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.
Adults age 18 years or older, any gender.
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.
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).
Sequential
Dextrose 20% Prolotherapy
DrugHypertonic 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.
Autologous Platelet-Rich Plasma
Biological/VaccineLeukocyte-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.
Doxycycline Hyclate Injectable (Investigational)
DrugDoxycycline 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.
Visco-3 Sodium Hyaluronate Viscosupplementation
DeviceVisco-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.
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.
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.
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.
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.
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.
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