Osteoarthritis, Post-traumatic Osteoarthritis
Conditions
Brief summary
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.
Detailed description
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
Interventions
DRUGamobarbital/Gel-One (one dose)
One dose of amobarbital/Gel-One during the initial surgical intervention
One dose of placebo during the initial surgical intervention
DRUGamobarbital/Gel-One (two doses)
One dose of amobarbital/Gel-One during the initial surgical intervention. A second dose will be administered during the second surgical intervention.
One dose of placebo during the initial surgical intervention. A second dose will be administered during the second surgical intervention.
Sponsors
J L Marsh
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Intervention model description
Phase I: 6 patients will be treated with single dose open label, and safety measures will be assessed. Phase IIa: Once initial safety is confirmed, 20 amobarbital:10 control patients will be treated with the single dose at the initial operation. Patients and attending surgeons will be blinded to the identity of the dose. Assuming continued safety, an additional 20 amobarbital: 10 control patients will be treated with two doses and evaluated. The second dose of 2.5 mM amobarbital will be administered during the second operation.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
United States
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 39.6 years STANDARD_DEVIATION 13.4 |
| BMI | 30.3 kg/m2 STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 5 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
None listed