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Trial registered on ANZCTR


Registration number
ACTRN12616000103460
Ethics application status
Approved
Date submitted
25/01/2016
Date registered
1/02/2016
Date last updated
13/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Control Trial of Cannabinoid Replacement Therapy (SATIVEX - registered trademark) for the Management of Treatment-Resistant Cannabis Dependent Patients in the Community
Scientific title
A randomised control trial of cannabinoid replacement therapy (Sativex - registered trademark) for the management of treatment-resistant cannabis dependent patients
Secondary ID [1] 288441 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cannabis dependence 296014 0
Condition category
Condition code
Mental Health 296293 296293 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigational drug: Sativex (1 spray: 2.7 mg THC and 2.5 mg CBD) in an alcohol and peppermint oil liquid administered as an oromucosal spray onto the inside of the mouth. The spray container should be shaken before use and the spray should be directed at different sites inside the mouth changing the application site each time the product is used. A 2-5 second time frame between each spray administered should be allowed in order for the spray to be absorbed through the lining of the cheeks.

Dosage form/strength: Medication is in 10 ml containers; maximum dose of individually titrated doses, up to 8 sprays (21.6 mg THC:20 mg CBD) delivered as buccal spray up to four times a day. Participants are in a 12 week outpatient treatment.

Week 1: all participants will be advised the following doses. Day 1: up to 2 sprays 4 times a day, Day 2-3: can increase to 4 sprays, 4 times a day. Days 4-7: can increase up to 8 sprays, 4 times a day. Dosage for the first week will be dependent on a participant-to-participant bases and their levels of cannabis craving.
Weeks 2-12: Doses during the maintenance phase will be based upon the dose determined by the doctor and participant at the end of week 1, and individually titrated up to a maximum of 8 sprays, 4 times a day.

Adherence will be monitored by weekly clinical reviews with the research nurse. The nurse will weigh bottles to measure maximum prescribed dose and expect participants to return any empty bottle containers at each review.
Intervention code [1] 292690 0
Treatment: Drugs
Comparator / control treatment
Placebo spray - comprising alcohol and peppermint oil
Control group
Placebo

Outcomes
Primary outcome [1] 295946 0
Unsanctioned cannabis use will be quantified as 4-weekly point prevalence abstinence during the 12 week maintenance phase by combining self-report data from researcher interviews (modified Timeline Followback recording number of days and average daily amount (grams) of cannabis use), with objective measures of unsanctioned cannabis use (weekly UDS with quantitative analysis of urinary THC, CBD and their metabolites). Unsanctioned cannabis use will also be reported as mean days used, and percentage of positive urine drug screens.
Timepoint [1] 295946 0
At baseline (week one, day one), week 5, week 9, week 13 (maintenance phase) and week 25 (follow up).
Primary outcome [2] 295947 0
Treatment retention (days in protocol treatment). This will be assessed by the weekly clinical records review and research interviews.
Timepoint [2] 295947 0
Recorded as needed from the weekly clinical records and from the research interviews at Weeks 5, 9, 13 and week 25 (follow up)
Primary outcome [3] 295948 0
Adverse events will be assessed by self-report using a structured symptom checklist at 4-weekly research interviews, and by clinical assessment with the study medical officer.

Possible side-effects/adverse events include; dizziness, disturbance in attention, dry mouth, tachycardia, and gastro-intestinal symptoms.

