Regenerative Medicine for Joint Hypermobility and Instability

NCT07688096 | Not Yet Recruiting Phase 1 FDA Drug FDA Device

• 1 other identifier: MPM-2026-06
• Study Type: interventional
• Target: 100
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Ehlers-Danlos Syndrome (EDS); Joint Hypermobility; Joint Instability; Hypermobility Spectrum Disorder; Chronic Pain Syndrome; Sprain; Dislocation; Craniocervical Disfunction; Ehlers-Danlos Syndrome Hypermobility Type (hEDS); Musculoskeletal Pain; Subluxation

Keywords

prolotherapy; dextrose prolotherapy; platelet-rich plasma; PRP; doxycycline; regenerative medicine; joint hypermobility; hEDS; hypermobile Ehlers-Danlos syndrome; viscosupplementation; hyaluronic acid; step-care; ligament instability; MMP inhibition; dislocation; Subluxation; CCI; Craniocervical Disfunction; Craniocervical instability

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (14)

• Change in Brief Pain Inventory (BPI) Pain Severity Score

  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

  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

  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)

  Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months

• Change in Lower Extremity Functional Scale (LEFS) Score

  Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months

Study Arms (1)

Step-Care Regenerative Injection Treatment

EXPERIMENTAL

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; Biological: Autologous Platelet-Rich Plasma; Drug: Doxycycline Hyclate Injectable (Investigational); Device: Visco-3 Sodium Hyaluronate Viscosupplementation

Interventions

Dextrose 20% Prolotherapy DRUG

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.

Step-Care Regenerative Injection Treatment

Autologous Platelet-Rich Plasma BIOLOGICAL

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.

Also known as: PRP

Step-Care Regenerative Injection Treatment

Doxycycline Hyclate Injectable (Investigational) DRUG

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.

Step-Care Regenerative Injection Treatment

Visco-3 Sodium Hyaluronate Viscosupplementation DEVICE

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.

Step-Care Regenerative Injection Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults age 18 years or older, any gender.
• Symptomatic joint hypermobility or instability attributable to one of the following:
• hEDS diagnosed using the 2017 International Classification of the Ehlers-Danlos Syndromes diagnostic criteria;
• HSD classified using the 2017 framework (generalized, peripheral, localized, or historical HSD) with Beighton scoring; or
• 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:
• a positive joint-specific instability provocation test on standardized physical examination;
• generalized hypermobility (Beighton score ≥ 5/9 for adults) or documented joint-specific hypermobility at the target joint; or
• 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.
• Has completed at least one regenerative medicine phase (dextrose, PRP, or doxycycline) and either

You may not qualify if:

• 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).

Sponsors & Collaborators

• Manhattan Pain Medicine, PLLC: lead

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MeSH Terms

Conditions

Ehlers-Danlos syndrome type 3; Ehlers-Danlos Syndrome; Joint Instability; Musculoskeletal Pain; Sprains and Strains; Joint Dislocations

Interventions

Glucose; Prolotherapy

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Hexoses; Monosaccharides; Sugars; Carbohydrates; Complementary Therapies; Therapeutics

Study Officials

• Jason Siefferman, MD

  Manhattan Pain Medicine

  PRINCIPAL INVESTIGATOR

• Mariia Safroshkina, MD

  Manhattan Pain Medicine

  STUDY DIRECTOR

Central Study Contacts

Mariia Safroshkina, MD, Medical Doctor

CONTACT

2139329721; research@manhattanpainmedicine.com

Jason Siefferman, MD, Medical Doctor

CONTACT

7735052512; research@manhattanpainmedicine.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants begin with dextrose prolotherapy. 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 the same treatment. Those who do not improve enough are offered the next treatment in the sequence: platelet-rich plasma (PRP) prolotherapy, then 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 treatments. Not all participants will receive all treatments - progression through the steps depends on each participant's response.

Study Record Dates

• First Submitted: June 25, 2026
• First Posted: July 7, 2026
• Study Start: July 15, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: July 10, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share