Regenerative Medicine for Joint Hypermobility and Instability

Regenerative Medicine for Joint Hypermobility and Instability: A Prospective, Open-Label, Single-Arm, Step-Care Clinical Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Musculoskeletal Pain; Sprain; Joint Instability; Chronic Pain Syndrome; Joint Hypermobility; Dislocation; Ehlers-Danlos Syndrome (EDS); Ehlers-Danlos Syndrome Hypermobility Type (hEDS); Subluxation; Craniocervical Disfunction; Hypermobility Spectrum Disorder
• Intervention / Treatment: Drug: Dextrose 20% Prolotherapy; Biological: Autologous Platelet-Rich Plasma; Device: Visco-3 Sodium Hyaluronate Viscosupplementation; Drug: Doxycycline Hyclate Injectable (Investigational)

Detailed Description

This is a prospective, open-label, single-arm, step-care interventional study evaluating a structured regenerative medicine treatment protocol for adults with symptomatic joint hypermobility or instability who have failed conservative therapy including physical therapy.

All eligible participants begin with dextrose prolotherapy (20% final concentration). Response is assessed at 2 weeks after the second injection using the Global Percentage of Improvement (GPI) scale. Participants who improve by 40% or more continue with that treatment. Those who do not improve enough are offered the next treatment in the sequence.

The step-care sequence is:

Phase 1: Dextrose prolotherapy (20% dextrose with local anesthetic) Phase 2: Autologous platelet-rich plasma (PRP) prolotherapy Phase 3: Investigational injectable doxycycline hyclate prolotherapy (10 mg/mL; 5-25 mg per joint site; maximum 100 mg per session) Alternative pathway: Visco-3 hyaluronic acid viscosupplementation (FDA-approved for knee osteoarthritis; off-label use in other joints disclosed in consent)

Each phase follows the same cycle: 2 injections approximately 2 weeks apart, followed by a decision point at 2 weeks after the second injection. The dextrose phase decision point is the study primary endpoint.

Outcome measures collected include the Brief Pain Inventory (BPI), Global Percentage of Improvement (GPI), and region-appropriate joint-specific functional measures (DASH for upper extremity, KOOS for knee, LEFS for lower extremity, ODI for spine). Long-term follow-up occurs at 3, 6, and 12 months.

Safety is monitored continuously. An Independent Medical Monitor reviews all serious adverse events. The injectable doxycycline use is investigational; an IND exemption determination request has been submitted to the FDA. Enrollment into the doxycycline phase will not begin until the FDA determination is received and IRB approval is in place.

The study is investigator-initiated with no external funding. It is conducted at a single site - Manhattan Pain Medicine, New York, NY.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Mariia Safroshkina, MD, Medical Doctor; Phone Number: 2139329721; Email: research@manhattanpainmedicine.com
• Study Contact Backup: Name: Jason Siefferman, MD, Medical Doctor; Phone Number: 7735052512; Email: research@manhattanpainmedicine.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults age 18 years or older, any gender.

• Symptomatic joint hypermobility or instability attributable to one of the following:

  1. hEDS diagnosed using the 2017 International Classification of the Ehlers-Danlos Syndromes diagnostic criteria;
  2. HSD classified using the 2017 framework (generalized, peripheral, localized, or historical HSD) with Beighton scoring; or
  3. post-traumatic joint instability with ligamentous injury documented by examination and/or imaging.

• Objective evidence of instability or clinically relevant hypermobility at one or more target joints, defined as at least one of:

  1. a positive joint-specific instability provocation test on standardized physical examination;
  2. generalized hypermobility (Beighton score ≥ 5/9 for adults) or documented joint-specific hypermobility at the target joint; or
  3. imaging evidence of ligamentous laxity or injury at the target joint (dynamic ultrasound, stress radiograph, or MRI).
• Pain attributable to the target joint for at least 3 months.
• Baseline pain score of 4 or greater on a 0-10 numeric rating scale.
• Failure of conservative treatment, including at least 6 weeks of physical therapy directed at the affected joint(s).
• Not currently using NSAIDs and willing to avoid NSAIDs during the active treatment period, when clinically appropriate.
• Able to provide informed consent and to comply with study procedures and follow-up.

