L-arginine for Knee Osteoarthritis Patients

Study Overview
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Brief Summary
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This study will examine the pain-relief efficacy and safety of L-arginine in knee OA patients.

Detailed Description
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Pain is the dominant symptom of knee osteoarthritis (KOA). The main management goal for people with KOA is to control pain without increasing treatment-related adverse effects (AEs). However, the commonly prescribed systemic analgesics have safety concerns, such as increased risk of cardiovascular and gastrointestinal AEs. Therefore, it is urgent to develop safe and effective treatment options. L-arginine is one of the most commonly used oral nutritional supplements that has been widely used in patients with peripheral arterial disease, cystic fibrosis, and pregnant women with high risk of pre-eclampsia. The supplement has a high safety profile. Previous case-control and cross-sectional studies have found plasma L-arginine levels were lower in patients with knee OA than controls, suggesting that arginine deficiency may increase the risk of OA. The investigators previously observed an inverse dose-response relationship between levels of serum L-arginine and the risk of incident symptomatic KOA. Additionally, the investigators demonstrated that intra-articular injection of L-arginine solution relieved pain symptoms in a surgical rat model of OA. However, there is a paucity of high-quality clinical evidence on the effect of intake of L-arginine supplement on pain relief among patients with symptomatic KOA. The investigators propose to conduct a randomized, double-blind, placebo-controlled trial to examine the efficacy and safety of oral L-arginine in patients with knee OA.

Official Title
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Efficacy and Safety of Oral L-Arginine for Pain Relief in Knee Osteoarthritis: a Randomized, Double-Blind, Placebo-Controlled Trial

