Regenerative Medicine for Joint Hypermobility and Instability
Summary
This clinical trial is designed to evaluate whether a stepwise injection-based treatment approach can reduce pain and improve function in adults with joint hypermobility, connective tissue laxity, and joint instability. Joint hypermobility occurs when joints move beyond their normal range, often because of looser connective tissue. For some patients, this can contribute to chronic pain, recurrent instability, reduced function, and disability. This study focuses on adults with hypermobile Ehlers-Danlos syndrome (hEDS), hypermobility spectrum disorder (HSD), or joint instability after injury who have already completed physical therapy without adequate relief. The main question this study aims to answer is whether the first treatment step, dextrose prolotherapy, can reduce pain by 40% or more two weeks after the second injection. Participants will receive treatment in a step-by-step sequence, based on their response: Step 1: Dextrose prolotherapy A dextrose-based injection used to stimulate a healing response in ligament, tendon, or joint-supporting tissue. Step 2: Platelet-rich plasma (PRP) An injection prepared from the participant's own blood, designed to support tissue repair and recovery. Step 3: Doxycycline injections A low-dose injectable treatment used in this study to help protect joint-supporting tissue. It is not being used to treat infection. Alternative option: Hyaluronic acid injections An injection into the joint that may be offered if the earlier treatment steps do not provide enough improvement. Each treatment step begins with two injections, given approximately two weeks apart. If a participant improves by 40% or more, they may continue with that treatment pathway. If they do not improve enough, they may be offered the next step in the study. Participants will be followed for up to 12 months, with study visits used to monitor pain, function, treatment response, and safety.
Timeline
- Start
- 2026-07-15
- Primary completion
- 2027-09-30
- Completion
- 2028-12-31
Publications
- Background Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.
- Background Mahesh M; National Council on Radiation Protection and Measurements. NCRP 168: its significance to fluoroscopically guided interventional procedures. J Am Coll Radiol. 2013 Jul;10(7):551-2. doi: 10.1016/j.jacr.2013.04.003. No abstract available.
- Background Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis. 1973 Sep;32(5):413-8. doi: 10.1136/ard.32.5.413. No abstract available.
- Background Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine (Phila Pa 1976). 2000 Nov 15;25(22):2940-52; discussion 2952. doi: 10.1097/00007632-200011150-00017.
- Background Binkley JM, Stratford PW, Lott SA, Riddle DL. The Lower Extremity Functional Scale (LEFS): scale development, measurement properties, and clinical application. North American Orthopaedic Rehabilitation Research Network. Phys Ther. 1999 Apr;79(4):371-83.
- Background Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee Injury and Osteoarthritis Outcome Score (KOOS)--development of a self-administered outcome measure. J Orthop Sports Phys Ther. 1998 Aug;28(2):88-96. doi: 10.2519/jospt.1998.28.2.88.
- Background Hudak PL, Amadio PC, Bombardier C. Development of an upper extremity outcome measure: the DASH (disabilities of the arm, shoulder and hand) [corrected]. The Upper Extremity Collaborative Group (UECG). Am J Ind Med. 1996 Jun;29(6):602-8. doi: 10.1002/(SICI)1097-0274(199606)29:63.0.CO;2-L.
- Background Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.
- Background Glinkowski WM, Tomaszewski W. Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: A Systematic Umbrella Review. J Clin Med. 2025 Feb 14;14(4):1272. doi: 10.3390/jcm14041272.
- Background Peck J, Slovek A, Miro P, Vij N, Traube B, Lee C, Berger AA, Kassem H, Kaye AD, Sherman WF, Abd-Elsayed A. A Comprehensive Review of Viscosupplementation in Osteoarthritis of the Knee. Orthop Rev (Pavia). 2021 Jul 10;13(2):25549. doi: 10.52965/001c.25549. eCollection 2021.
- Background Castro MM, Kandasamy AD, Youssef N, Schulz R. Matrix metalloproteinase inhibitor properties of tetracyclines: therapeutic potential in cardiovascular diseases. Pharmacol Res. 2011 Dec;64(6):551-60. doi: 10.1016/j.phrs.2011.05.005. Epub 2011 May 31.
- Background Golub LM, Lee HM, Lehrer G, Nemiroff A, McNamara TF, Kaplan R, Ramamurthy NS. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res. 1983 Sep;18(5):516-26. doi: 10.1111/j.1600-0765.1983.tb00388.x. No abstract available.