Timepoint [3] 295948 0
At week 5, week 9, week 13 (maintenance phase) and week 25 (follow up)
Secondary outcome [1] 316995 0
Other substance use (alcohol, opioids, stimulants, benzodiazepines, cigarettes) will be recorded by self-report (number of days used past 4 weeks) by TLFB at 4-week research interviews and validated with UDS and/or breath testing collected to coincide with researcher interviews.
Timepoint [1] 316995 0
At baseline (week 1), Weeks 5, 9, 13 (maintenance phase) and Week 25 (follow up)
Secondary outcome [2] 316996 0
SF-36 will be administered at research interviews to assess dimensions of physical and mental health and psychosocial function
Timepoint [2] 316996 0
At baseline (week 1), Weeks 5, 9, 13 (maintenance phase) and Week 25 (follow up)
Secondary outcome [3] 316997 0
Mental health will be also be assessed using the Depression, Anxiety and Stress Scale (DASS-21
Timepoint [3] 316997 0
At baseline (week 1), Weeks 5, 9, 13 (maintenance phase) and Week 25 (follow up)
Secondary outcome [4] 316998 0
Physical health outcomes will be also assessed using the Physical Health Questionnaire-15 (PHQ-15).
Timepoint [4] 316998 0
At baseline (week 1), Weeks 5, 9, 13 (maintenance phase) and Week 25 (follow up)
Secondary outcome [5] 317037 0
Self-reported drug related crime (e.g. drug dealing, income generating crime) will be examined using the Crime Section of the Opiate Treatment Index.
Timepoint [5] 317037 0
At baseline (week 1), Weeks 5, 9, 13 (maintenance phase) and Week 25 (follow up)
Secondary outcome [6] 317038 0
A targeted series of tests sensitive to acute THC effects (acute battery: Eriksen Flanker Task, Stop Signal Task, N-Back, Digit-Symbol Substitution, and Rapid Visual Information Processing) will be administered to assess cognitive function.
Timepoint [6] 317038 0
At baseline (week 1), Week 5 (30 min prior and after dosing), and Week 25 (follow up)
Secondary outcome [7] 317039 0
A control measure (Wechsler Test of Adult Reading) will be administered to assess cognitive function.
Timepoint [7] 317039 0
At baseline (week 1), Week 5 (30 min prior and after dosing), and Week 25 (follow up)
Secondary outcome [8] 317040 0
A measure of memory and learning (Ray Auditory Verbal Learning Test) will be conducted to assess cognitive function.
Timepoint [8] 317040 0
At baseline (week 1), Week 5 (30 min prior and after dosing), and Week 25 (follow up)
Secondary outcome [9] 317042 0
Blood samples will be taken for plasma cannabinoid levels (THC, CBD) to assist in the interpretation of findings. (Week 25 cognitive performance assessment will examine for within-subject longtitudinal changes over time.)
Timepoint [9] 317042 0
At baseline (week 1), Week 5 (30 min prior and after dosing), and Week 25 (follow up)
Secondary outcome [10] 317043 0
Details regarding participation in trial interventions will be obtained from electronic and paper clinical records and include details regarding doses of trial medication used, participation in medical, counselling and clinical review sessions, and reasons for trial completion (as per protocol, treatment drop out, administrative or medical discharge).
Timepoint [10] 317043 0
Details of participation in trial interventions will be taken from clinical records throughout the trial period and from research interviews at weeks 5, 9 and 13.
Secondary outcome [11] 317044 0
At the completion of the medication phase of the trial participants will also be asked to rate their satisfaction with the trial medication using a 5-point Likert Scale, and for them to estimate which medication group they were assigned to (testing the blind).
Timepoint [11] 317044 0
Week 13
Secondary outcome [12] 320284 0
Aberrant medication behaviours (missed doses, extra doses, misuse or diversion) will be assessed by measuring amounts of medication used at clinical review (by weighing bottles) and by self-report at the researcher interviews using the modified ORBIT a validated aberrant medication behaviours self-report instrument. In addition, a series of subjective assessments of abuse liability (ratings of subjective liking, comparability to cannabis, strength of effect and subjective physiological effects) will be included in line with recent recommendations by the US FDA.
Timepoint [12] 320284 0
Aberrant medication behaviours to be assessed at weekly clinical appointments.
Subjective assessments to be conducted at week 5, week 9, week 13 (maintenance phase) and week 25 (follow up)

Eligibility
Key inclusion criteria
(a) aged 18 to 65 years,

(b) meet ICD-10 cannabis dependence criteria;

(c) have previously attempted but not responded to treatment for cannabis use (operationalized as relapsed to regular cannabis use within 28 days of treatment cessation); and

(d) willing and able to provide informed consent to study procedures (including not driving or operating machinery if Sativex is affecting their ability to perform these tasks, consistent with the Product Label).
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) Presence of another substance use disorder (alcohol, other illicit or prescription drug dependence), diagnosed by specialist clinical assessment, including urine drug screen (UDS);

