The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients

Overview

Metformin, a traditional antidiabetic medication, exerts glucose lowering effects by activating AMP-activated protein kinase (AMPK), a critical enzyme involved in the lipid and glucose metabolism. In addition to the antidiabetic effect, metformin has been shown to inhibit Lipopolysaccharide-Induced Inflammation (LPS)-induced inflammation by suppress NF-κB production, which is also regulated by AMPK. These regulatory effects of AMPK on the inflammation, immune and fibroblast-like synovial cells have prompted the investigation on the effects of metformin on rheumatoid arthritis.

Full Title of Study: “The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: December 31, 2020

Detailed Description

Rheumatoid arthritis (RA) is a chronic, multisystem inflammatory disorder of unknown etiology. It is characterized by polyarthritis and systemic inflammation. The inflammation in the hyperplastic synovium can destruct the structure of affected joints. Although the exact molecular mechanism underlying the pathogenesis of RA remains unknown, it is suggested that T helper cell (Th) 17 plays a central role. Interleukin (IL)-17, mostly secreted by Th17, has synergistic effects with tumor necrosis factor- (TNF-α), IL-1β and IL-6 in cases of RA. Metformin, a traditional antidiabetic medication, exerts glucose lowering effects by activating AMP-activated protein kinase (AMPK), a critical enzyme involved in the lipid and glucose metabolism. In addition to the antidiabetic effect, metformin has been shown to inhibit Lipopolysaccharide-Induced Inflammation (LPS)-induced inflammation by suppress NF-κB production, which is also regulated by AMPK . In addition, metformin activated AMPK may inhibit mammalian target of rapamycin (mTOR), which then regulate the differentiation of T cells in vitro and in vivo. In particular, AMPK has been reported to be associated with the inhibition of TH17 cells through suppressing the phosphorylation of mTOR and its downstream signal transducers, suggesting the therapeutic potential of AMPK agonists. Besides the imbalance between Th17 cells and Treg cells is responsible for the chronic inflammation in RA, synovium hyperplasia also plays a central role in the joint destruction. It has been reported that rapamycin, an inhibitor of mTOR, is able to significantly reduce fibroblastlike synovial cell invasion in RA via suppressing mTOR signaling pathway. These regulatory effects of AMPK on the inflammation, immune and fibroblast-like synovial cells have prompted the investigation on the effects of metformin on rheumatoid arthritis.

Interventions

  • Drug: Metformin
    • 1000 mg of Metformin table taken orally daily plus Methotrexate 7.5 mg weekly
  • Drug: Placebo
    • Placebo tablet plus plus Methotrexate 7.5 mg weekly

Arms, Groups and Cohorts

  • Placebo Comparator: Control group
    • patients will receive the standard therapy (methotrexate) plus placebo tablets
  • Experimental: Metformin group
    • patients will receive the standard therapy plus 1 g metformin daily.

Clinical Trial Outcome Measures

Primary Measures

  • ACR 20% improvement criteria (ACR20) response rate
    • Time Frame: week 12
    • based on tender and swollen joint counts, patient’s assessment of pain, patient and physician global assessment of arthritis, Health Assessment Questionnaire Disability Index (HAQ DI), and CRP level
  • ACR50 & ACR70 response rate
    • Time Frame: week 12
    • based on tender and swollen joint counts, patient’s assessment of pain, patient and physician global assessment of arthritis, Health Assessment Questionnaire Disability Index (HAQ DI), and CRP level
  • Disease activity scale in 28 joints (DAS-28)
    • Time Frame: week 12
    • Scale assessing severity of rheumatoid arthritis based on number of tender, swollen joints, erythrocyte sedimentation rate (ESR) levels, and patient self-assessment of his condition (global health assessment). Whereas “28” describes the number of different joints including in the measurement: proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2), knees (2).

Secondary Measures

  • the Short Form 36 (SF-36) Health Survey
    • Time Frame: week 12
    • both the physical component score [PCS] and the mental component score [MCS])
  • HAQ-DI (Health Assessment Score- Disability index)
    • Time Frame: week 12
    • HAQ-DI (Health Assessment Score- Disability index), in which patients are asked to rate their capacity to perform 20 activities of daily living (ADL). Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section the score given to that section is the worst score within the section
  • AMPK expression
    • Time Frame: at baseline and at week 12
    • AMPK expression in synovium or serum
  • IGF-IR expression
    • Time Frame: at baseline and at week 12
    • IGF-IR expression in Blood
  • TNF-α
    • Time Frame: at baseline and at week 12
    • Serum level Tumor necrosis factor- alpha (TNF-α)
  • TGF-Beta1
    • Time Frame: at baseline and at week 12
    • Serum level tissue growth factor beta 1
  • Inteleukins
    • Time Frame: at baseline and at week 12
    • Serum levels of Interleukins (IL) IL-17, IL-1β , IL-6 & IL-10
  • CRP
    • Time Frame: at baseline and at week 12
    • Serum level of C-reactive protein (CRP)
  • Drug Adverse effects
    • Time Frame: 3 months
    • Adverse effect incidence: adverse effect will be reported by patients or their caregivers and recorded by investigator.

Participating in This Clinical Trial

Inclusion Criteria

  • Patients with active rheumatoid arthritis based on DAS28 score. Patients received the standard therapy (i.e. one or more conventional DMARDs) for at least three months. Exclusion Criteria:

  • Known hypersensitivity to metformin. – Patients who have a prior diagnosis with diabetes mellitus. – Patients receive metformin for any other indications. – Patients with congestive heart failure. – Patients with a history of myocardial infarction. – Patients with severe anemia. – Patients with active infections or other inflammatory diseases. – Patients receiving biological therapy. – Pregnancy or lactation. – Patients with impaired liver functions. – Patients with impaired kidney functions (serum creatinine concentrations ≥1.5 and ≥1.4 mg/dL in males and females respectively). – Patients with malignancies.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Sadat City University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Mahmoud Samy Abdallah, Lecturer of Clinical Pharmacy, PhD. – Sadat City University

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