviour in the last 4-weeks. | |||
3.Health and Well-being; 11-items investigating the participants’ accommodation arrangements, psychological and physical health and quality of life. | |||
FagerstrÖm Test for nicotine dependence (FTND) [69] | 6 item questionnaire that measures nicotine dependency, with a total available score of 10. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
The Alcohol Use Disorders Identification Test (AUDIT) [70] | 10 item questionnaire covering domains of alcohol consumption, drinking behaviour and alcohol related problems. Responses to each question are scored from 0 to 4, giving a maximum possible score of 40. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Opioid Related Behaviours in Treatment (ORBIT) scale (modified) [71] | 8 item questionnaire on a 5-point Likert scale ranging from 0 = never to 4 = very often. The questionnaire explores opioid-related behaviours that are divergent, unexpected, non-adherence to medication, unsanctioned diversion of medication to others, hazardous use or misuse. ORBIT questions modified for cannabis dependent population. | Research Interview: Week 12 | |
Mental Health | Depression, Anxiety and Stress scale (DASS) Short-form [51] | 21 item questionnaire on a 4-point Likert scale, ranging from 0 = did not apply to me at all to 3 = applied to me very much or most pf the time. The DASS 21 measures the severity of symptoms of depression, anxiety and stress and enables clinicians to measure a patient’s response to treatment. | Research Interview: Weeks 0, 4, 8, 12, 24 |
Primary Care Post Traumatic Stress Disorder (PC-PTSD) [72] | 4 item questionnaire that explores whether a patient has ever experienced a traumatic event (e.g. a serious accident, physical/sexual assault/abuse, natural or political disaster etc.) over the course of their life. If so, participants answer a series of Yes/No questions. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Brief Psychiatric Rating Scale (BPRS) [37] | 18 item questionnaire on a 7-point Likert scale, ranging from 1 = not present to 7 = extremely severe. Clinicians measure psychiatric symptoms such as depression, anxiety, hallucinations and unusual behaviour. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Physical Health | Short form 36 health survey questionnaire (SF-36) [50] | 36 item questionnaire using a mixed scale. Domains covered in the survey include; physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality and general health problems. | Research Interview: Weeks 0, 4, 8, 12, 24 |
Brief Pain Inventory - Short form (BPI) [53] | 5 items taken from Brief Pain Inventory-Short form using a 10-point Likert scale, ranging from 0-no pain to 10 = worst pain imaginable. Participants are asked to think about any abnormal pain experienced in the last 7 days and rate the intensity and interference of the pain in the participants’ life. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Athens Insomnia Scale (AIS) [54] | 7 item questionnaire using a 4-point Likert scale ranging from 0 = none to 4 = very severe. The AIS is a self-assessment psychometric instrument designed for quantifying sleep difficulty based on the ICD-10 criteria. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Sheehan Disability Scale (SDS) [73] | 3 item instrument using a 10-point Likert scale ranging from 0 = not at all to 10 = very severe. The SDS asks participants to best rate their impairment with work, social life/leisure activities and family life/home responsibilities. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Visual Analogue Scale of client ratings on medication effects [42] | 5 item questionnaire using a scale from 0 to 100 measuring subjective liking and strength of drug effect, comparability to cannabis, sedation, bad effects and subjective physiological effects | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Social/ Other | Opioid Treatment Index- Crime (OTI-Crime) [55] | 8 questions modified from the full Opioid Treatment Index. The modified version concentrates on questions relating to criminality and focuses on the frequency of recent criminal behaviour in four areas: property crime, drug dealing, fraud and crimes involving violence. | Research Interview: Weeks 0, 4, 8, 12, 24 |
Health and Work Performance Questionnaire (HPQ) -Short Form Absenteeism and Presenteeism [74] | 4 Questions modified from the Health and Work Performance questionnaire (HPQ). The HPQ is designed to estimate the workplace costs of health problems in terms of reduced job performance, sickness absence, and work-related accidents/injuries. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD) - Health Service Utilisation (HSU) [75] | 5 questions adapted from the NEPOD study. The HSU section of the NEPOD focusses on health services used in the last 4-weeks, frequency of use and cost of service to the participant. | Research Interview: Weeks 0, 4, 8, 12, 24 | |
Testing the Blind | 5 questions exploring the participants’ subjective opinion of study drug allocation. | Research Interview: Weeks 4, 8, 12, 24 | |
Patient’s Global Impression of Change Scale (PGICS) [64] | 1 question modified from the Global Rating of Change (GLOC) survey exploring the participants’ subjective opinion of change since starting study. | Day: 85 | |
Cognitive Assessment | Wechsler Test of Adult Reading (WTAR) [61] | Verbal pronunciation of 50 words with irregular phoneme-to-grampheme conversion. Total correct recorded | Research Interview: Weeks 0 |
Eriksen Arrow Flankers (with no-go) [56] | Speed of response to target stimuli flanked with either neutral, congruent or incongruent stimuli (24 each). Random 10% (n = 8) trials require with-holding of response (no-go). Reaction time; errors and false alarms recorded | Research Interview: Weeks 0, 4, 24 | |
1,2,3-Back Task [58] | Identification of repetition in a rapid sequence of stimuli, either 1, 2, or 3 stimuli prior (30, 75, 75 stimuli respectively; 25% targets). Reaction time, accuracy, false-positives recorded | Research Interview: Weeks 0, 4, 24 | |
Symbol-Digit Substitution Task (SDMT) [59] | Decoding symbols related to presented digit; 87 trials; Reaction Time and Accuracy recorded | Research Interview: Weeks 0, 4, 24 | |
Stop-Signal Task (SST) [57] | Withholding of already initiated motor response after a delay; 12 target trials of 48; reaction time, errors, stop signal response time recorded | Research Interview: Weeks 0, 4, 24 | |
Rapid Visual Information Processing (RVIP) [60] | Response to high working memory load (3 back) stimuli; 24 targets in 300 stimuli; reaction time; accuracy and false positive responses recorded | Research Interview: Weeks 0, 4, 24 | |
Rey Auditory Verbal Learning Task [62] | Retention of a 15 item word list presented on 5 occasions. Number of words recalled on each presentation, following presentation of a novel list of 15 words; and then after brief and long delays recorded. Recognition of target stimuli also assessed. | Research Interview: Weeks 0, 4, 24 |
Objective 1
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Illicit cannabis use is quantified as self-reported number of days of illicit cannabis use and average daily amount of cannabis use in grams at the 4 weekly research interviews using modified Timeline Followback [40] techniques. The primary end-point is self-reported illicit cannabis use days during the maintenance phase of treatment (weeks 1-12). Objective measures of illicit cannabis use will be determined from weekly urine collection with quantitative analysis of urinary THC, THC-COOH, CBD and other cannabinoids. 4-weekly point prevalence abstinence during maintenance phase (weeks 1-4, 5-8, 9-12), and post-treatment period (week 24) will be ascertained by combining self-report data from researcher interviews and urinalysis.
