Prolotherapy Intervention Effect in Patient With Knee Osteoarthritis

Study Overview
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Brief Summary
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Introduction : Prolotherapy is regenerative tissue therapy which is considered to be efficacious in reducing symptoms and morbidity of Knee Osteoarthritis (KOA), but only a few studies demonstrate the effect of prolotherapy at the biomolecular level, particularly the level of Cartilage Oligomeric Matrix Protein (COMP), and Urinary C-Terminal Telopeptides of Type II Collagen (uCTX-II) as the biomarkers of cartilage repair. Objective: To determine the effect of prolotherapy on COMP and uCTX-II levels, and functional outcomes in KOA patients. Method: a double-blind randomized controlled trial study involving 36 participants who had been diagnosed with KOA. History taking, functional outcome assessment, COMP, and uCTX-II were measured. The prolotherapy via intraarticular and extraarticular was performed at Day-1, Day-29, and Day-57 followed by the evaluation of functional outcome, COMP, and uCTX-II at day 78 Alternative Hypothesis : Prolotherapy provides improvement of cartilage based on COMP and UCTX-II levels and functional outcome among KOA patients

Detailed Description
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Design : Double-blind randomized trial Randomization : Simple Randomization generated by an online randomizer Sample Size : Difference between two means of primary outcome where mean difference (μ 1 - μ 2 ) = 0.05 pool variance = 0.09 Z 1-α/2 = 1.95 with type 1 error 5% 1-β = 1.282 with power 90%. Yielding 16 patients for each arm Time Period of Recruitment September 2019- August 2020 Detailed Intervention Intervention group : Prolotherapy given three times (Day-1, Day-29, and Day-57 ) Comparison group : Hyaluronate given five times (Day-1, Day-8, Day-15, Day-22, and Day-29.) Outcome Measurement : Cartilage Oligomeric Matrix Protein (COMP) Source of Sample : Median Cubital Vein Whole Blood Measurement : Enzyme-linked Immunoassay Urinary C-Terminal Telopeptides of Type II Collagen (uCTX-II) Source of Sample : 50 cc of random urine sample Measurement : Enzyme-linked Immunoassay Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for functional Outcome (self-reported assessment) Domains : five elements of pain (score range 0-20), two for stiffness (score range 0-8), 17 for functional limitation (score range 0-68) Classification : 0 - 24 : Mild 25 - 48 : Moderate 49 - 72 : Severe 73 - 96 : Extremely Severe Statistical analysis : Descriptive statistic to elaborate baseline characteristic Assuming the baseline characteristic between groups are similar, the independent t-test will be conducted to see the differences between group, whereas Mann Whitney will be performed for non parametric data Difference within group (baseline and last day) will be measured by paired-t test or wilcoxon for non parametric scenario

Official Title
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The Level of Cartilage Oligomeric Matrix Protein (COMP) and Urinary C-Terminal Telopeptides of Type II Collagen (uCTX-II) After Prolotherapy Intervention and The Functional Outcome in Patient With Knee Osteoarthritis

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Drug: Prolotherapy
* Drug: Sodium Hyaluronate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient provides consent to be part of the research. The diagnosis of Knee Osteoarthritis was made based on clinical criteria/radiology American College of Rheumatology (ACR) 2012 with radiology grading according to Kellgren-Lawrence 2-3 Exclusion Criteria: The Patient has received other forms of intraarticular injection therapy. The patient has received Non Steroid Anti inflammation drug (NSAID) therapy for one week before the start of the intervention. The patient has one or more contraindications for prolotherapy (e.g., Abscess, cellulitis, or septic arthritis). Drop Out Criteria : The patient has undergone a strenuous physical activity that precipitates a degree of complication (i.e., joint effusion). The use of NSAID within one week after the intervention. The patient does not adhere to the intervention. The patient developed or being diagnosed with osteoarthritis or other forms of inflammatory disease in other joints.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: This study involves two arms assigned randomly for receiving different treatment. One arm for Prolotherapy and Sodium Hyaluronate in the comparison group.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sodium Hyaluronate<br>Hyaluronate sodium injection is performed intra-articularly using 2 mL of Adant® Disposable. The treatment will be given five times, on day 1st, 8th, 15th, 22nd, and 29th | Drug: Sodium Hyaluronate<br>* Hyaluronan sodium injection is performed intra-articularly using 2 mL of Adant® Disposable. The treatment will be given five times, on day 1st, 8th, 15th, 22nd, and 29th<br>* Other names: 2 mL Sodium Hyaluronate;|
| Experimental: Prolotherapy<br>Prolotherapy injection is performed intra-articularly and extra-articularly by a physician. Intra-articular injection with 25% dextrose will be carried out with the following details: 5 mL of 40% dextrose, 2 mL of lidocaine, and 1 mL of aqua dest are inserted into the 10-mL syringe, then 5 mL are injected with the superolateral approach. An extra-articular injection with 15% dextrose will be carried out with the following details: in the 10-mL syringe 4 mL of 40% dextrose, 2 mL lidocaine, and 4 mL of distilled water are injected, to make a total of 30-40 mL injections. Treatment will be carried out on day 1st, 29th, and 57th. | Drug: Prolotherapy<br>* Prolotherapy injection is performed intra-articularly and extra-articularly by a physician. Intra-articular injection with 25% dextrose will be carried out with the following details: 5 mL of 40% dextrose, 2 mL of lidocaine, and 1 mL of aqua dest are inserted into the 10-mL syringe, then 5 mL are injected with the superolateral approach. An extra-articular injection with 15% dextrose will be carried out with the following details: in the 10-mL syringe 4 mL of 40% dextrose, 2 mL lidocaine, and 4 mL of distilled water are injected, to make a total of 30-40 mL injections. Treatment will be carried out on day 1st, 29th, and 57th.<br>* Other names: Prolotherapy Dextrose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cartilage Oligomeric Matrix Protein (COMP) | cartilage oligomeric matrix protein from whole blood measured using Enzyme-linked Immunoassay (ELISA). Mean difference between group will be assessed | Measured on the first day before intervention and day 78 after the first dose of treatment in all groups | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary C-Terminal Telopeptides of Type II Collagen (uCTX-II) | Urinary C-Terminal Telopeptides of Type II Collagen from urine sample measured using Enzyme-linked Immunoassay (ELISA) | Measured on the first day before intervention and day 78 after the first injection on the prolotherapy group and Day 50 after the first injection for the hyaluronate group | 
| Functional Outcome | the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index ) measuring three domains (pain, function limitation and stiffness) ranging from 0-96 of total score. | Measured on the first day before intervention and day 78 after the first injection on the prolotherapy group and Day 50 after the first injection for the hyaluronate group | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Knee Osteoarthritis, COMP, uCTX-II, Prolotherapy, Functional Outcome