Translating Metabolic Responses to Mechanical Insult Into Early Interventions to Prevent PTOA

This is a small-scale proof-of concept clinical trial of amobarbital as a treatment to prevent post-traumatic osteoarthritis in fractured ankle joints. The study is a double blind, prospective, randomized, placebo-controlled, stepwise trial. Amobarbital will be delivered to ankle joints in solution with hyaluronic acid (HA) as a vehicle. Amobarbital/HA injections (active dose) will be compared to HA alone (placebo dose). Our primary goal is to confirm safety, but we will also assess whether treatment improves chondrocyte viability and decreases synovial inflammation. The intervention that will be utilized has proven to be effective using vitro and in vivo models. The study team will assess safety and begin to evaluate efficacy of amobarbital/Gel-One in patients having sustained tibial pilon fractures. The study team will use advanced imaging-based methods we have developed to characterize how joints subjected to varying levels of fracture severity and residual elevated contact stress respond in treated and control groups.

Phase I:6 subjects will be treated with a single dose open label, and safety measures will be assessed.

Phase II: Once initial safety is confirmed, 20 amobarbital:10 control subjects will be treated with the single dose at the initial operation.

Assuming continued safety, an additional 20 amobarbital:10 control subjects will be treated with two doses and evaluated. The second dose of 2.5 mM amobarbital will be administered during the second operation.

Subjects will participate in the following procedures:

SOC surgical intervention Randomization to Amobarbital/Gel-One arm or control arm X-rays CT scans Blood and urine Questionnaires

• amobarbital/Gel-One (one dose) (Drug): One dose of amobarbital/Gel-One during the initial surgical intervention
• Placebo (single dose) (Drug): One dose of placebo during the initial surgical intervention
• amobarbital/Gel-One (two doses) (Drug): One dose of amobarbital/Gel-One during the initial surgical intervention. A second dose will be administered during the second surgical intervention.
• Placebo (two doses) (Drug): One dose of placebo during the initial surgical intervention. A second dose will be administered during the second surgical intervention.

Primary outcomes

• Number of Participants With Systemic Adverse Events Defined as Abnormal Laboratory Values and Number Where Amobarbital is Detected Systemically [Pre-op baseline on the day before external fixation surgery (within 24 hours of injury), immediately post-op, and at 1, 2, and 4 days post-op. At the time of internal fixation (3-21 days after external fixation) and at 1, 2, and 4 days post-op.]]: Safety Measures: CBC and standard clinical chemistry assays to quantify circulating, ALT, AST, Bilirubin, Creatinine, and BUN and the measurement of urine protein content will be evaluated and the number of participants with clinically significant abnormal laboratory values will be determined. Presence of amobarbital will be tested in blood and urine samples and the number of subjects it is detected in will be reported.
• Determine the Number of Participants With a Change of Local Toxicity in Tissues. (Outcome Discontinued) [Pre-op baseline on the day before external fixation surgery (within 24 hours of injury), immediately post-op, and at 1, 2, and 4 days post-op. At the time of internal fixation (3-21 days after external fixation) and at 1, 2, and 4 days post-op.]: Local toxicity will be determined by examining the osteochondral fragments obtained during the internal fixation surgery for cartilage and synovial histological changes. This outcome was discontinued. Samples were not taken and this measurement was not completed.

Secondary outcomes

• Patient Reported Outcome Measurement Information Systems (PROMIS) - Pain Interference [3, 6, 12, and 24 months]: Pain Interference scale. Higher scores indicate greater pain interference (worse score). Result is reported as a T-score, with the population norm at 50 and a standard deviation of 10.
• Patient Reported Outcome Measurement Information Systems (PROMIS) Physical Function [3, 6, 12 and 24 month follow-up visit]: Physical Function - T-score - mean of 50 and a standard deviation (SD) of 10. Therefore a person with a T-score of 40 is one SD below the mean. Higher is better.
• Patient Reported Outcome Measurement Information Systems (PROMIS) Global Health Questionnaires - Mental Health and Physical Health Scores [6, 12 and 24 month follow-up]: Global Health - T-score - mean of 50 and a standard deviation (SD) of 10. Therefore a person with a T-score of 40 is one SD below the mean. Higher is better.
• American Orthopaedic Foot and Ankle Society (AOFAS) Score. [6,12 and 24 month follow-up]: 0-100 point scale with 100 perfect ankle function
• Foot and Ankle Disability Index (FADI). ADL and Sports Scores [6, 12 and 24 month follow-up]: Description: Results are reported on a percentage scale with 100% perfect (higher is better)
• CT-based Fracture Energy [calculated at 6 month follow-up]: Fracture energy is measured in Joules. It is from CT data and measured computationally. It is a continuous measure - Higher Joules = more energy = worse fracture
• CT-based Contact Stress [6, 12 and 24 month follow-up]: Vertical CT scan of ankle are segmented and analyzed using finite element analysis. Results are expressed as Contract Stress Exposure (MPa) across areas. Scans were completed in 4 participants at baseline, 4 participants at 6 month visit, 1 participant at month 12 and 1 participant at month 24. Contact stress measurements were not completed on any scans and are not avaialble.
• CT-based Joint Space Width [Month 0, 6, 12]: Vertical CT scan of ankle used to measure Joint Space Width at several locations to measure distance to calculate the mean tibiotalar joint space (mm).

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Age 18-60 years
* Acute closed or type 1 open ankle fractures (classified as OTA/AO 43 B 1-3 and 43 C 1- 3 or classified as 42 B and C fractures with 25% talar displacement and one of the following; syndesmosis injury or medial malleolar fracture at or above the shoulder) (Marsh et al., 2007)) without operative ipsilateral extremity trauma
* Posterior malleolar and supination adduction rotational fractures that have an articular fracture line across the articular surface of the distal tibia. Posterior malleolar fractures should affect 25% of the articular surface or greater.
* Fractures must have initial treatment within 72 hours of injury including initial injection of amobarbital or placebo.

Exclusion Criteria:

* Diabetes
* Pregnant or nursing mothers and individuals with child-bearing potential that are not using birth control methods with >99% efficacy.
* Allergy to poultry products or cinnamon
* Previous injuries to the ankle
* High grade open wounds
* Pre-existing immunologic or hematologic diseases
* Pre-existing ankle arthritis
* Ipsilateral fractures
* Associated injuries that preclude standard rehabilitation
* Pre-existing dysfunction of the kidneys, liver, blood, immune system, endocrine system (excluding diabetes)
* Serum creatinine >/= 1.4 mg/dl; BUN > 30 mg/dl; ALT >/= 60 IU/L in males and >/= 50 IU/L in females; AST >/= 45 IU/L in males and > 40 IU/L in females; bilirubin > 1.3 mg/dL; platelets </= 50,000/ul; glucose > 200 mg/dL

Participant flow

Outcome results

• Number of Participants With Systemic Adverse Events Defined as Abnormal Laboratory Values and Number Where Amobarbital is Detected Systemically (Primary), Count of participants, Participants: Phase I Single Amobarbital/Gel-One Dose 0
• Determine the Number of Participants With a Change of Local Toxicity in Tissues. (Outcome Discontinued) (Primary), Count of participants, Participants: Phase I Single Amobarbital/Gel-One Dose 0
• Patient Reported Outcome Measurement Information Systems (PROMIS) - Pain Interference (Secondary), Mean, t-score: Phase I Single Amobarbital/Gel-One Dose 50.5 +/- 8.2
• Patient Reported Outcome Measurement Information Systems (PROMIS) Physical Function (Secondary), Mean, score on a scale: Phase I Single Amobarbital/Gel-One Dose 39.0 +/- 2.6
• Patient Reported Outcome Measurement Information Systems (PROMIS) Global Health Questionnaires - Mental Health and Physical Health Scores (Secondary), Mean, score on a scale: Phase I Single Amobarbital/Gel-One Dose 54.2 +/- 8.1
• American Orthopaedic Foot and Ankle Society (AOFAS) Score. (Secondary), Mean, score on a scale: Phase I Single Amobarbital/Gel-One Dose 77.8 +/- 16.9
• Foot and Ankle Disability Index (FADI). ADL and Sports Scores (Secondary), Mean, score on a scale: Phase I Single Amobarbital/Gel-One Dose 75 +/- 16.3
• CT-based Fracture Energy (Secondary), Mean, Joules: Phase I Single Amobarbital/Gel-One Dose 20.89 (12.56 to 32.60)
• CT-based Contact Stress (Secondary), Number, mPA: Phase I Single Amobarbital/Gel-One Dose 0
• CT-based Joint Space Width (Secondary), Mean, mm: Phase I Single Amobarbital/Gel-One Dose 3.281 (2.658 to 3.504)

Adverse events

Time frame: Adverse event information was assessed immediately post Open Reduction and Internal Fixation (ORIF) surgery, and at 1 and 2 days post-ORIF. This was also assessed at each follow-up visit. This included the first clinic follow-up visit (approximately 2 weeks post ORIF) and at the 3, 6, 12 and 24 month follow-up visits.

• Study Protocol and Statistical Analysis Plan (PDF, 2022-03-01)
• Informed Consent Form (PDF, 2022-08-17)