Methods

Multi‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group pilot study

Participants

Male or female participants (N = 60) aged 18 years or above (18‐65 years in the Czech Republic)

Inclusion criteria included:

(1) diagnosed with mild to moderate ulcerative colitis and on a fixed dose of 5‐ASA treatment and have been on a stable dose for at least 2 weeks prior to screening (0 mg dose of 5‐ASA is acceptable)

(2) had at screening (Visit 1) and baseline (Visit 2) with a Mayo assessment score of greater than or equal to 4 (≥ 4) but less than or equal to 10 (≤ 10) and with an endoscopy score of at least 1 (≥ 1) , following an adequate exposure to oral or topical 5‐ASA, in the opinion of the investigator

(3) In the opinion of the investigator, capable of complying with the study requirements and completing the study

(4) Willing and able to give informed consent

(5) Willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable

(6) Willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study

Interventions

Patients received either cannabidiol with up to 4.7% THC (n = 29) or placebo (n = 31) gelatin capsules

The cannabidiol dose ranged from 50 mg to 250 mg twice daily(GWP42003 is purified from a proprietary Cannabis sativa L. chemotype containing predominantly CBD, up to 4.7 % THC and other compounds) The placebo capsules had excipients alone

The cannabidiol with 4.7% THC dose was titrated up to maximal tolerated dose over two‐weeks with maximum dose of 250 mg twice daily (i.e. intervention ranged from 1‐5 capsules taken twice daily)

Treatment duration was 10 weeks.

Outcomes

Note: The original outcome measures submitted in March 2012 were changed in July 2015, one year after completion of the study

2012: Primary outcome was percentage of participants achieving remission, defined as a Mayo Score of < 2 with no sub‐score > 1

Secondary outcomes included serum C‐reactive protein (CRP), serum cytokines (IL‐6, IL‐2 & TNF‐α), fecal calprotectin, body weight measurement, clinical assessments with IBDQ, SGIC, PGAS, MAYO score; and daily diary of stool frequency (0‐4 numerical rate scale), rectal bleeding (0‐4 numerical rate scale), and pain (0‐10 numerical rate scale)

2015: Primary outcome was same, but included PP analysis as well as ITT

Secondary outcomes included CRP, IL‐2, IL‐6, TNF‐alpha, stool calprotectin, Inflammatory Bowel Disease Questionnaire (IBDQ) total score, Subject Global Impression of Change (SGIC), Physician's Global Assessment of Illness Severity (PGAS), pain scores using a 0‐10 numerical rate scale, stool frequency scores using a 0‐4 numerical rate scale and PP analysis, rectal bleeding scores using a 0‐4 numerical rate scale and PP analysis, plasma endocannabinoid levels (2‐arachidonoyl glycerol (2‐AG), anandamide (AEA), oleoylethanolamide (OEA), and PEA, Mayo Total Score, Mayo Partial Score, Mayo responder analysis (responder defined as participant with a decrease in their Mayo total score of ≥ 3 points, compared to baseline, with a reduction of at least 1 point in endoscopy findings sub‐score, and body weight.

Notes

Industry funded by GW Research Limited

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

An independent statistician produced a randomization schedule which was held centrally

A unique number was then assigned to either the treatment or placebo group according to the randomization schedule

Allocation concealment (selection bias)

Low risk

Centralized randomization

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Reported double blinding, but also "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)"

Used identical gelatin capsules for the treatment and placebo groups

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Reported double blinding, but also "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)"

The review of the data was blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

There was a higher rate of withdrawals in the treatment group (13/29) compared to the placebo group (8/31)

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes were reported in the manuscript or on the clinicaltrials.gov web site

Other bias

Low risk

Although a higher proportion of the intervention group had previously used cannabis compared to the placebo group and the time since last cannabis use was greater in intervention group compared to the placebo group, these differences were not statistically significant

The study appears to be free of other sources of bias

Methods

Randomized placebo controlled trial

Participants

Patients with UC who did not respond to conventional medical treatment (N = 32)

Interventions

Either two cigarettes of cannabis (0.5 g of cannabis, corresponding to 11.5 mg THC, n = 17) or placebo (cannabis leaves from which THC was extracted, n = 15) daily for eight weeks

Outcomes

General outcomes reported as Disease activity (DAI), Mayo endoscopic score, endoscopic findings and laboratory tests (CRP, fecal calprotectin)

Abstract does not specify primary outcome

Notes

Additional information was supplied by the principal investigator Timna Naftali which informed our risk of bias assessment

NCT01040910

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly assigned using block method in a 1:1 ratio to receive either medical cannabis or placebo

Allocation concealment (selection bias)

Low risk

The investigators used sequentially numbered drug containers of identical appearance, which were given to the patients outside of the hospital by the pharmacy staff so the medical team did not see them

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Although placebo cigarettes were used, blinding was likely to be broken due to the psychotropic effects of cannabis

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors were blinded

Blinding was open only at the end of the study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no drop‐outs

Selective reporting (reporting bias)

Unclear risk

The primary outcome reported in the study protocol was for Crohn's disease ‐ a reduction in CDAI of 70 points (the study enrolled participants with Crohn's disease and ulcerative colitis)

The secondary outcomes reported in the study protocol included adverse events due to cannabis smoking, change in quality of life, change in IL‐10, IL‐2, and TGF beta

None of these outcomes were reported in the abstract publication but could potentially be reported in a full manuscript

Other bias

Low risk

The study appears to be free of other sources of bias