A randomised trial to see if an oral cannabis-based medicine (CBD) can help to treat chemotherapy related nerve pain

ISRCTN	ISRCTN15275553
DOI	https://doi.org/10.1186/ISRCTN15275553
Integrated Research Application System (IRAS)	1012593
Protocol serial number	AC25008
Sponsor	University of Edinburgh
Funder	National Institute for Health and Care Research

Submission date: 15/10/2025
Registration date: 03/12/2025
Last edited: 03/12/2025

Recruitment status: Not yet recruiting
Overall study status: Ongoing
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
One in 3 people will have cancer in their lifetime and many will be treated using treatments such as Chemotherapy. One harmful side effect of these treatments is that they can damage the nerves in the body. This is called Chemotherapy Induced Peripheral Neuropathy (CIPN). CIPN is very common, can affect up to 90% of patients and causes long-term pain in up to half of patients. This leads to problems carrying out normal day to day activities and affects their quality of life. CIPN is hard to treat with current medicines.
We want to improve pain levels in CIPN patients. Laboratory work and early studies in patients has shown that substances found in the Cannabis sativa plant called cannabinoids (CBDs) can help with nerve pain like that seen in CIPN. As there hasn’t been much research using CBDs in CIPN, our study will test CBD. We also want to include in our study tests which look at what happens in the pain and mood systems in the brain when you take CBD. We can measure the different CBDs in the blood before and after treatment and look at the effects on the patient’s own natural CBD system.

Who can participate?
Patients aged 18 years or over with at least 3 months post neurotoxic chemotherapy and stable CIPN over at least 6 weeks

What does the study involve?
Patients will answer questions that measure their CIPN symptoms, questions about their quality of life, and ask if they are worried and depressed. We will take blood samples to measure the body’s natural CBD levels and perform a brain scan in patients using a machine called an MRI scanner. Patients will be split into one of two groups, taking either drug or placebo for 5 weeks, then switching to the other treatment for another 5 weeks. After 5 weeks, the study tests will be repeated and the patient will not take treatment for 2 weeks (a 'washout' period). At the end of the study, we will look at the effects of the treatment on pain relief, quality of life, physical function, the brain and mood. This work is important as it will tell us if a larger study is needed to show that CBDs are an effective treatment for CIPN, and how the study should be done.

What are the possible benefits and risks of participating?
You may or may not get a direct personal benefit from using the study medication. If you do not, the information you give and the results from this study may help to improve the healthcare of patients in the future.
The results of this study may be used for the future commercial development of a new medicinal product, treatment or test. Your participation in this study will not entitle you to benefit financially from the commercial development of the product, treatment or test.
Possible sides effects of CBD are weight changes, diarrhoea, nausea, urine infections, increased liver tests, fever, cough, a rash, irritability, depression or thoughts of suicide. This is not common and the nurses will ensure that participants are safe throughout the trial. While enrolled in this study, participants will be unable to take part in any other drug trial. If any unexpected abnormalities show up on routine blood tests or on MRI scans, these will be followed up by the team and appropriate others clinically and communicated to the participant and their GP. Some people may find the extra visits to the clinic, the number of assessments, telephone calls and questionnaires tiring. These are kept to a minimum and collect only the information required for the study. These may be inconvenient however participants will be guided through this process by a member of the research team. There may be some discomfort or bruising after blood is taken. Participants having the MRI scans will have to attend the Royal Infirmary of Edinburgh for two MRI scans (before treatment begins and after 5 weeks of treatment). Some people may feel uncomfortable in the MRI scanner.
Safety: The research team will record adverse events that they become aware of, and promptly report SARs and SUSARs to the study Sponsor. The trial will have a Data Monitoring Committee that will monitor safety throughout the study.

Where is the study run from?
University of Edinburgh (UK)

When is the study starting and how long is it expected to run for?
January 2026 to January 2027

Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK).

Who is the main contact?
action.trial@ed.ac.uk

Contact information

Ms Emma Ward
Public, Scientific

Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, 5-7 Little France Road
Edinburgh
EH16 4UX
United Kingdom

Email	ACTION.trial@ed.ac.uk

Prof Marie Fallon
Principal investigator

Edinburgh Cancer Centre, Western General Hospital, Crewe Road South
Edinburgh
EH4 2XR
United Kingdom