Additional eligibility for the Hyaluronic Acid (HA) alternative pathway - a participant may enter the HA pathway if ALL of the following apply, in addition to the inclusion criteria above:

• Has completed at least one regenerative medicine phase (dextrose, PRP, or doxycycline) and either

  1. was classified as an inadequate responder at the phase decision point (GPI < 40%) and declined further regenerative rotation,
  2. completed all available regenerative phases without adequate response, or
  3. experienced an adverse reaction during a regenerative phase that, in the investigator's judgment, contraindicates further regenerative treatment.
• A minimum waiting period of 4 weeks has elapsed since the last regenerative medicine treatment attempted, to allow resolution of post-injection effects before HA administration.
• The target joint(s) have clinical or imaging features amenable to HA viscosupplementation (e.g., articular/osteoarthritic pain component identifiable on examination or imaging).
• No contraindication to HA (see Exclusion Criteria).

Exclusion Criteria:

• Impaired decision-making capacity that precludes valid informed consent.
• Active local or systemic infection.
• Known allergy or contraindication to study injections, local anesthetics, iodinated contrast (if fluoroscopy is planned), or required procedural materials.
• Known hypersensitivity or intolerance to tetracycline-class antibiotics, including doxycycline (relevant to the doxycycline treatment phase).
• Mast cell activation syndrome (MCAS) or other mast cell disorder that, in the investigator's judgment, elevates the risk of injection-related hypersensitivity or systemic reactions.
• Active autoimmune or systemic inflammatory connective-tissue disease that, in the investigator's judgment, may confound the response to regenerative treatment or increase procedural risk.
• Known hypersensitivity to sodium hyaluronate or to the specific HA product to be used (Visco-3); active skin disease or infection over the planned injection site; venous or lymphatic stasis in the limb of the planned injection.
• Active malignancy or anticancer treatment within the prior 12 months; a prior malignancy in documented remission may be enrolled at the investigator's discretion with documented rationale.
• Uncontrolled diabetes mellitus, defined as HbA1c ≥ 8.5% on the most recent value within the prior 3 months; the investigator may also exclude for other objectively documented diabetes-related procedural or healing risk.
• Prior joint replacement at the target joint.
• Planned surgery during study participation.
• Corticosteroid injection to the target joint(s) within the prior 6 weeks.
• Concurrent enrollment in another interventional study for the same pain condition.
• Active litigation or disability claim related to the target condition (to limit secondary-gain confounding of self-reported outcomes).
• Pregnancy, or unwillingness to undergo pregnancy testing when fluoroscopy is planned (persons of childbearing potential).
• Inability to comply with study procedures or follow-up.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Step-Care Regenerative Injection Treatment; All participants receive a step-care sequence beginning with dextrose prolotherapy. Those who do not improve by 40% or more are offered rotation to platelet-rich plasma (PRP) prolotherapy, then to investigational doxycycline prolotherapy. A hyaluronic acid viscosupplementation pathway is available as an alternative for participants who do not respond to or cannot tolerate the regenerative steps.

