CCMR Two: A Phase IIa, Randomised, Double-blind, Placebo-controlled Trial of the Ability of the Combination of Metformin and Clemastine to Promote Remyelination in People With Relapsing-remitting Multiple Sclerosis Already on Disease-modifying Therapy

NCT05131828 | Completed Phase 2 DMC

• 1 other identifier: CCTU0269
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

The greatest unmet need for people with multiple sclerosis is an effective therapy for the progressive phase. Current treatments suppress the damage caused by the immune system but there is only a limited window in which these can work. Consequently, much of the research community is turning its attention to the process of repair, called remyelination, in which the lining of nerve cells is reformed. This protects nerves from dying and therefore can delay, prevent, or even reverse, disability progression. It has previously been shown that stem cells are already present in the brain that can carry out this process. Clemastine, an anti-histamine drug, can instruct them to become active and has already shown a beneficial effect in a phase 2 trial. Now, more recent experiments have shown that changes take place within these stem cells as they age, which prevents them responding to drugs like clemastine, but that this can be reversed by treatment with metformin, a commonly used anti-diabetes drug. Our goal is to establish whether the combination of metformin and clemastine can promote remyelination in people with MS. We will focus on people with relapsing MS as they will have a greater proportion of nerves healthy enough to allow remyelination to take place, which will maximise the chance of detecting an effect with a smaller sample size. Participants will also continue treatment with a current disease-modifying MS treatment, to reduce the chance of developing new areas of damage, allowing the trial to focus on the repair process. The treatment duration will be 24 weeks, but given the established safety of the proposed medications, we are able to limit the number of visits to the trial centre to ensure participation is not overly burdensome.

Conditions

Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• the change in the P100 latency of the full-field visual evoked potential (VEP) between baseline and week 26 for each affected eye of participants

  Baseline to week 26

Secondary Outcomes (4)

• The change in MF-VEP latency, between baseline and week 26, for those eyes with delayed latency at baseline

  Baseline to week 26

• The change in lesional MTR, between baseline and week 26, for the lesions stratified by location

  Baseline to week 26

• The change in lesional MTR between baseline and week 26, for the lesions stratified by tissue-specific cohort baseline lesional MTR values

  Baseline to week 26

• Adverse events and withdrawals attributable to metformin and/or clemastine

  Baseline to week 28

Other Outcomes (13)

• The change, between baseline and week 26, in the N75 and N145 latencies of the full-field VEP

  Baseline to week 26

• The change in full field VEP amplitude, between baseline and week 26, for those eyes with delayed latency at baseline

  Baseline to week 26

• The change in MF-VEP amplitude, between baseline and week 26, for those eyes with delayed latency at baseline

  Baseline to week 26

Study Arms (2)

Research arm: metformin and clemastine

EXPERIMENTAL

Drug: Metformin and clemastine in combination

Control arm: placebos for both metformin + clemastine

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Metformin and clemastine in combination DRUG

Metformin hydrochloride 500 mg prolonged release (SR) tablet for oral administration. Clemastine hydrogen fumarate 1.34 mg tablet for oral administration.

Research arm: metformin and clemastine

Placebo DRUG

Placebo tablets to match both metformin and clemastine tablets.

Control arm: placebos for both metformin + clemastine

Eligibility Criteria

• Age: 25 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Participant is willing and able to give written informed consent for participation in the trial;
• Male or female, aged between 25 and 50 years (inclusive) at time of signing informed consent form (ICF);
• Relapsing-remitting multiple sclerosis as per the McDonald 2017 criteria (Thompson et al., 2018), including an MRI brain satisfying the McDonald 2017 criteria;
• VEP P100 latency in at least one eye of ≥118 ms;
• Kurtzke EDSS 0.0-6.0;
• At the time of screening being treated with a stable dose for at least 6 months of a category 1 multiple sclerosis DMT or for at least 2 years with a category 2 DMT;
• Able (in the Investigator's opinion) and willing to comply with all trial requirements.

You may not qualify if:

• Female participants who are pregnant, lactating or planning pregnancy during the course of the trial;
• Female participants of child-bearing potential whom are unwilling or unable to use one highly effective method of contraception during the trial (as outlined in section 11.11). For the purpose of this document, a woman is considered of childbearing potential, i.e. fertile, following menarche and until post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause;
• Male participants who are unwilling or unable to use contraception during and for 3 months after the trial;
• Participants whom have received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the screening assessment or is currently enrolled in an interventional investigational trial;
• Retinal nerve layer thickness on spectral-domain optical coherence tomography (OCT) \<70 μm in the qualifying eye;
• A clinical episode of optic neuritis in the qualifying eye within the 2 years preceding screening;
• Any unlicensed treatment of multiple sclerosis;
• Any concomitant use of oxybutynin, monoamine oxidase inhibitors (MAOIs), hypnotics or high-dose opiates at screening;
• Significant renal impairment (eGFR \<60 mL/min/1.73 m2);
• Screening liver function (alanine aminotransferase, ALT) value greater than 3 times the upper limit of normal;
• Known hypersensitivity to metformin or clemastine (or other arylalkylamine antihistamines) or any of the excipients of these products;
• People taking medication for Diabetes Mellitus at screening;
• People with a diagnosis of epilepsy;
• People with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption;
• Concurrent use of 4-aminopyridine or fampridine;

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator

Study Sites (1)

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

Related Publications (1)

• Riboni-Verri G, McMurran CE, Mukherjee T, Daruwalla C, Holland J, Gautam R, Chen BS, Cutting E, Qian W, MacManus D, Chard DT, Brown JWL, Coles AJ, Cunniffe NG. The Cambridge Centre for Myelin Repair trial Two (CCMR Two): a trial protocol for a phase 2a, randomised, double-blind, placebo-controlled clinical trial of the ability of the combination of metformin and clemastine to promote remyelination in people with relapsing-remitting multiple sclerosis already on disease-modifying therapy. Trials. 2025 Dec 8;26(1):562. doi: 10.1186/s13063-025-09254-2.

  PMID: 41361285 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Metformin; Clemastine

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Nick Cunniffe

  Cambridge University Hospitals NHS Foundation Trust & University of Cambridge

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Academic Clinical Lecturer

Study Record Dates

• First Submitted: November 12, 2021
• First Posted: November 23, 2021
• Study Start: March 8, 2022
• Primary Completion: March 31, 2025
• Study Completion: September 26, 2025
• Last Updated: December 11, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)