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Trial registered on ANZCTR


Registration number
ACTRN12615000211561
Ethics application status
Approved
Date submitted
5/11/2014
Date registered
5/03/2015
Date last updated
4/04/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
A randomized controlled trial of daily aerobic exercise for inpatient cannabis withdrawal
Scientific title
A prospective, parallel-group randomized controlled trial comparing an exercise versus control intervention across a range of cannabis detoxification outcome measures during a 7-day inpatient admission
Secondary ID [1] 284324 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cannabis Withdrawal 291474 0
Condition category
Condition code
Mental Health 291840 291840 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will compare a behavioural intervention (exercise) with a control (stretching) regime during standard inpatient detoxification for cannabis withdrawal.

All participants will present with 1 known CVD risk factor (current smoker or have quit within the past 6 months). It is therefore likely that the majority of participants will be classified as “moderate risk” (2 or more CVD risk factors). As such, participants will be screened and the exercise intensity will be maintained at low – moderate intensity in accordance with American College of Sports Medicine (ACSM) guidelines. Participants assigned to the exercise condition will complete 7 individual consecutive daily sessions of submaximal aerobic training, specifically 35 minutes of static cycling at 60% VO2 max. This will take place in dedicated rooms in each of the withdrawal facilities, equipped with a Kaiser M3 exercise bicycle, computerised cognitive testing equipment, and standard venepuncture facilities. Exercise or control interventions will occur in supervised sessions (sessions will be supervised by either an Exercise Physiology student or by a Registered Nurse who will be trained by CIC Dr Kieron Rooney, or a Nurse who is trained by a trained nurse) at the same time each day (11-12.30 pm) approximately 3 h after a standardized breakfast.
Intervention code [1] 290550 0
Treatment: Other
Intervention code [2] 290648 0
Behaviour
Comparator / control treatment
Participants randomized to the control group will experience identical duration and timing of daily sessions to the exercise group, but with a series of 7 low intensity stretch exercises over a 35 min period. Each major muscle group will be trained including chest, shoulders, abdomen, back, hips, legs and arms for 2 – 4 sets. The stretching regime is specifically designed so that it does not stimulate the specific metabolic effects of increased lipolysis hypothesised to come from aerobic exercise. Controls will have blood collected on Days 1, 3 and 7 and will receive cognitive testing and withdrawal assessment as per the exercise group. Participants and researchers cannot be blinded given the obvious differences in the two interventions, but one participant will take part per week and thus will not be aware of the alternative intervention. Additionally, as many of the primary outcome measures are objective (e.g. plasma assays), or involve automated tests (i.e. cognitive tests) they are unlikely to be affected by the lack of blinding.
Control group
Active

Outcomes
Primary outcome [1] 293521 0
Rates of completion of the 7 day inpatient detoxification regime
Timepoint [1] 293521 0
Day of discharge from the 7 day inpatient stay
Primary outcome [2] 293522 0
Daily measures of cannabis withdrawal severity using the Cannabis Withdrawal Scale
Timepoint [2] 293522 0
Daily during the 7 day inpatient detox
Primary outcome [3] 293523 0
Daily measures of cannabis cravings using the Marijuana Cravings Questionnaire
Timepoint [3] 293523 0
Daily during the 7 day inpatient detox
Secondary outcome [1] 311250 0
Plasma measures of THC, THC-COOH, 11-OH-THC, CBD, lipolysis, anandamide, 2-AG, and BDNF pre- and post-exercise
Timepoint [1] 311250 0
Days 1, 3 and 7
Secondary outcome [2] 311251 0
Daily urinary cannabinoid levels
Timepoint [2] 311251 0
Daily during the 7 day inpatient detox
Secondary outcome [3] 311252 0
Pre-post exercise measures of cognitive function and psychomotor performance using computerised cognitive performance measures (RAVLT, Erickson flankers task, Stop-Signal Task, Rapid Visual Information Processing, Digit symbol substitution)
Timepoint [3] 311252 0
Days 1, 3 and 7
Secondary outcome [4] 311253 0
Any adverse events during the 7 day admission such as an unexpected reaction to exercise regime
Timepoint [4] 311253 0
Daily during the 7 day inpatient detox
Secondary outcome [5] 311254 0
Mood (DASS-21)
Timepoint [5] 311254 0
28 day follow-up
Secondary outcome [6] 311496 0
Self-reported measures of drug use (days used Timeline Followback)
Timepoint [6] 311496 0
28-day follow up
Secondary outcome [7] 311497 0
psychosocial functioning (SF-12)
Timepoint [7] 311497 0
28 day follow up
Secondary outcome [8] 313436 0
Patient ratings of global improvement
Timepoint [8] 313436 0
Day 7 of inpatient stay

Eligibility
Key inclusion criteria
(a) At least 18 years of age,

(b) meets ICD-10 criteria for cannabis dependence,

(c) reports significant cannabis withdrawal symptoms in previous periods of abstinence,

(d) capacity to tolerate moderate exercise, and

(e) willing and capable of providing informed consent to the study procedures.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) Alcohol dependence (and associated alcohol withdrawal sequel by clinical assessment);

(b) Regular use of other drugs (excluding caffeine, alcohol, and tobacco) or injecting drug use more than once per week on average in previous 28 days;

(c) Any Drug and Alcohol treatment in the last 28 days;

(d) Significant medical conditions impacting upon exercise capacity, metabolism and excretion of cannabinoids, or assessment of cognition and performance (including severe cardiovascular, neurological, hepatic, renal, respiratory and endocrine disorders; or haematological conditions:

(e) Active and severe psychiatric disorders that warrant immediate psychiatric treatment (outside of experimental trial conditions), impact upon capacity for consent, or assessment of outcomes, such as psychosis, suicidality, delirium and severe affective disorders (mild or moderate levels of depression or anxiety not excluded);

(f) Use of medications that may impact upon the metabolism and excretion of cannabinoids (e.g. CYP450 enyzme inducers/inhibitors), or may impact upon measurement of withdrawal features (e.g. mood stabilisers, sedatives); and

(g) Pregnancy (plasma hCG screen in women of child bearing potential).