Phone	+44 131 651 8611
Email	marie.fallon@ed.ac.uk

Study information

Primary study design	Interventional
Study design	Interventional double blind randomized cross over placebo controlled trial
Secondary study design	Randomised cross over trial
Scientific title	A Phase II randomised cross-over trial of orAl Cannabinoid versus placebo in the Treatment of chemotherapy Induced peripheral neurOpathic paiN (ACTION)
Study acronym	ACTION
Study objectives	Main clinical objective: To determine if taking an oral CBD solution for 5 weeks provides effective pain relief for chemotherapy induced peripheral nerve pain, assessed using the EORTC CIPN20 (sensory subscale) questionnaire. Main mechanistic objective: To determine whether there are pre/post-treatment changes in key pain brain regions (linked with pain and mood) in participants taking a CBD oral solution by performing an MRI brain scan, and whether this can be linked to changes in clinical pain/well-being scores. Clinical: To determine whether 5 weeks of a CBD solution (MRX1) affects: • Side effects • Severity of the different components of nerve pain • Overall pain • Mood • Cognition • Sleep • Quality of life • Specific bedside examination for nerve pain • Patient's own impression of effectiveness of treatment Health economic: • Potential impact of CBD treatment on health care costs and carer costs Mechanistic: • Whether wider brain changes on MRI scans, which are associated with inflammation change after 5 weeks of CBD treatment • Is there a relationship between pain relief from CBD and the patient's background cannabinoid levels, known as the endocannabinoid system Exploratory: • To understand questionnaire responses at specific time points in relation to patient diaries, evaluating pain, sleep, mood, function and general well-being
Ethics approval(s)	Approved 26/11/2025, East of Scotland Research Ethics Service (EoSRES) (Tayside medical Science Centre, Residency Block Level 3, George Pirie Way, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom; -; tay.eosres@nhs.scot), ref: 25/ES/0092
Health condition(s) or problem(s) studied	Chemotherapy induced peripheral neuropathy
Intervention	A clinical efficacy and mechanistic phase 2 RCT, of MRX1 versus matched placebo oral solution, using a randomised, double-blind, placebo-controlled, cross-over design. Participants will be randomised 1:1 to one of two treatment sequences (placebo, IMP or IMP, placebo) using a web-based randomisation service. Participants will receive each of the treatment sequences in a period lasting 5 weeks (10 weeks in total for both), separated by a wash-out period of 2 weeks (no study drug medication), meaning that it takes 12 weeks for each patient to get through the 2 treatment sequences. During each sequence the patient will follow a pre-determined dosing regimen, with the possibility of escalating the dose after clinical assessment each 6-8 days. The assessment is either phone or face to face to coincide with collecting more IMP from pharmacy. The decision by the clinician to escalate dose, remain on a stable dose, reduce dose or even stop IMP depends on clinical assessment of wanted effects (pain relief) versus unwanted effects (side effects). The decision will be made in conversation with the patient during the consult each week. Trial assessments will include structured validated questionnaires to assess CIPN and associated symptom clusters and QoL, as well as 6 blood samples in total for cytokines and endocannabinoid levels along with 2 MRI scans for mechanistic endpoints. We will only do the MRI scans in the first treatment sequence-at baseline and at end of week 5, to minimise what we ask of patients.
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	MRX1 [Cannabidiol]
Primary outcome measure(s)	1. Sensory peripheral neuropathy is measured using the EORTC QLQ-CIPN20 sensory scale at weeks 5 and 12 2. Resting-state functional connectivity of the anterior cingulate cortex is measured using rsfMRI at baseline and week 5
Key secondary outcome measure(s)	Clinical: 1. Adverse events and side effects are measured using participant self-report and clinical records at weeks 5 and 12 2. Chemotherapy-induced peripheral neuropathy is measured using total EORTC CIPN 20 scores and EORTC QLQc30 scores at week 5 and 12 3. CIPN pain severity is measured using the Brief Pain Inventory short form (BPI sf) at weeks 5 and 12 4. Mood is measured using Generalised Anxiety Disorder-7 questionnaire (GAD7) and (Patient Health Questionnaire-9) PHQ9 total scores at week 5 and 12 5. Perceived cognitive function is measured using the FACT-Cog Version 3 total score at weeks 5 and 12 6. Sleep quality is measured using the Pittsburgh Sleep Quality Index at weeks 5 and 12 7. Health-related quality of life is measured using total EORTC QLQ-C30 scores at weeks 5 and 12 8. Somatosensory function is measured using quantitative sensory testing (QST) at weeks 5 and 12 9. Patient Global Impression of Change (PGIC) is measured using standardised questions at weeks 5 and 12 Health economic: 10. Health status is measured using the EQ-5D-5L at weeks 5, 8 and 12 11. Health care utilisation is measured using participant self-report and clinical records at weeks 5, 8 and 12 12. Cost-effectiveness is measured using modelled cost per QALY at weeks 5, 8 and 12 Mechanistic: 13. Resting-state functional connectivity and white matter microstructural integrity are measured using rsfMRI and diffusion MRI at week 5 14. Brain metabolite concentrations are measured using magnetic resonance spectroscopy at week 5 15. Endocannabinoid levels are measured using blood samples at baseline, weeks 5, 8 and 12 16. Inflammatory markers are measured using blood samples at weeks 5 and 12 Exploratory: 17. Period-dependent fluctuations in clinical outcomes including chemotherapy-induced peripheral neuropathy, quality of life, depression, anxiety and pain are measured using EORTC QLQ-CIPN20, EORTC QLQ-C30, PHQ-9, GAD-7 and BPI-SF at baseline, weeks 5, 8 and 12 18. Temporal fluctuations in pain, sleep, mood, function and general well-being are measured using participant daily diary entries during the 1-week pre-randomisation period, and at weeks 5 and 12
Completion date	31/10/2027

