Clinical trial NCT05298670: Drug Repurposing Using Metformin for Improving the Therapeutic Outcome in Multiple Sclerosis Patients
Official title: Drug Repurposing Using Metformin for Improving the Therapeutic Outcome in Multiple Sclerosis Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Multiple Sclerosis
Lead sponsor: German University in Cairo
Sponsor class: OTHER
First posted: 2022-03-28
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate the effect of Metformin as add- on therapy for improving the outcome in RRMS patients.

Detailed description: Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection. Worldwide, there are about 2.3 million MS patients. Women are twice as likely to have MS as men. MS typically presents in young adults (mean age of onset, 20-30 years) and can lead to physical disability, cognitive impairment, and decreased quality of life.

The four main types of multiple sclerosis are clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). This research focuses on RRMS as it is the most common type (80%- 85%).

Elevated level of Interleukins, and oxidative stress parameters are associated with MS pathology which exaggerated the myelin destruction, axonal degradation, and inflammatory cascade.

Metformin has a global safety record, is well-tolerated by the majority of patients and is used by roughly 125 million people worldwide, so a lot of studies inside and outside Egypt investigates their potential effect in different disorders as neurodegenerative diseases and cancer. Despite the prevalence of animal studies which explored Metformin neuroprotective effects by decreasing T- helper cells (Th 1 and Th 17) and improving Oligodendrocyte progenitor cell responsiveness to induce remyelination, clinical trials are still insufficient which motivate us to investigate the promising effect of Metformin as add-on treatment in RRMS patients

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 50 years at time of signing informed consent form.
* Relapsing- remitting multiple sclerosis as per the McDonald 2017 criteria, including an MRI brain satisfying the 2017 radiological criteria.
* Full-field visual evoked potential (VEP) P100 latency in at least one eye of ≥118 ms.
* Kurtzke EDSS step 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.

Exclusion Criteria:

* People taking medication for Diabetes Mellitus at screening.
* Female participants who are pregnant, lactating, planning pregnancy, or unwilling to use reliable contraception during the trial.
* Significant liver impairment; alanine aminotransferase \> 3 times the upper limit of normal.
* People suffering from congestive heart failure, chronic lung disease with hypoxia, and severe anemia.
* Patients with compromised renal function ((eGFR \<60 mL/min/1.73m2) or coexistent hypoxic conditions should not be given metformin.
* Chronic or acute intake of large amounts of alcohol may potentiate the effect of metformin on lactate metabolism.
* Patients had been prescribed oral, intravenous, and intramuscular corticosteroids for one month prior to study.

