Prolotherapy Intervention Effect in Patient With Knee Osteoarthritis

Knee Osteoarthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04557943
• Other study ID #: 2708201904
• Status: Completed
• Phase: Phase 4
• Start date: September 1, 2019
• Est. completion date: August 1, 2020

Study information

• Verified date: November 2020
• Source: Hasanuddin University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

Design :

Double-blind randomized trial

Randomization :

Simple Randomization generated by an online randomizer

Sample Size :

Difference between two means of primary outcome where

1. mean difference (μ 1 - μ 2 ) = 0.05

2. pool variance = 0.09

3. Z 1-α/2 = 1.95 with type 1 error 5%

4. 1-β = 1.282 with power 90%. Yielding 16 patients for each arm

Time Period of Recruitment September 2019- August 2020

Detailed Intervention

1. Intervention group : Prolotherapy given three times (Day-1, Day-29, and Day-57 )

2. Comparison group : Hyaluronate given five times (Day-1, Day-8, Day-15, Day-22, and Day-29.)

Outcome Measurement :

1. Cartilage Oligomeric Matrix Protein (COMP) Source of Sample : Median Cubital Vein Whole Blood Measurement : Enzyme-linked Immunoassay

2. Urinary C-Terminal Telopeptides of Type II Collagen (uCTX-II) Source of Sample : 50 cc of random urine sample Measurement : Enzyme-linked Immunoassay

3. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for functional Outcome (self-reported assessment)

Domains :

1. five elements of pain (score range 0-20),

2. two for stiffness (score range 0-8),

3. 17 for functional limitation (score range 0-68)

Classification :

0 - 24 : Mild 25 - 48 : Moderate 49 - 72 : Severe 73 - 96 : Extremely Severe

Statistical analysis :

1. Descriptive statistic to elaborate baseline characteristic

2. 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

3. Difference within group (baseline and last day) will be measured by paired-t test or wilcoxon for non parametric scenario

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: August 1, 2020
• Est. primary completion date: April 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. The patient provides consent to be part of the research.

2. 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:

1. The Patient has received other forms of intraarticular injection therapy.

2. The patient has received Non Steroid Anti inflammation drug (NSAID) therapy for one week before the start of the intervention.

3. The patient has one or more contraindications for prolotherapy (e.g., Abscess, cellulitis, or septic arthritis).

Drop Out Criteria :

1. The patient has undergone a strenuous physical activity that precipitates a degree of complication (i.e., joint effusion).

2. The use of NSAID within one week after the intervention.

3. The patient does not adhere to the intervention.

4. The patient developed or being diagnosed with osteoarthritis or other forms of inflammatory disease in other joints.

Related Conditions & MeSH terms

• Knee Osteoarthritis
• Osteoarthritis
• Osteoarthritis, Knee

Intervention

Drug:
• Prolotherapy
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.
• Sodium Hyaluronate
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

Locations

Country	Name	City	State
Indonesia	Hasanuddin University, Faculty of Medicine	Makassar	South Sulawesi

Sponsors (1)

Lead Sponsor	Collaborator
Hasanuddin University

Country where clinical trial is conducted

Indonesia, 

References & Publications (12)

Arias-Vázquez PI, Tovilla-Zárate CA, Legorreta-Ramírez BG, Burad Fonz W, Magaña-Ricardez D, González-Castro TB, Juárez-Rojop IE, López-Narváez ML. Prolotherapy for knee osteoarthritis using hypertonic dextrose vs other interventional treatments: systematic review of clinical trials. Adv Rheumatol. 2019 Aug 19;59(1):39. doi: 10.1186/s42358-019-0083-7. — View Citation

Eslamian F, Amouzandeh B. Therapeutic effects of prolotherapy with intra-articular dextrose injection in patients with moderate knee osteoarthritis: a single-arm study with 6 months follow up. Ther Adv Musculoskelet Dis. 2015 Apr;7(2):35-44. doi: 10.1177/1759720X14566618. — View Citation

Garnero P, Conrozier T, Christgau S, Mathieu P, Delmas PD, Vignon E. Urinary type II collagen C-telopeptide levels are increased in patients with rapidly destructive hip osteoarthritis. Ann Rheum Dis. 2003 Oct;62(10):939-43. — View Citation

Hoch JM, Mattacola CG, Medina McKeon JM, Howard JS, Lattermann C. Serum cartilage oligomeric matrix protein (sCOMP) is elevated in patients with knee osteoarthritis: a systematic review and meta-analysis. Osteoarthritis Cartilage. 2011 Dec;19(12):1396-404. doi: 10.1016/j.joca.2011.09.005. Epub 2011 Oct 5. Review. — View Citation

Huang M, Zhao J, Huang Y, Dai L, Zhang X. Meta-analysis of urinary C-terminal telopeptide of type II collagen as a biomarker in osteoarthritis diagnosis. J Orthop Translat. 2017 Aug 15;13:50-57. doi: 10.1016/j.jot.2017.06.005. eCollection 2018 Apr. — View Citation

Hung CY, Hsiao MY, Chang KV, Han DS, Wang TG. Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: a systematic review and meta-analysis. J Pain Res. 2016 Oct 18;9:847-857. eCollection 2016. — View Citation

Rabago D, Patterson JJ, Mundt M, Kijowski R, Grettie J, Segal NA, Zgierska A. Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2013 May-Jun;11(3):229-37. doi: 10.1370/afm.1504. Erratum in: Ann Fam Med. 2013 Sep-Oct;11(5):480. — View Citation

Rabago D, Zgierska A, Fortney L, Kijowski R, Mundt M, Ryan M, Grettie J, Patterson JJ. Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: results of a single-arm uncontrolled study with 1-year follow-up. J Altern Complement Med. 2012 Apr;18(4):408-14. doi: 10.1089/acm.2011.0030. — View Citation

Scarpellini M, Lurati A, Vignati G, Marrazza MG, Telese F, Re K, Bellistri A. Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the "Magenta osteoarthritis study". J Orthop Traumatol. 2008 Jun;9(2):81-7. doi: 10.1007/s10195-008-0007-5. Epub 2008 May 28. — View Citation

Shewale AR, Barnes CL, Fischbach LA, Ounpraseuth ST, Painter JT, Martin BC. Comparison of Low-, Moderate-, and High-Molecular-Weight Hyaluronic Acid Injections in Delaying Time to Knee Surgery. J Arthroplasty. 2017 Oct;32(10):2952-2957.e21. doi: 10.1016/j.arth.2017.04.041. Epub 2017 May 2. — View Citation

Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LL, Grasso R, Jamín A, Clark T, Rabago D. Chondrogenic Effect of Intra-articular Hypertonic-Dextrose (Prolotherapy) in Severe Knee Osteoarthritis. PM R. 2016 Nov;8(11):1072-1082. doi: 10.1016/j.pmrj.2016.03.008. Epub 2016 Apr 4. — View Citation

Verma P, Dalal K. Serum cartilage oligomeric matrix protein (COMP) in knee osteoarthritis: a novel diagnostic and prognostic biomarker. J Orthop Res. 2013 Jul;31(7):999-1006. doi: 10.1002/jor.22324. Epub 2013 Feb 19. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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