The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Patients With Knee Osteoarthritis

The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Patients With Knee Osteoarthritis: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

metformin alleviates drug-induced osteoarthritis (OA)-like change in mice knee joint through activating autophagy and downregulating apoptosis. Metformin exerts its protective effects against OA through the AMPKa2/ SIRT1 pathway. Metformin suppresses IL-1β-induced oxidative and osteoarthritis-like inflammatory changes by enhancing the SIRT3/PINK1/Parkin signaling pathway, thereby indicating metformin's potential in prevention and treatment of osteoarthritic joint disease.

Study Overview

• Status: Recruiting
• Conditions: Osteo Arthritis Knee
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Egypt
  • Menoufia
    • Shibīn Al Kawm, Menoufia, Egypt, 13829
      • Recruiting
      • Faculty of pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 58 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Primary osteoarthritis Patients recruited were between 30 to 60 years of age, with X-ray confirmed Kellgren-Lawrence grade13 II or III severity primary tibiofemoral OA, according to the American College of Rheumatology criteria.

Exclusion Criteria:

Those patients were excluded from the present study who:

• were of age less than 30 years or more than 60 years
• presented with active concomitant gastroduodenal disorders, hepatic and renal impairment within last 30 days prior to receiving the study drug
• were diagnosed to have any inflammatory arthritis, gout or acute trauma of the knee, hip or spine; accompanying OA of the hip of sufficient severity to interfere with the functional assessment of the knee
• had previous or ongoing treatment with oral SYSDOA (e.g., glucosamine sulphate, chondroitin sulphate, diacerein, piascledine), anti-depressants, tranquillisers, antacids or antibiotics; were having active cardiac lesion or hypertension, were pregnant females and those who were planning their pregnancy during the study
• were having a known hypersensitivity to the used medications
• have persistent diarrhoea or laxative use; severe gastrointestinal disorders, severe obesity, severe parenchymal organ disease, or anaemia (haemoglobin< 10.0 g/ dl or haematocrit < 30%).
• Patients who received oral, intramuscular, intraarticular or soft tissue injections of corticosteroids within last eight weeks before receiving the first dose of the study medication, or had undergone joint lavage and arthroscopic procedures in the previous 6 months, were also excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Metformin 1000 mg daily plus Celecoxib 200mg capsule	Drug: Metformin; Metformin 1000mg tablet plus celecoxib 200 mg capsule
Experimental: Placebo; Placebo tablet daily plus Celecoxib 200mg capsule	Drug: Placebo; Placebo tablet plus celecoxib 200 mg capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analogue scale assessment of pain	the change of Visual Analogue Scale (VAS) pain score from baseline to posttreatment	week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
WOMAC change	the change of WOMAC Osteoarthritis Index from baseline to posttreatment	week 12
the change of Short Form 36 Questionnaire (SF-36) score from baseline to posttreatment	The SF-36 is a generic instrument to assess health-related quality of life. It consists of 36 questions and assesses 8 dimensions: physical functioning, role physical, pain index, general health, vitality, social functioning, role emotional, and mental health index. It also provides 2 summary measures of physical and mental components. The SF-36 score ranges from 0 to 100, with higher scores indicating better health status.	week 12
Adverse drug reaction	Clinical side effects	12 weeks
AMPK expression	AMPK gene expression	12 weeks
Serum level Tumor necrosis factor- alpha (TNF-α)	Serum level Tumor necrosis factor- alpha (TNF-α)	12 weeks
Serum levels of IL-1β	Serum levels of IL-1β	12 weeks
IL-17	Serum levels of IL-17	12 weeks

Collaborators and Investigators

• Sponsor: Sadat City University

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2021
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: February 16, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 23, 2021

Study Record Updates

• Last Update Posted (Actual): April 11, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 10/2021RHU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No