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Dietary Supplement: L-arginine tablet
* Dietary Supplement: Placebo tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 40 and 80 years. Knee OA according to the American College of Rheumatology (ACR) clinical criteria. Knee pain lasting 3 months or longer and a score of 7 or greater on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (standardized to range from 0-20). Kellgren-Lawrence (KL) grade 2 or 3. Willing to and able to provide written informed consent. Exclusion Criteria: Any use of NSAIDs or other analgesics in the past two weeks. History of injections of corticosteroids in the past three months or hyaluronic acid in the past 6 months in the index knee. History of arthroscopy or open surgery in the index knee in the past 12 months. History of a knee replacement in the index knee or planning to receive such a procedure within 3 months. History of a severe injury in the index knee. Pain in the index knee caused by inflammatory, autoimmune, neoplastic diseases or other diseases. Abnormal liver or kidney functions, as defined by alanine transaminase or aspartate aminotransferase >two times the upper limit of normal, or blood urea nitrogen or serum creatinine >two times the upper limit of normal. Severe respiratory diseases. History of coronary artery disease and heart failure. Uncontrolled hypertension or diabetes mellitus. Diagnosis of malignant tumors. Pregnant or contemplating pregnancy or breast-feeding.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral L-arginine<br>Participants in the intervention arm will receive oral L- arginine tablets, 2 g three times daily | Dietary Supplement: L-arginine tablet<br>* L-arginine, 2 g, three times daily, for 12 weeks<br>|
| Placebo Comparator: Placebo<br>The control group will receive an identical inert placebo tablet, three times daily | Dietary Supplement: Placebo tablet<br>* Identical inert placebo, three times daily, for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. | WOMAC is a self-administered, disease-specific questionnaire that assesses the severity of OA symptoms. The reliability and validity of WOMAC have been confirmed in many clinical trials. WOMAC subscales consist of pain (5 items), stiffness (2 items), and physical function (17 items). Each item is rated from 0 to 4, totaling scores of 0-20, 0-8, and 0-68 for pain, stiffness, and function subscales, respectively. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC pain score. | WOMAC is a self-administered, disease-specific questionnaire that assesses the severity of OA symptoms. The reliability and validity of WOMAC have been confirmed in many clinical trials. WOMAC subscales consist of pain (5 items), stiffness (2 items), and physical function (17 items). Each item is rated from 0 to 4, totaling scores of 0-20, 0-8, and 0-68 for pain, stiffness, and function subscales, respectively. | Baseline, Weeks 2, 4, 6, 8 and 10 | 
| Knee pain on a visual analogue scale (VAS). | Knee pain will be graded by a VAS from 0 to 100 mm, with 0 indicating No pain and 100 indicating Worst possible pain. | Baseline, Weeks 2, 4, 6, 8, 10, and 12 | 
| Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score. | WOMAC is a self-administered, disease-specific questionnaire that assesses the severity of OA symptoms. The reliability and validity of this index have been confirmed in many clinical trials. WOMAC subscales consist of pain (5 items), stiffness (2 items), and physical function (17 items). Each item is rated from 0 to 4, totaling scores of 0-20, 0-8, and 0-68 for pain, stiffness, and function subscales, respectively. | Baseline, Weeks 2, 4, 6, 8, 10, and 12 | 
| WOMAC stiffness score. | WOMAC is a self-administered, disease-specific questionnaire that assesses the severity of OA symptoms. The reliability and validity of WOMAC have been confirmed in many clinical trials. WOMAC subscales consist of pain (5 items), stiffness (2 items), and physical function (17 items). Each item is rated from 0 to 4, totaling scores of 0-20, 0-8, and 0-68 for pain, stiffness, and function subscales, respectively. | Baseline, Weeks 2, 4, 6, 8,10, and 12 | 
| WOMAC function score. | WOMAC is a self-administered, disease-specific questionnaire that assesses the severity of OA symptoms. The reliability and validity of WOMAC have been confirmed in many clinical trials. WOMAC subscales consist of pain (5 items), stiffness (2 items), and physical function (17 items). Each item is rated from 0 to 4, totaling scores of 0-20, 0-8, and 0-68 for pain, stiffness, and function subscales, respectively. | Baseline, Weeks 2, 4, 6, 8, 10 and 12 | 
| Patient global assessment of osteoarthritis (PGA-OA). | PGA-OA score will be assessed using a 100 mm visual analogue scale (higher is worse). | Baseline, Weeks 2, 4, 6, 8, 10 and 12 | 
| SF-12 questionnaire. | The SF-12 Quality of Life questionnaire includes 8 multi-item domains (physical function, social function, role-emotional, role-physical, bodily pain, general health, mental health, and vitality). These can be combined into 2 summary measures (physical and mental component summary measures). | Baseline, Weeks 2, 4, 6, 8, 10 and 12 | 
| Timed Up and Go Test (TUG). | TUG is a functional performance measure specifically studied in persons with OA of the hip and knee, which directly evaluates an individual's ability to transfer, ambulate, and maintain balance during transitions. The TUG assesses the time it takes participants to get up from a standard-height chair, walk 3 m, turn and return to the chair, and sit down again. The TUG has good interrater and intrarater reliability and validity for functional testing in older adults. | Baseline, Weeks 4, 8, and 12 | 
| 20-m Walk Test. | The 20-m walk test has been recommended to assess physical function in individuals with knee OA. Participants will be instructed to walk at their usual walking speed from the start to finish points of a marked 20-m distance. | Baseline, Weeks 4, 8, and 12 | 
| Chair-stand Test. | The chair-stand test will use a standard chair with a 47-cm seat height. Participants start the test seated, with arms crossed over the chest, and are instructed to rise to a full stand and return to the initial seated position as many times as possible in 30 seconds. The total number of completed chair stands is averaged across two trials and used for analysis. A greater number of chair stand repetitions is interpreted as better performance. | Baseline, Weeks 4, 8, and 12 | 
| Ultrasound-assessed knee synovitis. | Both knees will be assessed with the participant supine and the knee in 30° flexion. The suprapatellar bursa will be scanned according to the Outcome Measures in Rheumatology (OMERACT) atlas. Maximal depth of effusion and synovial thickness will be measured in millimeters. Power Doppler signal observed in the synovial membrane in both longitudinal and transverse planes will be scored using a semi-quantitative grading system, from 0 to 3 (0 = absent, 1 = mild, 2 = moderate, 3 = marked or severe). | Baseline, Week 12 | 
| Rescue medicine consumption. | The consumption of rescue medication will be recorded at each visit and in the daily logs. | Weeks 2, 4, 6, 8, 10 and 12 | 
| C-reactive protein (CRP). | The blood samples will be collected in the morning after an overnight fast at baseline and the following visits to measure the level of CRP in serum. | Baseline, Weeks 4, 8, and 12 | 
| Microbiota diversity and composition. | Stool and saliva samples will be collected at baseline and the following visits. Microbial diversity will be quantified via the Shannon diversity index (α diversity) and unweighted Unifrac distance (β diversity), and microbiota composition will be identified on different levels, including phylum, family, and genus. | Baseline, Weeks 4, 8, and 12 | 
| Incidence of adverse events and serious adverse events. | Adverse events and serious adverse events will be measured and recorded. | Weeks 2, 4, 6, 8, 10, and 12 |