Clinical trial NCT04068246: The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients
Official title: 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: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Rheumatoid Arthritis
Lead sponsor: Sadat City University
Sponsor class: OTHER
First posted: 2019-08-28
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: ACR 20% improvement criteria (ACR20) response rate
timeFrame: week 12
measure: ACR50 & ACR70 response rate
timeFrame: week 12
measure: Disease activity scale in 28 joints (DAS-28)
timeFrame: week 12
Secondary outcomes:
measure: the Short Form 36 (SF-36) Health Survey
timeFrame: week 12
measure: HAQ-DI (Health Assessment Score- Disability index)
timeFrame: week 12
measure: AMPK expression
timeFrame: at baseline and at week 12
measure: IGF-IR expression
timeFrame: at baseline and at week 12
measure: TNF-α
timeFrame: at baseline and at week 12
measure: TGF-Beta1
timeFrame: at baseline and at week 12
measure: Inteleukins
timeFrame: at baseline and at week 12
measure: CRP
timeFrame: at baseline and at week 12
measure: Drug Adverse effects
timeFrame: 3 months
Other outcomes:
Locations:
city: Shibīn Al Kawm
country: Egypt
facility: Faculty of Pharmacy
state: Menoufia
Study officials:
References:
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.