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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT04068246
Other study ID # PMRR-8-2019
Secondary ID
Status Completed
Phase Phase 1/Phase 2
First received
Last updated
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
Health authority
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.

Study Design


Related Conditions & MeSH terms


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
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