Primary outcomes:
measure: Change in IL17 in both arms as measured by ELISA.
timeFrame: After 6 months
Secondary outcomes:
measure: Percentage of Quality of Life deterioration in both arms measured by MSQOL-54.
timeFrame: After 6 months
measure: Change in IL22 in both arms as measured by ELISA.
timeFrame: After 6 months
measure: Malondialdehyde in both arms as measured by Colorimetric tests.
timeFrame: After 6 months
measure: Degree of remyelination visualized by MRI, it depends on clinician's overview.
timeFrame: After 6 months
measure: Degree of disability assessed by Expanded Disability Status Scale.
timeFrame: After 6 months
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Nasser Institute for Research and Treatment
Study officials:
References:
citation: Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011 Sep;9(3):409-16. doi: 10.2174/157015911796557911.
citation: Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, Thompson AJ. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014 Sep 9;83(11):1022-4. doi: 10.1212/WNL.0000000000000768. No abstract available.
citation: Sormani MP, De Rossi N, Schiavetti I, Carmisciano L, Cordioli C, Moiola L, Radaelli M, Immovilli P, Capobianco M, Trojano M, Zaratin P, Tedeschi G, Comi G, Battaglia MA, Patti F, Salvetti M; Musc-19 Study Group. Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis. Ann Neurol. 2021 Apr;89(4):780-789. doi: 10.1002/ana.26028. Epub 2021 Feb 9.
citation: Pegoretti V, Swanson KA, Bethea JR, Probert L, Eisel ULM, Fischer R. Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development. Oxid Med Cell Longev. 2020 May 12;2020:7191080. doi: 10.1155/2020/7191080. eCollection 2020.
citation: Negrotto L, Farez MF, Correale J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016 May 1;73(5):520-8. doi: 10.1001/jamaneurol.2015.4807.
citation: Triggle CR, Ding H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium. Acta Physiol (Oxf). 2017 Jan;219(1):138-151. doi: 10.1111/apha.12644. Epub 2016 Jan 13.
citation: Sportelli C, Urso D, Jenner P, Chaudhuri KR. Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson's Disease-Viewpoint. Front Neurol. 2020 Jun 12;11:556. doi: 10.3389/fneur.2020.00556. eCollection 2020.
citation: Demare S, Kothari A, Calcutt NA, Fernyhough P. Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system. Expert Rev Neurother. 2021 Jan;21(1):45-63. doi: 10.1080/14737175.2021.1847645. Epub 2020 Dec 4.
citation: Shi Q, Liu S, Fonseca VA, Thethi TK, Shi L. Effect of metformin on neurodegenerative disease among elderly adult US veterans with type 2 diabetes mellitus. BMJ Open. 2019 Jul 30;9(7):e024954. doi: 10.1136/bmjopen-2018-024954.
citation: Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011 Apr 6;9:33. doi: 10.1186/1741-7015-9-33.
citation: Brown JR, Chan DK, Shank JJ, Griffith KA, Fan H, Szulawski R, Yang K, Reynolds RK, Johnston C, McLean K, Uppal S, Liu JR, Cabrera L, Taylor SE, Orr BC, Modugno F, Mehta P, Bregenzer M, Mehta G, Shen H, Coffman LG, Buckanovich RJ. Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer. JCI Insight. 2020 Jun 4;5(11):e133247. doi: 10.1172/jci.insight.133247.
citation: Ayoub R, Ruddy RM, Cox E, Oyefiade A, Derkach D, Laughlin S, Ades-Aron B, Shirzadi Z, Fieremans E, MacIntosh BJ, de Medeiros CB, Skocic J, Bouffet E, Miller FD, Morshead CM, Mabbott DJ. Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin. Nat Med. 2020 Aug;26(8):1285-1294. doi: 10.1038/s41591-020-0985-2. Epub 2020 Jul 27.
citation: El-Khayat SM, Abouegylah M, Abdallah D, Geweil AG, Elenbaby AM, Zahra OS. The effect of metformin when combined with neoadjuvant chemotherapy in breast cancer patients. Med Oncol. 2021 Nov 5;39(1):1. doi: 10.1007/s12032-021-01599-3.
citation: El-Fatatry BM, Ibrahim OM, Hussien FZ, Mostafa TM. Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study. Int J Colorectal Dis. 2018 Dec;33(12):1675-1683. doi: 10.1007/s00384-018-3104-9. Epub 2018 Jun 21.
citation: Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, Foerster S, McClain CR, Chalut K, van Wijngaarden P, Franklin RJM. Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells. Cell Stem Cell. 2019 Oct 3;25(4):473-485.e8. doi: 10.1016/j.stem.2019.08.015.
citation: Houshmand F, Barati M, Golab F, Ramezani-Sefidar S, Tanbakooie S, Tabatabaei M, Amiri M, Sanadgol N. Metformin-induced AMPK activation stimulates remyelination through induction of neurotrophic factors, downregulation of NogoA and recruitment of Olig2+ precursor cells in the cuprizone murine model of multiple sclerosis. Daru. 2019 Dec;27(2):583-592. doi: 10.1007/s40199-019-00286-z. Epub 2019 Oct 16.
citation: Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995 Jun;4(3):187-206. doi: 10.1007/BF02260859.
citation: Abdallah MS, Alarfaj SJ, Saif DS, El-Naggar ME, Elsokary MA, Elsawah HK, Abdelsattar Zaki S, Wahsh EA, Abo Mansour HE, Mosalam EM. The AMPK modulator metformin as adjunct to methotrexate in patients with rheumatoid arthritis: A proof-of-concept, randomized, double-blind, placebo-controlled trial. Int Immunopharmacol. 2021 Jun;95:107575. doi: 10.1016/j.intimp.2021.107575. Epub 2021 Mar 24.