Evaluation of Metformin Hydrochloride as an Adjunctive Therapy in Non-Active Progressive Multiple Sclerosis: A Phase IIb Randomized, Triple-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate whether treatment with **metformin** can delay disease progression in patients with non-active progressive multiple sclerosis compared to placebo. This is clinically relevant as it aims to establish metformin as a potential therapeutic option to slow the progression of this debilitating condition. The primary outcome measure is the change in walking speed, assessed by the Timed 25-Foot Walk (T25FW) test, over a 96-week treatment period.

Secondary objectives include: - Demonstrating that metformin delays disease progression in various domains such as general disability, walking function, hand function, and cognitive function, using measures like the Expanded Disability Status Score (EDSS), 2-minute walking test, 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT). - Comparing the Overall Disability Response Score between metformin and placebo groups. - Assessing the slowing of neurodegeneration and/or improvement of remyelination through brain MRI volumetrics and Diffusion Tensor Imaging analysis. - Comparing quality of life between treatment groups. - Evaluating paramagnetic (iron) rim lesions using SWI-MRI. - Investigating caregiver strain. - Conducting a cost-effectiveness analysis.

The clinical trial involves participants diagnosed with **Progressive Multiple Sclerosis** (PMS), specifically non-active forms including Primary Progressive Multiple Sclerosis (PPMS) and Secondary Progressive Multiple Sclerosis (SPMS), as per the 2017 McDonald criteria and Lublin 2013 disease course definitions. The study population includes both male and female subjects, aged between 18 and 70 years, with an Expanded Disability Status Scale (EDSS) score ranging from 2.0 to 6.5. Participants are required to have stable use of disease-modifying therapies (DMT) or no treatment in the past year. The trial does not include a vulnerable population. Participants must be able to provide informed consent and adhere to study procedures, with language proficiency in Dutch/Flemish or French. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the use of adequate contraceptive measures in females of reproductive age. The selection criteria ensure that participants have not experienced relapses or new T2 lesions and/or enhancing T1 lesions on brain MRI in the past 1-2 years, with progression of disability independent of relapses.

The clinical trial is designed to evaluate the efficacy of **metformin** as an add-on treatment in patients with non-active progressive multiple sclerosis. This study is a phase IIb, triple-blind, placebo-controlled, randomized clinical trial. The primary objective is to assess whether metformin can delay disease progression compared to placebo, with the primary endpoint being the change in walking speed measured by the T25FW test over a 96-week treatment period. Secondary endpoints include changes in the Expanded Disability Status Scale (EDSS), cognitive function, hand function, brain volume, and quality of life, among others.

The trial will involve a sequence of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and disease stability. Participants will then be randomized to receive either metformin or placebo. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will conclude the trial, assessing the final outcomes and any long-term effects of the treatment.

Participants are expected to be involved in the study for a total duration of 96 weeks, with the trial estimated to end by March 31, 2025. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide valuable insights into the potential benefits of metformin in managing progressive multiple sclerosis, contributing to the broader understanding of treatment options for this condition.

The clinical trial involves the administration of several experimental medications and a placebo. **AUBAGIO** 14 mg film-coated tablets, containing the active substance **teriflunomide**, are administered orally. The maximum daily dose is 14 mg, with a total dose of 9800 mg over a treatment period of 100 weeks. **Tecfidera** 240 mg gastro-resistant hard capsules, containing **dimethyl fumarate**, are also administered orally with a maximum daily dose of 480 mg and a total dose of 336000 mg over the same period.

**Zeposia** 0.92 mg hard capsules, containing **ozanimod**, are administered orally with a maximum daily dose of 0.92 mg and a total dose of 644 mg. **Gilenya** 0.5 mg hard capsules, containing **fingolimod**, are administered orally with a maximum daily dose of 0.5 mg and a total dose of 350 mg. **Ocrevus** 300 mg concentrate for solution for infusion, containing **ocrelizumab**, is administered via intravenous infusion with a maximum daily dose of 600 mg and a total dose of 3000 mg.

**Ponvory** 20 mg film-coated tablets, containing **ponesimod**, are administered orally with a maximum daily dose of 20 mg and a total dose of 2000 mg. **Betaferon** 250 microgram/ml, powder and solvent for solution for injection, containing **recombinant interferon beta-1b**, is administered via subcutaneous injection with a maximum daily dose of 250 micrograms. **Copaxone** 20 mg/ml and 40 mg/ml solutions for injection, containing **glatiramer acetate**, are administered via subcutaneous injection with maximum daily doses of 20 mg and 40 mg, respectively.

**Mayzent** 2 mg and 1 mg film-coated tablets, containing **siponimod**, are administered orally with maximum daily doses of 2 mg and 1 mg, respectively. **Rebif** 22 micrograms solution for injection in pre-filled syringe, containing **interferon beta-1a**, is administered via subcutaneous injection with a maximum daily dose of 44 micrograms. **Plegridy** 125 micrograms solution for injection in pre-filled syringe, containing **peginterferon beta-1a**, is administered via subcutaneous injection with a maximum daily dose of 125 micrograms.

**TYSABRI** 300 mg concentrate for solution for infusion, containing **natalizumab**, is administered via subcutaneous and intravenous use with a maximum daily dose of 300 mg. **Glatiramyl** 40 mg/ml and 20 mg/ml solutions for injection, containing **glatiramer acetate**, are administered via subcutaneous injection with maximum daily doses of 40 mg and 20 mg, respectively. **Metformin STADA®** 850 mg film-coated tablets, containing **metformin hydrochloride**, are administered orally with a maximum daily dose of 2550 mg over a treatment period of 96 weeks.

**AVONEX** 30 micrograms/0.5 ml solution for injection, containing **interferon beta-1a**, is administered via intramuscular injection with a maximum daily dose of 30 micrograms. **Kesimpta** 20 mg solution for injection in pre-filled syringe, containing **ofatumumab**, is administered via subcutaneous injection with a maximum daily dose of 20 mg. The placebo is manufactured to match the characteristics of Metformin Hydrochloride 850 mg tablets without containing the active ingredient and is used as a comparator in the study.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in walking speed, measured by the Timed 25-Foot Walk (T25FW) test, between baseline and 96 weeks of treatment. This will compare the control group receiving placebo with the intervention group receiving metformin.

Secondary endpoints include a variety of measures to evaluate different aspects of disease progression and patient well-being. These include:

• Change in the Expanded Disability Status Scale (EDSS) between baseline and 96 weeks.
• Change in cognitive function as measured by the Symbol Digit Modalities Test (SDMT) over the same period.
• Change in hand function assessed by the Nine-Hole Peg Test (9HPT).
• Change in the Composite endpoint as measured by the Overall Disability Response Score (ODRS).
• Change in the 2-minute walk test.
• Change in brain volume, including whole brain and gray matter volume, as measured by MRI at various intervals (baseline to 48 weeks, baseline to 96 weeks, and 48 to 96 weeks).
• Change in brain MRI-DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD).
• Change in quality of life as measured by the EQ-5D-5L and the Multiple Sclerosis Impact Scale-29.
• Change in the number of SWI lesions and the Modified Caregiver Strain Index (MCSI).
• Average total costs and the incremental cost-effectiveness ratio over the treatment period.

These efficacy parameters will be collected and analyzed at specified time points, including baseline, 48 weeks, and 96 weeks, using validated scales and tests. The assessments will provide a comprehensive evaluation of the treatment's impact on disease progression and patient quality of life in individuals with non-active progressive multiple sclerosis.