Clinical trial NCT05243654: Efficacy and Tolerability of Adjunct Metformin for Multibacillary Leprosy
Official title: Efficacy and Tolerability of Adjunct Metformin in Combination With Multidrug Treatment for Multibacillary Leprosy: A Randomized Double-blind, Controlled Proof-of-Concept Phase 2 Trial in Indonesia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Leprosy
Leprosy, Multibacillary
Neglected Tropical Diseases
Keywords: Leprosy
Multibacillary leprosy
Skin-NTD
Lead sponsor: Eijkman Oxford Clinical Research Unit, Indonesia
Sponsor class: OTHER
Collaborators: name: University of Gadjah Mada, Faculty of Medicine
name: University of Diponegoro
name: Papua Agency of Health Research and Development (NIHRD)
name: London School of Hygiene and Tropical Medicine
name: Radboud University Medical Center
name: Oxford University Clinical Research Unit
First posted: 2022-02-17
Enrollment: 166
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-center, randomized double-blind, controlled phase 2 proof-of-concept trial. Subjects will be randomised 1:1 ratio to receive metformin 1000 mg XR tablets OD or matching placebo for 24 weeks. Randomization will be stratified by BI (BI ≥ or \< 4) and participating study site.
Primary purpose: TREATMENT

Brief summary: This trial aims to evaluate the efficacy, tolerability and safety of adjunct metformin added to standard-of-care multi-drug therapy (MDT) in patients with multibacillary leprosy, and explore its effects on immunological endpoints. A double-blind, placebo controlled proof-of-concept trial will be performed in which patients with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin 1000mg OD versus placebo for 24 weeks in addition to MDT during 48 weeks.

The main research question is whether adjunctive metformin, combined with MDT, will improve the clinical outcomes of patients with multibacillary leprosy by mitigating leprosy reactions, thereby reducing nerve damage and corticosteroid use and its associated morbidity. The second aim is to explore whether adjunct metformin, added to MDT, has an acceptable tolerability and safety in patients with multibacillary leprosy.

Detailed description: A double-blind, placebo-controlled randomized proof-of-concept Phase 2 trial will be performed evaluating the efficacy, safety and tolerability of adjunct metformin combined with standard of care MDT to mitigate leprosy reactions. Patients with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin 1000mg OD versus placebo for 24 weeks in addition to MDT during 48 weeks. The trial aims to enroll 166 patients, aged between 18-65 years old, in leprosy endemic areas in Indonesia. Primary endpoints are the proportion of participants experiencing a leprosy reaction during the full duration of the study and the proportion of participants with at least one adverse event within the first 28 weeks of the study. Secondary endpoints are the severity and time to first leprosy reaction, the number of leprosy reactions, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks.

This METLEP trial is financially supported by the Leprosy Research Initiative (grant number: FP20\\4).

Eligibility criteria: Inclusion Criteria:

* Participant is a male or female, aged ≥18 and ≤65 years.
* Participant is newly diagnosed with MB leprosy and has been receiving MDT ≤ 28 days.
* Participant is willing and able to give informed consent for participation in the trial.
* Participant is willing to adhere to study follow-up schedule for 48 weeks.

Exclusion Criteria:

* Participant has received MDT \>28 days for the current episode of MB leprosy, prior to study enrolment.
* Presence of leprosy reaction and/or nerve function impairment requiring systemic corticosteroids on screening/enrolment evaluation.
* Participants who have been treated for leprosy in the past.
* Chronic systemic corticosteroid use for any other medical condition on screening evaluation (chronic use defined as ≥ 2 weeks).
* History of diabetes mellitus or diabetes mellitus diagnosed on screening evaluation (random blood glucose is elevated ≥200 mg/dL (or ≥11,1 mmol/L) or fasting blood glucose ≥ 126 mg/dL (or ≥7.0 mmol/L)).
* History of hypoglycaemia (random blood glucose \<55 mg/dL (or \<3.0 mmol/L).
* History of cardiac failure, ischaemic heart disease, alcoholism, history of lactic acidosis or states associated with lactic acidosis such as shock or pulmonary insufficiency, and conditions associated with hypoxia.
* History of intolerance or hypersensitivity to metformin.
* Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m2 calculated by the CKDEPI equation.
* AST or ALT ≥3 times the upper limit of normal (ULN) on screening evaluation.
* Any serious medical condition for which participation in the trial, as judged by the investigator or treating physician, could compromise the well-being of the subject or prevent, limit or confound protocol-specified assessments.
* HIV-positive on screening evaluation.
* Female participant who is pregnant (clinically confirmed or urine dipstick for human chorionic gonadotrophin hormone) or breastfeeding.
* Use of metformin within 12 weeks prior to study enrolment.
* Use of other regular hypoglycaemic agents, including insulin.
* Participation in another research trial involving an investigational product within 12 weeks prior to study enrolment.

Primary outcomes:
measure: The proportion of participants experiencing a leprosy reaction
timeFrame: 48 weeks
measure: The proportion of participants with at least one adverse events
timeFrame: 28 weeks
Secondary outcomes:
measure: The proportion of participants experiencing a Type 1 Reactions (T1R)
timeFrame: 12, 24 and 48 weeks
measure: The proportion of participants experiencing a Type 2 Reactions (T2R)
timeFrame: 12, 24 and 48 weeks
measure: The time to the first leprosy reaction
timeFrame: 48 weeks
measure: The time to the first Type 1 Reactions (T1R)
timeFrame: 48 weeks
measure: The time to the first Tipe 2 Reaction (T2R)
timeFrame: 48 weeks
measure: The difference in the number of T1R episodes
timeFrame: 48 weeks
measure: The difference in the number of T2R episodes
timeFrame: 48 weeks
measure: The severity of T1R, based on investigator-assessed validated Clinical Severity Scores
timeFrame: 48 weeks
measure: The severity of T2R, based on investigator-assessed validated Clinical Severity Scores
timeFrame: 48 weeks
measure: The proportion of participants with at least one serious adverse event
timeFrame: 28 weeks
measure: Total number of adverse events
timeFrame: 28 weeks
measure: The cumulative corticosteroid usage
timeFrame: 48 weeks
measure: The proportion of participants experiencing clinical nerve function impairment
timeFrame: 48 weeks
measure: The difference in Quality of Life between start and end of treatment intervention, and end of study by means of SF-36 questionnaires
timeFrame: 24 and 48 weeks
measure: The difference in Quality of Life between start and end of treatment intervention, and end of study by means of the Dermatology Life Quality Index (DLQI) questionnaires.
timeFrame: 24 and 48 weeks
Other outcomes:
Locations:
city: Jayapura
country: Indonesia
facility: Abe Pantai Community Health Center
state: Papua
city: Jayapura
country: Indonesia
facility: Hamadi Community Health Center
state: Papua
city: Jayapura
country: Indonesia
facility: Jayapura Utara Community Health Center
state: Papua
city: Makassar
country: Indonesia
facility: Palangga Health Center
state: Sulawesi Selatan
city: Makassar
country: Indonesia
facility: Bajeng Health Center
state: Sulawesi Selatan
Study officials:
affiliation: Center of Tropical Medicine, University of Gadjah Mada
name: Hardiyanto Soebono, Prof.Dr.dr
role: PRINCIPAL_INVESTIGATOR
References: