Chronic Pain Syndrome, Craniocervical Disfunction, Dislocation, Ehlers-Danlos Syndrome (EDS), Ehlers-Danlos Syndrome Hypermobility Type (hEDS), Hypermobility Spectrum Disorder, Joint Hypermobility, Joint Instability, Musculoskeletal Pain, Sprain, Subluxation
Conditions
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
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.
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.
Interventions
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.
BIOLOGICALAutologous 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.
DRUGDoxycycline 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.
DEVICEVisco-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.
Sponsors
Manhattan Pain Medicine, PLLC
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Percentage of Improvement (GPI) Responder Rate After Dextrose Prolotherapy | 2 weeks after the second dextrose prolotherapy injection (approximately 4 weeks after enrollment) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 | Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months | 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 | Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months | 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) | Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months | 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. |
| Change in Lower Extremity Functional Scale (LEFS) Score | Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months | 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). |
| Change in Oswestry Disability Index (ODI) Score | Baseline, 2 weeks after second injection of each phase, and at 3, 6, and 12 months | 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. |
| Global Percentage of Improvement (GPI) Responder Rate After PRP Prolotherapy | 2 weeks after the second PRP prolotherapy injection | 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. |
| Global Percentage of Improvement (GPI) Responder Rate After Doxycycline Prolotherapy | 2 weeks after the second doxycycline prolotherapy injection | 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. |
| Global Percentage of Improvement (GPI) Response After Hyaluronic Acid Viscosupplementation | 2 weeks after the final hyaluronic acid injection of the course | 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. |
| Durability of Response: Global Percentage of Improvement (GPI) Score at 3, 6, and 12 Months | 3 months, 6 months, and 12 months from primary endpoint | 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. |
| Durability of Response: Brief Pain Inventory (BPI) Pain Severity Score at 3, 6, and 12 Months | 3 months, 6 months, and 12 months from primary endpoint | 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. |
| Durability of Response: Brief Pain Inventory (BPI) Pain Interference Score at 3, 6, and 12 Months | 3 months, 6 months, and 12 months from primary endpoint | 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. |
| Incidence and Severity of Adverse Events | From first injection through 12-month follow-up | 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. |
| Number of Treatments Required to Achieve Adequate Response | From enrollment through completion of active treatment phase, up to 12 months | 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. |
Contacts
CONTACTMariia Safroshkina, MD, Medical Doctor
CONTACTJason Siefferman, MD, Medical Doctor
PRINCIPAL_INVESTIGATORJason Siefferman, MD
Manhattan Pain Medicine
STUDY_DIRECTORMariia Safroshkina, MD
Manhattan Pain Medicine
Outcome results
None listed