A Phase II RCT Of OrAl Cannabinoid Versus Placebo In The Treatment Of Chemotherapy Induced Peripheral NeurOpathic PaiN (ACTION)

Research questions: What is the efficacy of a broad-spectrum cannabidiol (CBD) oral tincture containing CBD isolate and terpenes in patients with neuropathic pain due to chemotherapy induced peripheral neuropathy (CIPN); and what are the potential mechanisms of action?

Background: CIPN is a common and debilitating side effect of chemotherapy. It is an ongoing chronic problem in 50% of patients one year after treatment ends, leaving at least 140,000 new cases of CIPN per year in the United Kingdom. There are no preventative treatments, and symptomatic management is commonly ineffective.

Recent evidence indicates that neuroinflammation is an important potential mechanism underlying of CIPN. Therefore, the reported anti-neuroinflammatory properties associated with CBD and terpenes make these important targets for further investigation. There is intense interest in the appropriate use of CBD from patient groups, and the National Institute for Health and Care Excellence (NICE) specifically called for research into CBD in neuropathic pain.

Debate also exists about the mechanisms of perceived analgesia with CBD, hence the clear need for mechanistic clinical trials.

Primary clinical objective: To determine if the oral administration of a tincture containing a mixture of CBD and terpenes (IMP) for 5 weeks provides effective analgesia for CIPN, using the EORTC CIPN 20 (sensory subscale) questionnaire.

Primary mechanistic objective: To determine whether there are pre/post-treatment changes in key pain brain regions, focusing on Anterior Cingulate Cortex (ACC) connectivity in those receiving active treatment during resting state fMRI (rsfMRI), and whether these are associated with changes in clinical pain/wellbeing scores.

Secondary objectives: To determine (1) whether 5 weeks of CBD treatment causes side effects, and affects physical function, cognition and sleep along with various sensory and quality of life (QoL) outcomes, and whether CBD has the potential for cost-effectiveness; (2) whether changes in wider rsfMRI network architecture accompany 5 weeks of CBD treatment, beyond the ACC; (3) the relationship of CBD treatment effects and measured plasma levels of externally administered CBD; (4) the relationship of treatment effects to the endocannabinoid (eCB) system through measurement of eCB; (5) the relationship of CBD effect to inflammatory markers through the measurement of specific plasma cytokine levels.

Study design: A phase 2, double-blind, placebo-controlled, cross-over design RCT with an embedded fMRI mechanistic sub-study of CBD: terpene versus matched placebo tincture. Periods of IMP and placebo, each consisting of 5 weeks of treatment, will be separated by a 2 week wash-out period. The trial will last for 30 months. Participants will have stable chronic CIPN and will have met the inclusion:exclusion criteria.

Anticipated impact and dissemination: This study will give an early indication of safety and/or lack of safety, and of potential mechanisms of action, and will contribute early evidence towards clinical guidelines on the use of CBD in CIPN treatment. In addition, if appropriate to move forwards, it will help inform the design of a phase 3 trial. Our patient and public involvement (PPI) group have been actively involved from the start of this study development, and will help to progress dissemination plans.

International and National guidelines and research groups will be informed of results and have access to data.