Clinical trial NCT04589611: Translating Metabolic Responses to Mechanical Insult Into Early Interventions to Prevent PTOA
Official title: Translating Metabolic Responses to Mechanical Insult Into Early Interventions to Prevent PTOA
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Osteoarthritis
Post-traumatic Osteoarthritis
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2020-10-19
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Determine the number of participants with systemic adverse events including the change in laboratory values to assess the systemic safety of amobarbital.
timeFrame: 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.]
measure: Determine the number of participants with a change of local toxicity in tissues.
timeFrame: 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.
Secondary outcomes:
measure: Patient Reported Outcome Measurement Information Systems (PROMIS) - Pain Interference
timeFrame: 3, 6, 12, and 24 months
measure: Patient Reported Outcome Measurement Information Systems (PROMIS) Physical Function
timeFrame: 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.
measure: Patient Reported Outcome Measurement Information Systems (PROMIS) Global Health questionnaires.
timeFrame: 3, 6, 12, and 24 months
measure: American Orthopaedic Foot and Ankle Society (AOFAS) Score.
timeFrame: 3, 6, 12, and 24 months
measure: Foot and Ankle Disability Index (FADI).
timeFrame: 3, 6, 12, and 24 months
measure: X-Ray based Kellgren-Lawrence Grade
timeFrame: 3, 6, 12, and 24 months
measure: CT-based fracture energy
timeFrame: 6 months
measure: CT-based Contact Stress
timeFrame: 6 months
measure: CT-based Joint Space Width
timeFrame: 6 months
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
Study officials:
References: