This study will examine the pain-relief efficacy and safety of L-arginine in knee OA patients.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
340
L-arginine, 2 g, three times daily, for 12 weeks
Identical inert placebo, three times daily, for 12 weeks
Xiangya Hospital
Changsha, Hunan, China
RECRUITINGChange From Baseline in 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.
Time frame: Baseline, Week 12
Change From Baseline in 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.
Time frame: Baseline, Weeks 2, 4 and 8
Change From Baseline in 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".
Time frame: Baseline, Weeks 2, 4, 8 and 12
Change From Baseline in 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.
Time frame: Baseline, Weeks 2, 4, 8 and 12
Change From Baseline in Change From Baseline in WOMAC stiffness score.
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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.
Time frame: Baseline, Weeks 2, 4, 8 and 12
Change From Baseline in 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.
Time frame: Baseline, Weeks 2, 4, 8 and 12
Change From Baseline in Patient global assessment of osteoarthritis (PGA-OA) score.
PGA-OA score will be assessed using a 100 mm visual analogue scale (higher is worse).
Time frame: Baseline, Weeks 2, 4, 8 and 12
Change From Baseline in SF-12 questionnaire score.
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).
Time frame: Baseline, Weeks 2, 4, 8 and 12
Change From Baseline in 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.
Time frame: Baseline, Weeks 4, 8 and 12
Change From Baseline in 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.
Time frame: Baseline, Weeks 4, 8 and 12
Change From Baseline in 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).
Time frame: Baseline, Week 12
Rescue medicine consumption.
The consumption of rescue medication will be recorded at each visit and in the daily logs.
Time frame: Weeks 2, 4, 8 and 12
Change From Baseline in Level of 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.
Time frame: Baseline, Weeks 4, 8 and 12
Change From Baseline in 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.
Time frame: 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.
Time frame: Weeks 2, 4, 8 and 12