Prolotherapy Intervention in Patient With Frozen Shoulder

The Level of Matrix Metalloproteinase-1 (MMP-1), Tissue Inhibitor Matrix Metalloproteinase-1 (TIMP-1) After Prolotherapy Intervention and The Functional Outcome in Patient With Frozen Shoulder

Introduction :

Prolotherapy is regenerative tissue therapy that is considered to be efficacious in reducing symptoms and morbidity of frozen shoulder, but only a few studies demonstrate the effect of prolotherapy at the biomolecular level, particularly the level of Matrix Metalloproteinase- I (MMP-1), Tissue Inhibitor Matrix Metalloproteinase (TIMP-1), as the biomarkers of cartilage repair.

Objective:

To determine the effect of prolotherapy on MMP-1, TIMP-1, and functional outcomes in frozen shoulder patients

Method:

a double-blind randomized controlled trial study involving participants who had been diagnosed with Frozen Shoulder. History taking, functional outcome assessment, MMP-1, and TIMP-1 were measured. The prolotherapy via intraarticular and extraarticular was performed four times, followed by the evaluation of functional outcome, MMP-1, and TIMP-1 at week 12

Alternative Hypothesis :

Prolotherapy will increase the MMP-1, TIMP-1 levels, and improve functional outcome among Frozen Shoulder patients

Study Overview

• Status: Completed
• Conditions: Frozen Shoulder
• Intervention / Treatment: Drug: Dextrose 15 % in Water; Drug: Normal Saline 20 mL Injection

Detailed 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 ) = 0.47
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

Detailed Intervention

1. Intervention group: Prolotherapy is given four times (Week 0, Week 2, Week 4, and Week 6)
2. Comparison group: Normal Saline is given four times with a timeframe similar to the intervention group

Injection location

1. Rotator Cuff muscles
2. Intraarticular glenohumeral joint
3. Subacromial bursa
4. long-heap of the biceps tendon
5. Acromioclavicular joint

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

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 4

Contacts and Locations

Study Locations

• Indonesia
  • South Sulawesi
    • Makassar, South Sulawesi, Indonesia, 90245
      • Hasanuddin University, Faculty of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 33 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

1. Inclusion Criteria

   1. Age 35-70
   2. Diagnosed with frozen shoulder
   3. At least showing symptoms more than 3 months

2. Exclusion Criteria

   1. Receiving other intraarticular injection
   2. Taking Nonsteroid Antiinflammation drugs 1 week prior to intervention
   3. Skin disorder around the injection site
   4. Septic arthritis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prolotherapy; A solution of 7.5 ml of 15% dextrose with 2 ml of 40% lidocaine and 10.5 water is given to these shoulder segments as follows.; Supraspinatus muscle 2-4 ml; Infraspinatus muscle 2-4 ml; Teres minor muscle 2-3 ml,; Subscapularis muscle 2-3 ml.; Intraarticular glenohumeral joint 5 ml; Bursa sub acromial 1-2 ml,; Long head tendon biceps 1-2 ml; Acromioclavicular joint 1 ml	Drug: Dextrose 15 % in Water; A 15% dextrose solution is given to shoulder segments four times with 2 weeks interval (week 0,2,4, and 6); Other Names: Prolotherapy
Placebo Comparator: Normal Saline 0.9%; A solution of 20 ml normal saline 0.9% is given to these shoulder segments as follows.; Supraspinatus muscle 2-4 ml; Infraspinatus muscle 2-4 ml; Teres minor muscle 2-3 ml,; Subscapularis muscle 2-3 ml.; Intraarticular glenohumeral joint 5 ml; Bursa sub acromial 1-2 ml,; Long head tendon biceps 1-2 ml; Acromioclavicular joint 1 ml	Drug: Normal Saline 20 mL Injection; A Normal Saline 0.9% is given to shoulder segments four times with 2 weeks interval (week 0,2,4, and 6); Other Names: Comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Matrix Metalloproteinase 1 in Blood	Matrix Metalloproteinase 1 from whole blood measured using Enzyme-linked Immunoassay (ELISA). Mean difference between group will be assessed	changes of Matrix Metalloproteinase 1 value from baseline to week 6
Tissue Inhibitor Metalloproteinase 1 in Blood	Tissue Inhibitor Metalloproteinase 1 from whole blood measured using Enzyme-linked Immunoassay (ELISA). Mean difference between group will be assessed	changes of Tissue Inhibitor Metalloproteinase 1 value from baseline to week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Functional Outcome of the Shoulder	The functional outcome is measured using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire where the patient were asked to do simple task involving the arm, shoulder and hand and also the assessment of additional symptoms and impact to daily life. Higher score indicates disabilities	changes of Functional Outcome value from baseline to week 6

Collaborators and Investigators

• Sponsor: Bumi Herman
• Investigators: Principal Investigator: Nuralam Sarif, MD, Hasanuddin University; Study Chair: Irawan Yusuf, PhD, Hasanuddin University; Study Chair: Endy Adnan, PhD, Hasanuddin University; Study Chair: Irfan Idris, PhD, Hasanuddin University

Publications and helpful links

General Publications

• Cho CH, Song KS, Kim BS, Kim DH, Lho YM. Biological Aspect of Pathophysiology for Frozen Shoulder. Biomed Res Int. 2018 May 24;2018:7274517. doi: 10.1155/2018/7274517. eCollection 2018.
• Akcay S, Gurel Kandemir N, Kaya T, Dogan N, Eren M. Dextrose Prolotherapy Versus Normal Saline Injection for the Treatment of Lateral Epicondylopathy: A Randomized Controlled Trial. J Altern Complement Med. 2020 Dec;26(12):1159-1168. doi: 10.1089/acm.2020.0286. Epub 2020 Sep 28.
• Distel LM, Best TM. Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PM R. 2011 Jun;3(6 Suppl 1):S78-81. doi: 10.1016/j.pmrj.2011.04.003.
• Lubis AM, Lubis VK. Matrix metalloproteinase, tissue inhibitor of metalloproteinase and transforming growth factor-beta 1 in frozen shoulder, and their changes as response to intensive stretching and supervised neglect exercise. J Orthop Sci. 2013 Jul;18(4):519-27. doi: 10.1007/s00776-013-0387-0. Epub 2013 Apr 19.
• Saltzman BM, Leroux T, Meyer MA, Basques BA, Chahal J, Bach BR Jr, Yanke AB, Cole BJ. The Therapeutic Effect of Intra-articular Normal Saline Injections for Knee Osteoarthritis: A Meta-analysis of Evidence Level 1 Studies. Am J Sports Med. 2017 Sep;45(11):2647-2653. doi: 10.1177/0363546516680607. Epub 2016 Dec 27.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Actual): May 31, 2022
• Study Completion (Actual): November 30, 2022

Study Registration Dates

• First Submitted: November 4, 2021
• First Submitted That Met QC Criteria: November 10, 2021
• First Posted (Actual): November 23, 2021

Study Record Updates

• Last Update Posted (Estimate): December 22, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Functional Outcome; Frozen Shoulder; Prolotherapy; MMP-1; TIMP-1
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Bursitis
• Other Study ID Numbers: 0411211741

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: De-identified data will be shared accordingly

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No