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

Rheumatoid Arthritis Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04068246
• Other study ID #: PMRR-8-2019
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 1, 2019
• Est. completion date: February 28, 2021

Study information

• Verified date: October 2022
• Source: Sadat City University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: February 28, 2021
• Est. primary completion date: December 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

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

Locations

Country	Name	City	State
Egypt	Faculty of Pharmacy	Shibin Al Kawm	Menoufia

Sponsors (1)

Lead Sponsor	Collaborator
Sadat City University

Country where clinical trial is conducted

Egypt, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ACR 20% improvement criteria (ACR20) response rate	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	week 12
Primary	ACR50 & ACR70 response rate	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	week 12
Primary	Disease activity scale in 28 joints (DAS-28)	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).	week 12
Secondary	the Short Form 36 (SF-36) Health Survey	both the physical component score [PCS] and the mental component score [MCS])	week 12
Secondary	HAQ-DI (Health Assessment Score- Disability index)	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	week 12
Secondary	AMPK expression	AMPK expression in synovium or serum	at baseline and at week 12
Secondary	IGF-IR expression	IGF-IR expression in Blood	at baseline and at week 12
Secondary	TNF-a	Serum level Tumor necrosis factor- alpha (TNF-a)	at baseline and at week 12
Secondary	TGF-Beta1	Serum level tissue growth factor beta 1	at baseline and at week 12
Secondary	Inteleukins	Serum levels of Interleukins (IL) IL-17, IL-1ß , IL-6 & IL-10	at baseline and at week 12
Secondary	CRP	Serum level of C-reactive protein (CRP)	at baseline and at week 12
Secondary	Drug Adverse effects	Adverse effect incidence: adverse effect will be reported by patients or their caregivers and recorded by investigator.	3 months

External Links

•   The AMPK modulator metformin as adjunct to methotrexate in patients with rheumatoid arthritis: A proof-of-concept, randomized, double-blind, placebo-controlled trial