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Upper age limit	99 Years
Sex	All
Target sample size at registration	92
Key inclusion criteria	1. 18 years or over 2. At least 3 months post neurotoxic chemotherapy 3. Stable CIPN over at least 6 weeks 4. EORTC CIPN20 sensory scale > 10 5. 0-10 VAS (Visual Analogue Scale) PAIN ≥ 3 6. Willing and able to give written consent 7. Willing not to take additional cannabinoids during the trial period 8. Willing to use effective contraception throughout the trial (A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. See below for accepted effective contraception1. 9. Willing to continue effective contraception for 30 days after completion of trial for woman participants and for 90 days for male participants 10. No contraindications to MRI scan 1Methods considered to be effective contraceptives: - Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal) - Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable) - Intrauterine device (IUD) - Intrauterine hormone-releasing system (IUS) - Bilateral tubal occlusion - Vasectomised partner (provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success) - Sexual abstinence, defined as refraining from heterosexual intercourse during the entire trial period and for 90 days post study completion. The reliability of sexual abstinence will be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
Key exclusion criteria	1. Patients who have had any changes to analgesia in last 30 days 2. Patients who have had any intervention which may result in a change to CIPN during the course of the study 2 3. Patients currently taking any of the following medication; opioids, erythromycin, clarithromycin, fluconazole, itraconazole, sulfamethoxazole, clopidogrel, rifampicin, warfarin, selected antiepileptic agents (including phenytoin, carbamazepine, sodium valproate) clobazam, stiripentol, Everolimus 3 4. Patients currently taking any antidepressants and anticonvulsants if used as adjuvant analgesics 5. Routine use of cannabis products for medicinal or recreational purposes (at any time in the last 4 weeks) or of any illicit drug precludes inclusion in the study (CBD at Baseline) 4 6. Patients with severe pain due to CIPN on VAS;>8/10 7. Female patients who are not post-menopausal and not using highly effective contraception (as detailed at end of this section) 8. Male patients who are not using highly effective contraception with female partner (as detailed at the end of this section) 9. Patients who are pregnant or breastfeeding 10. Chronic alcohol use 11. Any liver disease with abnormal bilirubin, AST or ALT: History of severe liver disease (Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) more than 3-times the upper limit of normal (ULN)) and bilirubin greater than 2 times the ULN OR moderate to severe hepatic impairment (Child–Pugh class B or C). 12. Current or recent (≤12 months) substance use disorder or misuse of prescription medicines; positive drugs of abuse (DoA) screen when performed at investigator’s discretion. 13. Patients with hypersensitivity to any of constituents of IMP in the IB 14. Any hospital admission for mental ill health in last 5 years 15. Suicidal thoughts or severe depression within the past year 16. Any live vaccines within 14 days before study entry 2 Any treatment, oncological or non-oncological, which could change CIPN during the course of the study (including changes to hormone treatment in the 30 days prior to recruitment, patients who start neurotoxic chemotherapy during the study, patients who start any drug which can cause CIPN during the study). These are the most likely scenarios in our patient group which we are therefore giving as examples but this is not an exhaustive list. 3 All concomitant medication will be reviewed as part of the screening process. Relevant Cannabidiol–Psychoactive Drug Interactions, as listed in Appendix 1, will be considered. 4 Urine samples will be collected at baseline and week 8 (pre-dose) and analysed via a dipstick at time of collection. We can detect any THC taken in the previous 35-40 days with the dipstick which means in practical terms we will capture any illicit THC use. This is to measure any cannabis/cannabinoid use out with the IMP. If the test results are positive for THC the participant will be withdrawn.
Date of first enrolment	31/01/2026
Date of final enrolment	31/01/2027

Locations

Countries of recruitment

United Kingdom

Study participating centres

Western General Hospital

Crewe Road South
Edinburgh
Lothian
EH4 2XU
Scotland

NHS Lothian

Waverley Gate
2-4 Waterloo Place
Edinburgh
EH1 3EG
Scotland

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request. De-identified data will be shared with approved researchers and research projects post data analysis via the Edinburgh Clinical Trials Unit Data Sharing Committee.

Editorial Notes

15/10/2025: Trial's existence confirmed by NHS HRA.