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Treatment retention (days in protocol treatment) are recorded from clinical records. Participants who do not attend for more than two consecutive weeks are deemed to have dropped out of treatment, and the last scheduled day of dosing is calculated as the end of treatment date.
Objective 2
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Adverse events are assessed and addressed during clinical assessments with the study medical officer at 4-weekly appointments. At the end of study participation, the SMO records the severity of each AE (mild, moderate, severe), the outcome (ongoing or resolved, with or without treatment), and attribution to study medication.
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Abuse liability: Adherence to study medication is estimated by participants returning their medication canisters at the weekly clinical review and weighing the amounts of medication used (equivalent to a pill count). Aberrant medication behaviours (missed doses, extra ‘unsanctioned’ doses, misuse or diversion) are assessed by self-report at researcher interviews using the modified ORBIT [41], a validated aberrant medication behaviours self-report instrument. In addition, a series of subjective assessments of abuse liability using the Visual Analogue Scale (VAS) [42], (0-100) of subjective liking, comparability to cannabis, strength of effect and subjective physiological effects are conducted 4-weekly at researcher interviews.
Objective 3
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Cost effectiveness: Consistent with other drug treatment cost effectiveness evaluations [43‐45], the primary outcome is Quality Adjusted Life Years (QALY) measured by the SF-6D [46], (at 4 weekly research interviews) determined using area under the curve analysis [47] for each individual. Resources included are all clinical services provided as trial interventions (see Treatment Process Measures below), adverse event management, self-reported health care utilization outside of the trial (hospital, emergency department, primary care and other specialist health services) as well as self-reported participation in criminal activity that will be costed using unit costs (CPI adjusted if necessary) [48]. Lost productivity and personal costs are collected by structured self-report (WHO Health and Performance Questionnaire: Clinical Trials Version) [49]. The costs will be summed and combined with the outcome measure, and the incremental cost-effectiveness ratio [ICER = (CNabiximols-CControl)/(ENabiximols-EControl)] calculated.
Secondary objectives
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Other substance use (alcohol, opioids, stimulants, benzodiazepines, tobacco) are recorded by self-report number of days used in the past 28 days using the ATOP at 4-week research interview.
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Health outcomes and psychosocial function. The SF-36 [50] is administered at 4-week research interviews to assess dimensions of physical and mental health and psychosocial function. Mental health will be also be assessed using the Depression, Anxiety and Stress Scale (DASS-21) [51] at 4-weekly research interviews and the BPRS at 4-weekly medical reviews. Patient reported ratings of physical health are also assessed using the Physical Health Questionnaire-15 (PHQ-15) [52]. Pain severity and pain interference is assessed using the Brief Pain Inventory [53]. Subjective sleep ratings are assessed using the Insomnia Sleep Inventory [54]. Self-reported drug related crime (e.g. drug dealing, income generating crime) are examined using the Crime Section of the Opiate Treatment Index [55].
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Cognitive function is assessed by the researcher at baseline (week 0, day 1), during the maintenance phase (week 4), and at follow-up (week 24). A targeted series of computerised tests sensitive to acute THC effects are conducted, specifically an acute battery: Eriksen Flanker Task [56], Stop Signal Task [57], N-Back [58], Digit-Symbol Substitution [59], and Rapid Visual Information Processing [60] as well as a control measure (Wechsler Test of Adult Reading [61]) and a measure of memory and learning (Ray Auditory Verbal Learning Test, RAVLT [62]). At week 4 assessments, cognitive testing (acute battery) are performed 30 min prior to (trough) and 45-60 min after (peak effects) supervised dosing. Blood samples at trough and peak are taken for plasma cannabinoid levels (THC, 11-OH THC, THC-COOH, CBD, 11-OH CBD) to assist in the interpretation of findings. The acute battery uses computerised tests within the Penscreen system [63] that create random numbers for stimuli to minimise learning effects. Similarly, repeated memory assessment use parallel versions of the RAVLT. It will be of particular interest to examine whether nabiximols is associated with cognitive improvement relative to Placebo and relative to baseline. Week 24 cognitive performance assessment is examined to investigate within-subject longitudinal changes over time.
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Patient reported outcome and satisfaction measures: Many of the study outcomes use ‘patient reported outcome measures’ of specific domains. The Patient Global Impression of Change Scale (PGICS) [64] examines the participant’s assessment of change in their global condition at week 12 since entering treatment in the trial. Participants are also asked questions relating to their satisfaction of treatment medication and dose and their likelihood of recommending it to others.