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

NCT ID: NCT04589611

Last Updated: 2024-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-20
• Study Completion Date: 2023-12-01

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

Conditions

Osteoarthritis; Post-traumatic Osteoarthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Phase I single amobarbital/Gel-One dose

Phase I: An open label study of 3 patients will be done. If no dose limiting toxic (DLT) side effects occur, then an additional 3 patients will be done. If no DLT events occur, the study will proceed to Phase II.

Group Type: EXPERIMENTAL

amobarbital/Gel-One (one dose)

Intervention Type: DRUG

One dose of amobarbital/Gel-One during the initial surgical intervention

Phase IIa Part 1 amobarbital/Gel-One dose

20 subjects will be randomized to amobarbital/Gel-One single dose.

Group Type: ACTIVE_COMPARATOR

amobarbital/Gel-One (one dose)

Intervention Type: DRUG

One dose of amobarbital/Gel-One during the initial surgical intervention

Phase IIa Part 1 Placebo

10 subjects will be randomized to amobarbital/Gel-One single dose.

Group Type: PLACEBO_COMPARATOR

Placebo (single dose)

Intervention Type: DRUG

One dose of placebo during the initial surgical intervention

Phase IIa Part 2 amobarbital/Gel-One dose

20 subjects will be randomized to one dose of amobarbital/Gel-One during the initial surgical intervention. A second dose will be administered during the second surgical intervention.

Group Type: ACTIVE_COMPARATOR

amobarbital/Gel-One (two doses)

Intervention Type: DRUG

One dose of amobarbital/Gel-One during the initial surgical intervention. A second dose will be administered during the second surgical intervention.

Phase IIa Part 2 placebo

20 subjects will be randomized to one dose of placebo during the initial surgical intervention. A second dose will be administered during the second surgical intervention.

Group Type: PLACEBO_COMPARATOR

Placebo (two doses)

Intervention Type: DRUG

One dose of placebo during the initial surgical intervention. A second dose will be administered during the second surgical intervention.

Interventions

amobarbital/Gel-One (one dose)

One dose of amobarbital/Gel-One during the initial surgical intervention

Intervention Type: DRUG

Placebo (single dose)

One dose of placebo during the initial surgical intervention

Intervention Type: DRUG

amobarbital/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.

Intervention Type: DRUG

Placebo (two doses)

One dose of placebo during the initial surgical intervention. A second dose will be administered during the second surgical intervention.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United States Department of Defense

FED

Sponsor Role: collaborator

J L Marsh

OTHER

Sponsor Role: lead

Responsible Party

J L Marsh

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

University of Iowa

Iowa City, Iowa, United States

Countries

United States

Other Identifiers

201911366

Identifier Type: -

Identifier Source: org_study_id