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 Identifier: NCT05131828
• Recruitment Status: Recruiting
• First Posted: November 23, 2021
• Last Update Posted: June 15, 2022
• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborator: University of Cambridge
• Information provided by (Responsible Party): Alasdair Coles, Cambridge University Hospitals NHS Foundation Trust

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: Metformin and clemastine in combination; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 8, 2022
• Estimated Primary Completion Date: October 2023
• Estimated Study Completion Date: October 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Research arm: metformin and clemastine	Drug: Metformin and clemastine in combination; Metformin hydrochloride 500 mg prolonged release (SR) tablet for oral administration. Clemastine hydrogen fumarate 1.34 mg tablet for oral administration.
Placebo Comparator: Control arm: placebos for both metformin + clemastine	Drug: Placebo; Placebo tablets to match both metformin and clemastine tablets.

Outcome Measures

Primary Outcome Measures :

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 [ Time Frame: Baseline to week 26 ]

Secondary Outcome Measures :

1. 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 ]
2. The change in lesional MTR, between baseline and week 26, for the lesions stratified by location [ Time Frame: Baseline to week 26 ]
3. The change in lesional MTR between baseline and week 26, for the lesions stratified by the cohort baseline median lesional MTR [ Time Frame: Baseline to week 26 ]
4. Adverse events and withdrawals attributable to metformin and/or clemastine [ Time Frame: Baseline to week 28 ]

Other Outcome Measures:

1. The change, between baseline and week 26, in the N75 and N145 latencies of the full-field VEP [ Time Frame: Baseline to week 26 ]
2. The change in full field VEP amplitude, between baseline and week 26, for those eyes with delayed latency at baseline [ Time Frame: Baseline to week 26 ]
3. The change in MF-VEP amplitude, between baseline and week 26, for those eyes with delayed latency at baseline [ Time Frame: Baseline to week 26 ]
4. The change in the number of letters read (and the corresponding LogMAR score) on the Sloan 100%, 2.5% and 1.25% acuity charts, between baseline and week 28 [ Time Frame: Baseline to week 28 ]
5. The change in colour vision between baseline and week 28 [ Time Frame: Baseline to week 28 ]
6. The change in visual fields between baseline and week 28 [ Time Frame: Baseline to week 28 ]
7. The change in saccadic latency parameters in the step, antisaccade and Wheeless tasks between screening and week 28 [ Time Frame: Screening to week 28 ]
8. The change in retinal nerve fibre layer thickness between screening and week 28 [ Time Frame: Screening to week 28 ]
9. The change in MTR of subcomponents of lesions, between baseline and week 26 [ Time Frame: Baseline to week 26 ]
10. The change in MTR of lesions stratified by perfusion, between baseline and week 26 [ Time Frame: Baseline to week 26 ]
11. The change in MRI T2 lesion load between baseline and week 26 [ Time Frame: Baseline to week 26 ]
12. The change in EDSS between screening and week 26 [ Time Frame: Screening to week 26 ]

Eligibility Criteria

• Ages Eligible for Study: 25 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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 2017 radiological 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.

Exclusion Criteria:

• 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;
• 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;
• Known reaction to gadolinium (Gd, component of contrast agent);
• People taking medication for Diabetes Mellitus at screening;
• People with a diagnosis of epilepsy;
• 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;
• 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.

Contacts and Locations

Contacts

Contact: Cambridge Clinical Trials Unit - Neuroscience Theme; 01223 216187; neuroscienceCCTU@addenbrookes.nhs.uk

Locations

United Kingdom

Addenbrooke's Hospital; Recruiting

Cambridge, United Kingdom

Contact: Cambridge Clinical Trials Unit - Neuroscience Theme 01223 216187 neuroscienceCCTU@addenbrookes.nhs.uk

Sponsors and Collaborators

Cambridge University Hospitals NHS Foundation Trust

University of Cambridge

Investigators

• Principal Investigator: Alasdair Coles; Cambridge University Hospitals NHS Foundation Trust & University of Cambridge

More Information

• Responsible Party: Alasdair Coles, Honorary Consultant Neurologist and Professor of Neuroimmunology, Cambridge University Hospitals NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT05131828
• Other Study ID Numbers: CCTU0269
• First Posted: November 23, 2021
• Last Update Posted: June 15, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Metformin; Clemastine; Hypoglycemic Agents; Physiological Effects of Drugs; Antipruritics; Dermatologic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Allergic Agents