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)
All eligibility tests for the trial will be performed by people unaware of the allocation group for said participant. ELigibility is assessed in a two stage process, by telephone screen first, then by in person medical assessment. Participant treatment allocation is only released to the study/treatment team by the offsite independent statistician on day 1 of the inpatient stay, when the participant arrives at the hospital, after all screening steps have been completed. If eligible for the study subjects will be randomised upon presentation to the inpatient detoxification service, after they sign informed consent.

The randomisation schedule will be made available to all participating staff but not to the participant. As such it is a single blinded trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified for each trial site and by gender and BMI, treatments are balanced within blocks (to achieve approximately 1:1 ratio between conditions), and block size is randomised to improve blinding procedures.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Active (stretching) control
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
A sample size of 40 subjects per group is required to detect a statistically significant difference in cannabis craving scores (used as a proxy for withdrawal scores here) between exercise and control groups with 90% power and a = 0.05. This calculation assumes that the change in craving scores over the week is 1 (SD 3) unit on the Marijuana Craving Questionnaire (MCQ) in the exercise group (33) and 0 (SD 1.8) in the control group (56), giving an anticipated effect size, Cohens f, of 0.3.

The primary comparison will be severity scores on the Cannabis Withdrawal Scale and the Marijuana Cravings Questionnaire between each treatment group, compared across groups using a Mixed Model for Repeated Measures (MMRM), with main effects of time in treatment, treatment group, and their interaction. The model will assume a linear link function and account for within subject correlations with a first order Autoregressive correlation structure. The model will be used to incorporate data from blood analyses (endocannabinoid and THC levels) as covariates to assess biomarkers fit to behavioural observations, as well as any other interesting covariates.

Secondary analyses will explore the mechanistic reintoxification questions posed in this study with the use of a series of MMRM models with cognition indicators and blood analysis results as dependent variables: THC, THC-COOH, endocannabinoid levels, BDNF, with time, treatment and their interaction as predictors. The effects of exercise induced lipolysis on the time to 1st drug free urine will be determined using survival analysis. The impact of the intervention on post detoxification outcomes will compare changes in self-reported cannabis use (Time-line Followback) and urine THC-COOH levels at baseline and at one month follow up between the groups using MMRMs. Family-wise error corrections (e.g. Bonferroni) will control for Type 1 errors where multiple comparisons are being performed.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
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
Recruitment hospital [1] 3115 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 3116 0
Sydney Hospital and Sydney Eye Hospital - Sydney
Recruitment hospital [3] 3117 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 8865 0
2010 - Surry Hills
Recruitment postcode(s) [2] 8866 0
2050 - Camperdown
Recruitment postcode(s) [3] 8864 0
2139 - Concord Repatriation Hospital

Funding & Sponsors
Funding source category [1] 290187 0
Government body
Name [1] 290187 0
National Health and Medical Research Council
Address [1] 290187 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 290187 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
The University of Sydney
NSW 2006
Australia
Country
Australia
Secondary sponsor category [1] 288899 0
None
Name [1] 288899 0
Address [1] 288899 0
Country [1] 288899 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291898 0
Sydney Local Health District HREC
Ethics committee address [1] 291898 0
c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 291898 0
Australia
Date submitted for ethics approval [1] 291898 0
30/05/2014
Approval date [1] 291898 0
08/07/2014
Ethics approval number [1] 291898 0
HREC/14/RPAH/59

Summary
Brief summary
The study is a prospective, parallel-group randomized controlled trial comparing an exercise versus control intervention across a range of cannabis detoxification outcome measures during a 7-day inpatient admission, with follow-up at 28 days post-discharge. Specifically, the study will compare severity of cannabis withdrawal and cannabis cravings, detoxification completion rates, and adverse events between the two conditions in an intention-to-treat analysis. Mechanisms by which exercise affects cannabis withdrawal will be assessed through the analysis of markers of endogenous cannabinoids, and plasma and urine THC levels.
Trial website
http://www.psych.usyd.edu.au/forms/exercise-study/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 47210 0
A/Prof Nicholas Lintzeris
Address 47210 0
The Langton Centre,
591 South Dowling Street
Surry Hills, NSW, 2010
Country 47210 0
Australia
Phone 47210 0
+61 2 9332 8702
Fax 47210 0
Email 47210 0
nicholas.lintzeris@sesiahs.health.nsw.gov.au
Contact person for public queries
Name 47211 0
Dr Anjali Bhardwaj
Address 47211 0
The Langton Centre, 591 South Dowling Street Surry Hills, NSW, 2010
Country 47211 0
Australia
Phone 47211 0
+61 2 9351 7665
Fax 47211 0
Email 47211 0
anjali.bhardwaj@sydney.edu.au
Contact person for scientific queries
Name 47212 0
Dr David Allsop
Address 47212 0
Psychopharmacology Laboratory
School of Psychology
University of Sydney, NSW 2006
Country 47212 0
Australia
Phone 47212 0
+61 2 9351 7665
Fax 47212 0
Email 47212 0
david.allsop@sydney.edu.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