Multiple SclerosisPhase 2NCT05131828
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
A Phase 2 study testing Metformin and clemastine in combination in people with Multiple Sclerosis, run by Cambridge University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 25 to 50 years
- Conditions the study is for
- Multiple Sclerosis
- What is being tested?
- Metformin and clemastine in combination
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 70 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 8 Mar 2022to 26 Sep 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 50 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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;
- Known contraindication(s) to MRI scanning procedures;
- History of prostatic hypertrophy;
- History of major ophthalmologic disease or concomitant ophthalmologic disorders including glaucoma, macular degeneration, and severe myopia (>-7 Diopters);
- History of stenosing peptic ulcer or pyloroduodenal ulceration;
- History of significant cardiac conduction block or decompensated heart failure;
- History of acute porphyria;
- People with a history of alcohol or other recreational drug misuse within the 6 months preceding screening;
- People unable to avoid alcohol drinks for the course of the trial;
- Vitamin B12 deficiency as defined as B12 levels of < 150 pg/ml measured at screening;
- Any other significant disease, disability or investigation result which, in the opinion of the Investigator, may either put the participant at risk, or may influence the result of the trial, or the participant's ability to participate in the trial.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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
- Being tested
- Metformin and clemastine in combination, Placebo
- Medical subject headings
- Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin and clemastine in combinationDrug
Metformin hydrochloride 500 mg prolonged release (SR) tablet for oral administration.
Clemastine hydrogen fumarate 1.34 mg tablet for oral administration.
PlaceboDrug
Placebo tablets to match both metformin and clemastine tablets.
| Study group | Role | What they receive |
|---|---|---|
| Research arm: metformin and clemastine | Experimental | Not described Receives: Drug: Metformin and clemastine in combination |
| Control arm: placebos for both metformin + clemastine | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: Baseline to week 26
The change in lesional MTR, between baseline and week 26, for the lesions stratified by location
Measured: 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
Measured: Baseline to week 26
Adverse events and withdrawals attributable to metformin and/or clemastine
Measured: Baseline to week 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2021
- Study start8 Mar 2022
- Primary completion31 Mar 2025
- Study completion26 Sep 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cambridge University Hospitals NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- University of Cambridge
- Responsible party
- Principal investigator, Nicholas Cunniffe, Cambridge University Hospitals NHS Foundation Trust
- Investigators
- Nick Cunniffe, Principal investigator, Cambridge University Hospitals NHS Foundation Trust & University of Cambridge
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05131828
- Sponsor's protocol ID
- CCTU0269
- Status last verified
- Apr 2025
- First submitted
- 12 Nov 2021
- Last updated
- 11 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 41361285
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT05131828
- Acronym / sponsor ID
- CCTU0269
- Conditions
- Multiple Sclerosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- Cambridge University Hospitals NHS Foundation TrustUniversity, hospital or other
- Collaborators
- University of Cambridge
- Study start
- 8 Mar 2022 (actual)
- Primary completion
- 31 Mar 2025 (actual)
- Study completion
- 26 Sep 2025 (actual)
- First posted
- 23 Nov 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Research arm: metformin and clemastine | Experimental | Drug: Metformin and clemastine in combination |
| Control arm: placebos for both metformin + clemastine | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 25 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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;
Key exclusion criteria (25 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Metformin and clemastine in combinationMetformin hydrochloride 500 mg prolonged release (SR) tablet for oral administration. Clemastine hydrogen fumarate 1.34 mg tablet for oral administration. | Drug | Research arm: metformin and clemastine |
| PlaceboPlacebo tablets to match both metformin and clemastine tablets. | Drug | Control arm: placebos for both metformin + clemastine |
Primary outcome
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
Time frame: Baseline to week 26
4 secondary outcomes
The change in MF-VEP latency, between baseline and week 26, for those eyes with delayed latency at baseline
Time frame: Baseline to week 26
The change in lesional MTR, between baseline and week 26, for the lesions stratified by location
Time frame: 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
Time frame: Baseline to week 26
Adverse events and withdrawals attributable to metformin and/or clemastine
Time frame: Baseline to week 28
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2025.
- Derived from this study: PubMed 41361285Riboni-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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nick Cunniffe principal investigator
Cambridge University Hospitals NHS Foundation Trust & University of Cambridge
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin and clemastine in combination in people with Multiple Sclerosis, run by Cambridge University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: Baseline to week 26). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05131828, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Dec 2025.