Effect of Metformin on Patients With Osteoarthritis

Effect of Metformin on Tibiofemoral Cartilage Volume and Knee Symptoms Among Overweighted Knee Osteoarthritis patients-a Randomized Clinical Trial

This randomized controlled trial aims to investigate if metformin has osteoarthritis protective effects among overweighted knee osteoarthritis patients. The co-primary outcomes are changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Arthritis Index (WOMAC) from baseline to month 24. The secondary outcomes are changes in visual analog scale (VAS)-assessed knee pain, tibiofemoral cartilage defect, effusion-synovitis volume, and tibiofemoral bone marrow lesion maximum size from baseline to month 24.

Study Overview

• Status: Recruiting
• Conditions: Osteoarthritis
• Intervention / Treatment: Drug: Placebo; Drug: Metformin hydrochloride sustained release tablets

• Study Type: Interventional
• Enrollment (Anticipated): 262
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Guangfeng Ruan, Doctor; Phone Number: +86 13060627790; Email: ruan1989.ok@163.com

Study Locations

• China
  • Guangzhou, China, 510180
    • Recruiting
    • Guangzhou First People's Hospital
    • Contact: Guangfeng Ruan, Doctor; Phone Number: +86 13060627790; Email: ruan1989.ok@163.com
  • Guangzhou, China, 510282
    • Not yet recruiting
    • Liwan Central Hospital of Guangzhou
    • Contact: Aiju Lou, Doctor
  • Guangzhou, China, 510282
    • Not yet recruiting
    • Sun Yat-sen Memorial Hospital
    • Contact: Yingqian Mo, Doctor
  • Guangzhou, China, 510282
    • Not yet recruiting
    • Zhujiang Hospital
    • Contact: Yuan Qu, Doctor
  • Guangzhou
    • Foshan, Guangzhou, China
      • Not yet recruiting
      • Foshan First People's Hospital
      • Contact: Dongmei Guo, Master

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Meet the American College of Rheumatology (ACR) criteria for symptomatic knee osteoarthritis assessed by a rheumatologist;
2. Age 50 to 75 years;
3. Body mass index ≥ 24 kg/m2;
4. Knee pain ≥ 20 on a 100 mm visual analogue scale (VAS);
5. Able to listen, speak, read and understand Chinese; capable of understanding the study requirements and willing to cooperate with the study instructions; able to provide written, informed consent.

Exclusion Criteria:

1. Severe radiographic knee OA as grade 3 joint space narrowing according to the Osteoarthritis Research Society International (OARSI) atlas;
2. Severe knee pain as knee pain ≥ 80 on a 100 mm VAS;
3. Planned knee or hip surgery (including arthroscopy, joint replacement, and joint open operation) within 2 years;
4. Severe knee trauma history (including arthroscopy, severe injury of knee ligament or meniscus);
5. Contraindication to MRI scanning (e.g. implanted pacemaker, artificial metal valve or cornea, aneurysm clipping surgery, arterial dissection, metal foreign bodies in the eyeball, claustrophobia);
6. Other forms of inflammatory arthritis (e.g. rheumatoid arthritis, psoriatic arthritis);
7. Active malignant cancer or other life-threatening diseases;
8. Type 1 or type 2 diabetes mellitus;
9. Clinical manifestation of liver dysfunction or alanine aminotransferase/aspartate aminotransferase exceeding 2 times the upper limit of normal value;
10. Estimated glomerular filtration rate less than 60 ml/min/1.73 m2;
11. Hypoxic state (e.g. chronic heart insufficiency, acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, cor pulmonale, peripheral vascular disease);
12. Alcoholism;
13. Pregnancy or lactation;
14. Allergic to metformin hydrochloride;
15. Conditions affecting the absorption of oral drugs (e.g. postgastrectomy and malabsorption syndrome);
16. Use of metformin in recent 30 days or plan to use metformin in the next 2 years;
17. Use of investigational drug in recent 30 days.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Metformin hydrochloride sustained release tablet will administer orally in escalating doses to reduce side-effects and maintain masking: 0.5 g/day for the first two weeks, 1 g/day for the next 2 weeks, and then 2 g/day until the end of the study if tolerated. If the subject cannot tolerate the maximum dose (2 g/day), take their maximum tolerable dose. In case of adverse reaction, the researchers can determine whether the subject needs to reduce or stop the drug based on their discretion.	Drug: Metformin hydrochloride sustained release tablets; Oral
Placebo Comparator: Placebo; Placebo will administer the same as the experimental drug.	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of tibiofemoral cartilage volume from baseline to 24 months follow up	Cartilage volume will be automatically calculated based on a standardized view of 3D cartilage geometry by OsiriX software (University of Geneva, Geneva, Switzerland). The 3D cartilage geometry is composed from the 2D cartilage shapes, which are generated by drawing contours around the cartilage boundaries on section-by-section MR images. Tibiofemoral cartilage volume will be calculated as the sum of both the tibial and femoral compartments.	Baseline and 24 months follow up
Change of Western Ontario and McMaster Universities Osteoarthritis Index from baseline to 24 months follow up	The WOMAC system in a 100-mm visual analog format will be used to quantify the degree of knee pain (5 questions), joint stiffness (2 questions), and physical dysfunction (17 questions) during the last 7 days. The WOMAC score will be calculated by summing the score of each question (1 point for every 1 mm), and a higher score of WOMAC represents a severe OA symptom. The WOMAC score will be considered invalid and treated as missing data if more than 5 of the questions are not answered. In case no more than 5 items are missed, the remaining items will be averaged and then multiplied by 24 to create the WOMAC score.	Baseline and 3, 6, 12, 24 months follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of knee pain visual analog scale from baseline to 24 months follow up	The 100 mm VAS will be used to assess the knee pain during the last 7 days, and a higher VAS indicates a severe knee pain.	Baseline and 3, 6, 12, 24 months follow up
Change of tibiofemoral cartilage defect from baseline to 24 months follow up	Cartilage defects will be graded using a modified Outerbridge classification as follows: grade 0, normal cartilage; grade 1, focal blistering and intra-cartilaginous hyperintensity with a normal contour; grade 2, irregularities on the surface and loss of thickness of less than 50%; grade 3, deep ulceration with loss of thickness of more than 50% without exposure of subchondral bone; grade 4, full-thickness chondral wear with exposure of subchondral bone. Cartilage defects will be assessed at the medial tibial, medial femoral, lateral tibial, and lateral femoral compartments, and tibiofemoral cartilage defects will be obtained by summing the scores of the four compartments.	Baseline and 24 months follow up
Change of effusion-synovitis volume from baseline to 24 months follow up	Effusion-synovitis volume will be measured at suprapatellar pouch, central portion, posterior femoral recess, and subpopliteal recess according to the anatomy of the knee joint synovial cavity. Effusion synovitis will be isolated by selecting a region of interest with an intra-articular fluid-equivalent signal on the section-by-section 2D MR images. The volume of effusion-synovitis will be generated using OsiriX software. Total effusion-synovitis volume of the knee will be obtained by summing the volume of possible effusion synovitis in the four synovial cavities.	Baseline and 24 months follow up
Change of tibiofemoral bone marrow lesion maximum size from baseline to 24 months follow up	Bone marrow lesions is defined as discrete areas of increased signal in the subchondral bone. Bone marrow lesions maximum size will be assessed at the medial tibial, medial femoral, lateral tibial, and lateral femoral compartments. Slice with the greatest area of bone marrow lesions in a specific compartment will be chosen to assess bone marrow lesions maximum size of the corresponding compartment. Bone marrow lesions on adjacent slices will be measured and compared to locate the slice with the maximum lesion size. Tibiofemoral bone marrow lesions maximum size will be calculated by summing the maximum lesions size of the four compartments.	Baseline and 24 months follow up

Collaborators and Investigators

• Sponsor: Guangzhou First People's Hospital

Publications and helpful links

General Publications

• Ruan G, Yuan S, Lou A, Mo Y, Qu Y, Guo D, Guan S, Zhang Y, Lan X, Luo J, Mei Y, Zhang H, Wu W, Dai L, Yu Q, Cai X, Ding C. Can metformin relieve tibiofemoral cartilage volume loss and knee symptoms in overweight knee osteoarthritis patients? Study protocol for a randomized, double-blind, and placebo-controlled trial. BMC Musculoskelet Disord. 2022 May 21;23(1):486. doi: 10.1186/s12891-022-05434-2.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2021
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: August 25, 2021
• First Submitted That Met QC Criteria: September 2, 2021
• First Posted (Actual): September 5, 2021

Study Record Updates

• Last Update Posted (Actual): January 6, 2022
• Last Update Submitted That Met QC Criteria: December 16, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: K-2021-001-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No