- Background Alsousou J, Thompson M, Hulley P, Noble A, Willett K. The biology of platelet-rich plasma and its application in trauma and orthopaedic surgery: a review of the literature. J Bone Joint Surg Br. 2009 Aug;91(8):987-96. doi: 10.1302/0301-620X.91B8.22546.
- Background Everts P, Onishi K, Jayaram P, Lana JF, Mautner K. Platelet-Rich Plasma: New Performance Understandings and Therapeutic Considerations in 2020. Int J Mol Sci. 2020 Oct 21;21(20):7794. doi: 10.3390/ijms21207794.
- Background Refai H. Long-term therapeutic effects of dextrose prolotherapy in patients with hypermobility of the temporomandibular joint: a single-arm study with 1-4 years' follow up. Br J Oral Maxillofac Surg. 2017 Jun;55(5):465-470. doi: 10.1016/j.bjoms.2016.12.002. Epub 2017 Apr 29.
- Background Rabago D, Nourani B. Prolotherapy for Osteoarthritis and Tendinopathy: a Descriptive Review. Curr Rheumatol Rep. 2017 Jun;19(6):34. doi: 10.1007/s11926-017-0659-3.
- Background Nordstrom CR. Exploring pluralism--the many faces of Ayurveda. Soc Sci Med. 1988;27(5):479-89. doi: 10.1016/0277-9536(88)90371-1.
- Background Chopra P, Tinkle B, Hamonet C, Brock I, Gompel A, Bulbena A, Francomano C. Pain management in the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):212-219. doi: 10.1002/ajmg.c.31554. Epub 2017 Feb 10.
- Background Palmer S, Bailey S, Barker L, Barney L, Elliott A. The effectiveness of therapeutic exercise for joint hypermobility syndrome: a systematic review. Physiotherapy. 2014 Sep;100(3):220-7. doi: 10.1016/j.physio.2013.09.002. Epub 2013 Oct 5.
- Background Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H. Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):48-69. doi: 10.1002/ajmg.c.31538. Epub 2017 Feb 1.
- Background Yew KS, Kamps-Schmitt KA, Borge R. Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders. Am Fam Physician. 2021 Apr 15;103(8):481-492.
- Background Daylor V, Griggs M, Weintraub A, Byrd R, Petrucci T, Huff M, Byerly K, Fenner R, Severance S, Griggs C, Sharma A, Atwal P, Kautz SA, Shapiro S, Youkhana K, Lavallee M, Wilkerson A, Nichols M, Snyder A, Eichinger JK, Patel S, Maitland A, Gensemer C, Norris RA. Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs. J Clin Med. 2025 Aug 9;14(16):5636. doi: 10.3390/jcm14165636.
- Background Demmler JC, Atkinson MD, Reinhold EJ, Choy E, Lyons RA, Brophy ST. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case-control comparison. BMJ Open. 2019 Nov 4;9(11):e031365. doi: 10.1136/bmjopen-2019-031365.
- Background Tansey EM. Protection against dog distemper and Dogs Protection Bills: the Medical Research Council and anti-vivisectionist protest, 1911-1933. Med Hist. 1994 Jan;38(1):1-26. doi: 10.1017/s0025727300056027. No abstract available.
- Background Adam MP, Ardinger HH, Pagon RA, et al., eds. Hypermobile Ehlers-Danlos Syndrome [GeneReviews]. Seattle: University of Washington; updated 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1279/
- Background Hauser RA, Lackner JB, Steilen-Matias D, Harris DK. A Systematic Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain. Clin Med Insights Arthritis Musculoskelet Disord. 2016 Jul 7;9:139-59. doi: 10.4137/CMAMD.S39160. eCollection 2016.
- Background Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):8-26. doi: 10.1002/ajmg.c.31552.
- Background Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med. 2000 Mar;6(2):68-74, 77-80.
- Background Michalak N, Banks D, Kane L, Siefferman J. Dextrose Prolotherapy for the Treatment of Chronic Shoulder Pain in Patients With Joint Hypermobility: A Case Series. Clin Med Insights Arthritis Musculoskelet Disord. 2024 Jul 24;17:11795441241264821. doi: 10.1177/11795441241264821. eCollection 2024.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Dextrose | Unknown | 20 % | Other |
| Subject | Doxycycline | Small molecule | 5 mg | — |
| Subject | Doxycycline | Small molecule | 10 mg/ml | — |
| Subject | Doxycycline | Small molecule | 25 mg | — |
| Subject | Platelet Rich Plasma | Other / unclassified | — | — |
| Subject | Sodium Hyaluronate | Other / unclassified | 2.5 ml | Other |
| Subject | Sodium Hyaluronate | Other / unclassified | 25 mg | Other |