03361nas a2200385   4500000000100000008004100001260002300042653005700065653002900122653001900151653001400170100001700184700001500201700001700216700001600233700000800249700001300257700001800270700001600288700001300304700001600317700001500333700001700348700001300365700001300378700001200391700001400403700001400417700001500431245019900446856005500645490000600700520225500706022001402961       2023                            d  bF1000 Research Ltd10aGeneral Biochemistry, Genetics and Molecular Biology10aMedicine (miscellaneous)10aStudy Protocol10aMetformin1 aKrismawati H1 aMuchtar SV1 aRahardjani M1 aOktaviani M1 a. S1 aImbiri N1 aHasvitasari D1 aFajrianti D1 aTarino N1 aWulandari F1 aKestelyn E1 avan Crevel R1 aWalker S1 aGeskus R1 aGeluk A1 aHamers RL1 aSoebono H1 aGrijsen ML00aMetformin as adjunctive therapy in combination with multidrug treatment for multibacillary leprosy: A protocol for a randomized double-blind, controlled Phase 2 trial in Indonesia (MetLep Trial)  uhttps://wellcomeopenresearch.org/articles/8-289/v10 v83 a<p><strong>Background:</strong> The clinical management of leprosy is complicated by leprosy reactions (LR) causing irreversible nerve damage and disabilities. LR often require long-term use of corticosteroids causing serious side effects. Adjunct host-directed therapy (HDT) is a potentially attractive strategy in leprosy to prevent LR and associated immunopathology, modulate immunological memory that protects against recurrence, and thereby reduce nerve damage, disability and corticosteroid-associated morbidities. Metformin, a well-tolerated, safe and cheap anti-hyperglycaemic drug, is repurposed as HDT in auto-immune and infectious diseases, like tuberculosis (TB). Metformin use in people with diabetes is associated with reduced risks of TB-infection, progression to active TB, treatment failure and TB-mortality. Given the similarities both mycobacteria share, we hypothesize that among persons with multibacillary (MB) leprosy, adjunctive metformin may prevent/mitigate LR.</p>

<p><strong>Methods:</strong> We will perform a double-blind controlled proof-of-concept trial in which people with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin hydrochloride 1000mg extended release once daily versus placebo for 24 weeks in addition to standard-of-care WHO MB multidrug therapy (MDT) during 48 weeks. We aim to enrol 166 participants aged between 18 and 65 years, across five clinical sites in two leprosy endemic areas in Indonesia. Primary endpoints are the proportion of participants experiencing a LR and the frequency of (serious) adverse events. Secondary endpoints are the severity and time to first LR, the number of LR, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks.</p>

<p><strong>Discussion: </strong>LR signify the most important cause of irreversible nerve damage leading to anatomical deformities and disabilities, imposing a social and financial burden on those affected. Our study aims to evaluate the efficacy, tolerability and safety of adjunct metformin added to MDT in persons with multibacillary leprosy, and explore its effects on clinical and immunological endpoints. ClinicalTrials.gov registration: NCT05243654 (17/02/2022)</p>
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