Patients taking disulfiram for the treatment of alcohol dependence should be excluded due to the possible interaction with the small amounts of alcohol in Sativex. However, patients with a past history of alcohol dependence who are now in remission should not necessarily be discriminated against from participating in the study. Rather, the study medical officer will explain the amount of alcohol in a typical sativex dose used in this study (usually less than 0.5gm alcohol per dose or 0.2 standard drink per day), and then discuss with the patient the relative relapse risks. Of course, many individuals with a past history of alcohol dependence and in remission do not strictly adhere to abstinence from alcohol, and many such individuals may consider the risks of participating as acceptable. Others may want to remain completely abstinent from alcohol and avoid even small amounts of alcohol associated with Sativex. Hence in summary, past alcohol dependence in remission is not an automatic exclusion criteria, but will be individualised with each participant.
(b) severe medical (e.g. chronic pain, hepatic or cardiovascular disease) or psychiatric disorder (e.g. schizophrenia, recent drug-induced psychosis, severe affective disorder), assessed by the study medical officer;

(c) pregnant or lactating women (urine beta-hCG);

(d) concerns regarding safe storage of medication (e.g. unsuitable home environment or significant child protection concerns);

(e) not available for follow-up (e.g. likely travel or imprisonment).

(f) Mandated by court to attend cannabis treatment.

(g) History of epilepsy or recurrent seizures.

(h) Renal impairment

These criteria aim to exclude individuals with concurrent conditions that jeopardise safety or confound data interpretation.

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)
The central randomisation schedule will be developed by an independent statistician who will use a computer software to generate which arm the participant will be allocated to.

The person who determined that the participant was eligible or any staff involved in any one-on-one interaction with the participant will be concealed from knowing which arm the participant is allocated to.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible participants will be randomised in a 1:1 ratio between groups using variable block randomisation to help maintain blinding, with subjects stratified by site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Participants receive either Sativex or Placebo - never both.
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Psychotherapy treatment studies for cannabis abstinence rates of 12 to 23%, over follow-up periods from 2-6 months, and medication studies are similar (23.1% abstinence). We base the power analysis on the assumption that the Placebo group will achieve abstinence rates at 12-weeks or about 22%. We predict that the addition of Sativex to psychotherapy will double abstinence rates to approximately 44%. This estimate is based upon findings from a laboratory relapse model, in which heavy cannabis users consumed less than half the amount of cannabis (mean 43%) following repeated doses of nabilone, relative to placebo treatment. With 80% (two-tailed) and alpha=0.05, a total of 142 participants (71 per group) are needed to detect the predicted benefits in cannabis abstinence.

Chi square and ANOVA will identify any baseline covariates that differ between groups for controlling the main analyses. Missing data will be imputed using multiple imputation except for missing urine where cannabis use will be assumed to have taken place. All analyses will use Intention-to-treat, which is defined here as any person who is randomised to one of the study arms and receives at least one dose of study medications. Mixed Models for Repeated Measures (MMRM) will compare groups on changes in outcome variables (cannabis use and secondary outcomes) in the medication phase with the multiply imputed dataset, assuming that Littles Missing at Random test confirms the data to be missing at random). In addition we will perform a sensitivity analysis based on only those with complete data, and compare results to that from the MI dataset analysis. Adverse Events will be analysed using chi-square. A Cox proportional hazards model will compare retention in treatment between study arms, controlling for potential confounds. The impact of the intervention on post-medication outcomes will compare changes in cannabis use outcomes at baseline and at follow up between groups using MMRMs. Family-wise error corrections will control for Type 1 errors where multiple comparisons are performed within a particular analysis where post hoc contrasts are performed to further explore interesting (significant) findings.

