A Phase II randomised cross-over trial of orAl Cannabinoid versus placebo in the Treatment of chemotherapy Induced peripheral neurOpathic paiN (ACTION)
Chemotherapy induced peripheral neuropathy
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.
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.
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 cour