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

• ClinicalTrials.gov Identifier: NCT04589611
• Recruitment Status: Not yet recruiting
• First Posted: October 19, 2020
• Last Update Posted: June 4, 2021
• Sponsor: J L Marsh
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): J L Marsh, University of Iowa

Study Description

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 has proven to be effective in 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.

Condition or disease	Intervention/treatment	Phase
Osteoarthritis; Post-traumatic Osteoarthritis	Drug: amobarbital/Gel-One (one dose); Drug: Placebo (single dose); Drug: amobarbitol/Gel-One (two doses); Drug: Placebo (two doses)	Phase 1; Phase 2

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 has proven to be effective in 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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 66 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment

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.

• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Translating Metabolic Responses to Mechanical Insult Into Early Interventions to Prevent PTOA
• Estimated Study Start Date: August 2021
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: amobarbital/Gel-One (one dose); One dose of amobarbital/Gel-One during the initial surgical intervention
Active Comparator: Phase IIa Part 1 amobarbital/Gel-One dose; 20 subjects will be randomized to amobarbital/Gel-One single dose.	Drug: amobarbital/Gel-One (one dose); One dose of amobarbital/Gel-One during the initial surgical intervention
Placebo Comparator: Phase IIa Part 1 Placebo; 10 subjects will be randomized to amobarbital/Gel-One single dose.	Drug: Placebo (single dose); One dose of placebo during the initial surgical intervention
Active Comparator: 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.	Drug: amobarbitol/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.
Placebo Comparator: 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.	Drug: Placebo (two doses); One dose of placebo during the initial surgical intervention. A second dose will be administered during the second surgical intervention.

Outcome Measures

Primary Outcome Measures :

1. Determine the number of participants with systemic adverse events including the change in laboratory values to assess the systemic safety of amobarbital. [ Time Frame: 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.] ]
   By using CBC and standard clinical chemistry assays to quantify circulating, ALT, AST, Bilirubin, Creatinine, and BUN and the measurement of urine protein content, the number of participants that have abnormal laboratory values will be determined.
2. Determine the number of participants with a change of local toxicity in tissues. [ Time Frame: 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. ]
   By using osteochondral fragments obtained during the internal fixation surgery, local toxicity will be determined by examining the tissue for cartilage and synovial histological changes.

Secondary Outcome Measures :

1. Patient Reported Outcome Measurement Information Systems (PROMIS) - Pain Interference [ Time Frame: 3, 6, 12, and 24 months ]
   Description: Pain interference 6 questions 5 pt scale - the higher the score the greater the pain
2. Patient Reported Outcome Measurement Information Systems (PROMIS) Physical Function [ Time Frame: 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. ]
   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.
3. Patient Reported Outcome Measurement Information Systems (PROMIS) Global Health questionnaires. [ Time Frame: 3, 6, 12, and 24 months ]
   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.
4. American Orthopaedic Foot and Ankle Society (AOFAS) Score. [ Time Frame: 3, 6, 12, and 24 months ]
   0-100 point scale with 100 perfect ankle function
5. Foot and Ankle Disability Index (FADI). [ Time Frame: 3, 6, 12, and 24 months ]
   Description: total 104 points scored in a percentage scale with 100% perfect
6. X-Ray based Kellgren-Lawrence Grade [ Time Frame: 3, 6, 12, and 24 months ]
   Radiograph imaging graded on scale 1 (no arthritis)-4 (severe arthritis)
7. CT-based fracture energy [ Time Frame: 6 months ]
   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
8. CT-based Contact Stress [ Time Frame: 6 months ]
   Vertical CT scan of ankle are segmented and analyzed using finite element analysis. Results are expressed as Contract Stress Exposure (MPa) across areas.
9. CT-based Joint Space Width [ Time Frame: 6 months ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age ≥ 18 and ≤ 60 years
• Acute closed or type 1 open pilon fractures without operative ipsilateral extremity trauma
• Fractures will be classified as OTA/AO 43 B 1-3 and 43 C 1- 3.
• Fractures must be eligible for a staged treatment protocol and be treated within 24 hours of injury. They must have a CT scan prior to definitive ORIF

Exclusion Criteria:

• Diabetes
• Allergic to poultry products (HA in GelOne® is derived from chickens).
• Previous injuries to the ankle
• Pre-existing immunologic or hematologic diseases
• High grade open wounds
• Pre-existing immunologic or hematologic diseases.
• High grade open wounds
• 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; platelets ≤ 50,000/μl; urinalysis

Contacts and Locations

Contacts

Contact: Lawrence Marsh, MD; (319) 356-0430; j-marsh@uiowa.edu

Contact: James Martin, PhD; (319) 335-7549; james-martin@uiowa.edu

Locations

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52240

Sponsors and Collaborators

J L Marsh

United States Department of Defense

More Information

• Responsible Party: J L Marsh, Professor, University of Iowa
• ClinicalTrials.gov Identifier: NCT04589611
• Other Study ID Numbers: 201911366
• First Posted: October 19, 2020
• Last Update Posted: June 4, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified radiographic and clinical data will be shared.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Osteoarthritis; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Amobarbital; Hyaluronic Acid; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Viscosupplements; Protective Agents; Hypnotics and Sedatives; Central Nervous System Depressants; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action