Recruitment
Recruitment status
Completed
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

Funding & Sponsors
Funding source category [1] 291921 0
Government body
Name [1] 291921 0
National Health and Medical Research Council
Address [1] 291921 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 291921 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney
New South Wales, 2006
Country
Australia
Secondary sponsor category [1] 290589 0
None
Name [1] 290589 0
Address [1] 290589 0
Country [1] 290589 0
Other collaborator category [1] 278599 0
Hospital
Name [1] 278599 0
The Langton Centre
Address [1] 278599 0
591-623 South Dowling St
Surry Hills, NSW, 2010
Country [1] 278599 0
Australia
Other collaborator category [2] 278600 0
Hospital
Name [2] 278600 0
South East Sydney Local Health District, The Sutherland Cannabis Clinic
Address [2] 278600 0
Sutherland Hospital Cnr Kingsway and Kareena Road,
Caringbah, NSW, 2229
Country [2] 278600 0
Australia
Other collaborator category [3] 278601 0
Hospital
Name [3] 278601 0
Centre for Addiction Medicine, Cumberland Hospital
Address [3] 278601 0
Building 83,Cumberland Hospital Campus
North Parramatta, NSW, 2151
Country [3] 278601 0
Australia
Other collaborator category [4] 278602 0
Hospital
Name [4] 278602 0
Hunter New England Clinical Drug and Alcohol Services Site (Newcastle Cannabis Clinic)
Address [4] 278602 0
14 Wood St
Newcastle West, NSW, 2302
Country [4] 278602 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293426 0
South Eastern Sydney Local Health District
Ethics committee address [1] 293426 0
Research Support Office
G71, East Wing
Edmund Blacket Building
Prince of Wales Hospital
Randwick NSW 2031
Ethics committee country [1] 293426 0
Australia
Date submitted for ethics approval [1] 293426 0
27/11/2014
Approval date [1] 293426 0
14/05/2015
Ethics approval number [1] 293426 0
14/289

Summary
Brief summary
Cannabis is the most widely used illicit drug and is associated with considerable health related morbidity. About 1 in 10 cannabis users become dependent on the drug leading to high-level of treatment seeking. There is increasing interest in the idea that severe cannabis dependence might be effectively treated by substituting smoked cannabis for a safer, more benign cannabinoid agonist medication. Recent laboratory studies suggest this approach holds promise as an effective therapy in dependent users.

Our team has recently published the first ever-clinical trial of the cannabinoid agonist medication Sativex in alleviating cannabis withdrawal. This world first study demonstrated the safety and efficacy of Sativex relative to Placebo in an inpatient setting.
This project proposed the first ever outpatient randomised controlled trial (RCT) to test the efficacy, safety and cost effectives of Sativex for treating cannabis dependence the community. Sativex will be given to severely cannabis dependant patients who have not previously responded to conventional treatment. Subjects (n=142) will be randomly allocated to a 12-week course of Sativex or placebo, with standard counselling and clinical reviews across both groups, and a 12-week follow up after the completion of maintenance dosing.

This proposal presents an exciting innovation in the embryonic field of clinical research into the world’s most prevalent illicit drug. As well as examining the efficacy of this medication, the trial will address a range of issues important in any future translation of Sativex use into routine clinical practice. The development of an effective medication for treating cannabis dependence would have wide reaching clinical and public health benefits.
Trial website
https://sydneypsy.qualtrics.com/jfe/form/SV_9ZBWKO9w7t4SfmR
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59846 0
Prof Nicholas Lintzeris
Address 59846 0
The Langton Centre
591 South Dowling St,
Surry Hills, NSW, 2010
Country 59846 0
Australia
Phone 59846 0
+61 2 9332 8702
Fax 59846 0
Email 59846 0
nicholas.lintzeris@health.nsw.gov.au
Contact person for public queries
Name 59847 0
Prof Nicholas Lintzeris
Address 59847 0
The Langton Centre, 591 South Dowling Street, Surry Hills, NSW AUSTRALIA 2010
Country 59847 0
Australia
Phone 59847 0
+61 419261675
Fax 59847 0
Email 59847 0
nicholas.lintzeris@health.nsw.gov.au
Contact person for scientific queries
Name 59848 0
Prof Nicholas Lintzeris
Address 59848 0
The Langton Centre,
591 South Dowling Street, Surry Hills, NSW
AUSTRALIA 2010
Country 59848 0
Australia
Phone 59848 0
+61 419261675
Fax 59848 0
Email 59848 0
nicholas.lintzeris@health.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary