Melatonin for Knee Osteoarthritis Patients

Study Overview
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Brief Summary
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By recruiting knee osteoarthritis patients and treating them with melatonin, this study aims to determine the efficacy and safety of melatonin in alleviating pain in this patient population.

Detailed Description
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Knee osteoarthritis (KOA) is a major source of pain and disability among adults worldwide, but the treatment options for patients with painful KOA are inadequate. The current first-line oral drugs have only small to moderate benefits, and some may have serious adverse effects. Therefore, it is important to identify novel therapeutic medications with satisfactory efficacy and acceptable side-effect profiles for KOA. Melatonin (N-acetyl-5-methoxytryptamine), an indolamine mainly secreted in the pineal gland, is generated from the amino acid tryptophan via derivatization reactions. There are numerous experimental and clinical data supporting the analgesic role of melatonin. In experimental studies, melatonin shows potent analgesic effects in a dose-dependent manner. In clinical studies, melatonin has been shown to have analgesic benefits in people with chronic painful conditions, such as fibromyalgia, irritable bowel syndrome, and migraine. In an animal OA study, the investigators found that melatonin reverses pain behaviors and synovial inflammation, and down-regulates pain sensitization-related neuromediators in the synovium. These findings suggest that melatonin may be potentially effective in treating OA-related pain. However, there is a paucity of high-quality clinical evidence from human studies. The investigators propose to conduct a randomized, double-blind, placebo-controlled trial to examine the efficacy and safety of 12 weeks treatment with oral melatonin on pain and function in patients with KOA.

Official Title
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Efficacy and Safety of Melatonin for Pain Relief in Knee Osteoarthritis Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Dietary Supplement: Melatonin
* Dietary Supplement: Placebo


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 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 cardiopulmonary diseases. Uncontrolled hypertension or diabetes mellitus. Diagnosis of malignant tumors. Pregnant or contemplating pregnancy or breastfeeding. Any use of melatonin supplement before enrollment within 30 days. Allergic to melatonin or its preparation. Any use of anti-depressive/psychotropic drugs.

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 |
| --- | --- |
| Experimental: Oral melatonin supplementation<br>Participants in the intervention arm will receive one 3 mg melatonin tablet every night before going to bed | Dietary Supplement: Melatonin<br>* One 3 mg melatonin tablet every night before bedtime for 12 weeks<br>|
| Placebo Comparator: Placebo<br>The control group will receive an identical-looking inert placebo tablet every night before going to bed | Dietary Supplement: Placebo<br>* One placebo tablet, having an identical appearance to the melatonin tablet, every night before bedtime 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 |
| --- | --- | --- |
| 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 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 and 10 | 
| Knee pain on a visual analogue scale (VAS). | Knee pain will be assessed by a VAS from 0 to 100, with 0 indicating No pain and 100 indicating Very severe 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 | 
| Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness 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 | 
| Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function 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 | 
| 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 questionnaire includes 8 multi-item domains (i.e., physical function, social function, role-emotional, role-physical, bodily pain, general health, mental health, and vitality). These can be combined into 2 summary measures (i.e., physical and mental component summary measures). | Baseline, Weeks 2, 4, 6, 8, 10 and 12 | 
| Hospital Anxiety and Depression Scale (HADS). | HADS is a self-report scale comprising 14 items. Of them, 7 evaluate depression and 7 anxiety symptoms. The score of each domain ranges from 0 to 21. The higher scores equal greater involvement of either anxiety or depression. | Baseline, Weeks 2, 4, 6, 8, 10 and 12 | 
| Pittsburgh Sleep Quality Index (PSQI). | PSQI is a self-rated questionnaire that assesses sleep quality and disturbances over a 1-month interval. PSQI consists of 19 self-assessments and is categorized into seven dimensions (quality of sleep, fall asleep, sleeping time, sleep efficiency, sleep disorders, hypnotic medications, and daytime dysfunction). Each dimension scores from 0 to 3 points, and the total score of the PSQI is the sum of points of seven dimensions, ranging from 0 to 21 (higher is worse). | Baseline, Weeks 2, 4, 6, 8, 10 and 12 | 
| Timed Up and Go Test (TUG). | TUG is a functional performance measure specifically for knee and hip OA. TUG directly evaluates an individual's ability to transfer, ambulate and maintain balance during transitions. 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. 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 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 crossing 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 s. 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. Synovial hypertrophy and effusion will be assessed using OMERACT-7 definitions. The maximal synovial thickness and effusion depth will be measured in millimeters using the longitudinal axis. Synovial hypertrophy is defined as synovial thickness ≥4 mm, and joint effusion is defined as depth of effusion ≥4 mm according to the European League Against Rheumatism (EULAR) criteria. Power Doppler signal (PDS) 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). Participants will be defined as having synovial hypertrophy or PDS if these features are present in either knee. | Baseline, Week 12 | 
| Rescue medicine consumption. | Patients will be permitted to use acetaminophen as rescue medication, and 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, 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melatonin, Osteoarthritis, Pain