Drug: Dextrose 20% Prolotherapy; Hypertonic dextrose solution injected at periarticular ligament-bone junctions at 20% final concentration, combined with local anesthetic. Two injections approximately 2 weeks apart per phase. Up to 4 injections total.; Biological: Autologous Platelet-Rich Plasma; Leukocyte-poor platelet-rich plasma prepared from a 30-60 mL autologous whole blood draw using an FDA-cleared PRP preparation system. Two injections approximately 2 weeks apart per phase. Up to 4 injections total.; Other Names: PRP; Device: Visco-3 Sodium Hyaluronate Viscosupplementation; Visco-3 (sodium hyaluronate 25 mg/2.5 mL), FDA-approved for knee osteoarthritis. Used as an alternative pathway for participants who do not respond to or cannot tolerate regenerative phases. Up to 3 syringes per joint per course. Off-label use in non-knee joints is disclosed in the informed consent form.; Drug: Doxycycline Hyclate Injectable (Investigational); Doxycycline hyclate 10 mg/mL reconstituted from commercially available lyophilized powder at point of care, combined with 20% dextrose and local anesthetic. Dose: 5-25 mg per joint site; maximum 100 mg per session. Two injections approximately 2 weeks apart per phase. Up to 4 injections total. Use as prolotherapy agent is investigational.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global Percentage of Improvement (GPI) Responder Rate After Dextrose Prolotherapy	Proportion of participants achieving at least 40% improvement on the Global Percentage of Improvement (GPI) scale relative to baseline. The GPI is a validated patient-reported outcome measure used in prolotherapy research in which participants rate their overall percentage of improvement from 0% (no improvement) to 100% (complete improvement). A participant is classified as a responder if they report 40% or greater improvement. This threshold also serves as the step-care decision rule: responders continue dextrose; non-responders are offered rotation to the next treatment.	2 weeks after the second dextrose prolotherapy injection (approximately 4 weeks after enrollment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Brief Pain Inventory (BPI) Pain Severity Score	Change from baseline in the Brief Pain Inventory (BPI) pain severity subscale, a validated 4-item patient-reported measure assessing worst, least, average, and current pain on a 0-10 numeric rating scale. Scores range from 0 to 10, where 0 indicates no pain and 10 indicates pain as bad as you can imagine. Higher scores indicate worse outcome.	Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months
Change in Brief Pain Inventory (BPI) Pain Interference Score	Change from baseline in the Brief Pain Inventory (BPI) interference subscale, a validated 7-item patient-reported measure assessing how pain interferes with general activity, mood, walking, work, relationships, sleep, and enjoyment of life on a 0-10 numeric rating scale. Scores range from 0 to 10 per item and are averaged to a total interference score of 0 to 10, where 0 indicates no interference and 10 indicates complete interference. Higher scores indicate worse outcome.	Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months
Change in Disabilities of the Arm, Shoulder and Hand (DASH) Score	Change from baseline in the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, a validated 30-item patient-reported outcome measure assessing physical function and symptoms in people with musculoskeletal disorders of the upper extremity. Scores range from 0 to 100, where 0 indicates no disability and 100 indicates maximum disability. Higher scores indicate worse outcome. Administered to participants whose primary target joint is in the upper extremity.	Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months
Change in Knee Injury and Osteoarthritis Outcome Score (KOOS)	Change from baseline in the Knee Injury and Osteoarthritis Outcome Score (KOOS), a validated patient-reported outcome measure assessing symptoms, pain, function in daily living, function in sport and recreation, and knee-related quality of life. Each of five subscales is scored from 0 to 100, where 0 indicates extreme problems and 100 indicates no problems. Higher scores indicate better outcome. Administered to participants whose primary target joint is the knee.	Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months
Change in Lower Extremity Functional Scale (LEFS) Score	Change from baseline in the Lower Extremity Functional Scale (LEFS), a validated 20-item patient-reported outcome measure assessing function in people with lower extremity musculoskeletal conditions. Scores range from 0 to 80, where 0 indicates inability to perform any activities and 80 indicates no difficulty with any activities. Higher scores indicate better outcome. Administered to participants whose primary target joint is in the lower extremity (excluding knee).	Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months
Global Percentage of Improvement (GPI) Responder Rate After PRP Prolotherapy	Proportion of participants rotated to platelet-rich plasma (PRP) prolotherapy who achieve at least 40% improvement on the GPI scale at the PRP phase decision point, among participants who did not respond to dextrose prolotherapy.	2 weeks after the second PRP prolotherapy injection
Global Percentage of Improvement (GPI) Responder Rate After Doxycycline Prolotherapy	Proportion of participants rotated to investigational doxycycline prolotherapy who achieve at least 40% improvement on the GPI scale at the doxycycline phase decision point, among participants who did not respond to dextrose and PRP prolotherapy.	2 weeks after the second doxycycline prolotherapy injection
Global Percentage of Improvement (GPI) Response After Hyaluronic Acid Viscosupplementation	GPI score at end-of-course assessment among participants who entered the alternative hyaluronic acid (HA) viscosupplementation pathway after failure of or adverse reaction to regenerative phases. Reported descriptively; not compared to regenerative phase outcomes.	2 weeks after the final hyaluronic acid injection of the course
Durability of Response: Global Percentage of Improvement (GPI) Score at 3, 6, and 12 Months	Global Percentage of Improvement (GPI) score at 3, 6, and 12 months from the primary endpoint assessment, evaluating maintenance of treatment response and need for additional treatment over time. The GPI is a patient-reported scale ranging from 0% to 100%, where 0% indicates no improvement and 100% indicates complete improvement relative to baseline. Higher scores indicate better outcome.	3 months, 6 months, and 12 months from primary endpoint
Durability of Response: Brief Pain Inventory (BPI) Pain Severity Score at 3, 6, and 12 Months	Brief Pain Inventory (BPI) pain severity subscale score at 3, 6, and 12 months from the primary endpoint assessment, evaluating maintenance of pain reduction over time. Scores range from 0 to 10, where 0 indicates no pain and 10 indicates pain as bad as you can imagine. Higher scores indicate worse outcome.	3 months, 6 months, and 12 months from primary endpoint
Durability of Response: Brief Pain Inventory (BPI) Pain Interference Score at 3, 6, and 12 Months	Brief Pain Inventory (BPI) pain interference subscale score at 3, 6, and 12 months from the primary endpoint assessment, evaluating maintenance of functional improvement over time. Scores range from 0 to 10, where 0 indicates no interference and 10 indicates complete interference with daily activities. Higher scores indicate worse outcome.	3 months, 6 months, and 12 months from primary endpoint
Incidence and Severity of Adverse Events	Frequency, severity, and relatedness of adverse events for each study agent (dextrose, PRP, doxycycline) and for the hyaluronic acid pathway, assessed using a standardized Adverse Event Documentation Form at every study contact. Serious adverse events are reported separately. Severity is classified as mild, moderate, or severe.	From first injection through 12-month follow-up
Number of Treatments Required to Achieve Adequate Response	Total number of injection sessions required before a participant achieves GPI of 40% or greater, describing the treatment burden associated with the step-care approach.	From enrollment through completion of active treatment phase, up to 12 months
Change in Oswestry Disability Index (ODI) Score	Change from baseline in the Oswestry Disability Index (ODI), a validated 10-item patient-reported outcome measure assessing degree of disability and quality of life in people with low back pain. Scores range from 0 to 100, where 0 indicates no disability and 100 indicates maximum disability. Higher scores indicate worse outcome. Administered to participants whose primary target joint is in the spine.	Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months

Collaborators and Investigators

• Sponsor: Manhattan Pain Medicine, PLLC
• Investigators: Principal Investigator: Jason Siefferman, MD, Manhattan Pain Medicine; Study Director: Mariia Safroshkina, MD, Manhattan Pain Medicine

Publications and helpful links

General Publications

• 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.
• 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.
• Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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/
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): July 15, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: June 25, 2026
• First Submitted That Met QC Criteria: June 30, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: regenerative medicine; hyaluronic acid; dextrose prolotherapy; doxycycline; prolotherapy; PRP; platelet-rich plasma; dislocation; viscosupplementation; CCI; Subluxation; Craniocervical Disfunction; joint hypermobility; hEDS; hypermobile Ehlers-Danlos syndrome; step-care; ligament instability; MMP inhibition; Craniocervical instability
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Musculoskeletal Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Wounds and Injuries; Joint Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Hematologic Diseases; Skin Diseases; Congenital Abnormalities; Hemostatic Disorders; Hemorrhagic Disorders; Skin Diseases, Genetic; Skin Abnormalities; Collagen Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Signs and Symptoms; Hemic and Lymphatic Diseases; Musculoskeletal Pain; Joint Dislocations; Sprains and Strains; Ehlers-Danlos Syndrome; Joint Instability; Ehlers-Danlos syndrome type 3; Therapeutics; Complementary Therapies; Carbohydrates; Sugars; Hexoses; Monosaccharides; Glucose; Prolotherapy
• Other Study ID Numbers: MPM-2026-06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is a single-site, investigator-initiated feasibility study with no external funding and no data sharing agreement in place. Individual participant data (IPD) will not be shared with other researchers. All participants are assigned unique study ID numbers and their data are maintained under HIPAA-compliant privacy protections at Manhattan Pain Medicine. Aggregate de-identified findings will be reported through peer-reviewed publication. Future sharing of de-identified data may be considered on a case-by-case basis consistent with the IRB-approved consent form and applicable privacy regulations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes