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.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis; Post-traumatic Osteoarthritis
• Intervention / Treatment: Drug: amobarbital/Gel-One (one dose); Drug: Placebo (single dose); Drug: amobarbital/Gel-One (two doses); Drug: Placebo (two doses)

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

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Lawrence Marsh, MD; Phone Number: (319) 356-0430; Email: j-marsh@uiowa.edu
• Study Contact Backup: Name: James Martin, PhD; Phone Number: (319) 335-7549; Email: james-martin@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52240
      • University of Iowa

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / 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: 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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the number of participants with systemic adverse events including the change in laboratory values to assess the systemic safety of amobarbital.	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.	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.]
Determine the number of participants with a change of local toxicity in tissues.	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.	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 Outcome Measures

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

Collaborators and Investigators

• Sponsor: J L Marsh
• Collaborators: United States Department of Defense

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2022
• Primary Completion (Actual): December 1, 2023
• Study Completion (Actual): December 1, 2023

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: October 14, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Immunologic Factors; Protective Agents; Hypnotics and Sedatives; GABA Modulators; GABA Agents; Adjuvants, Immunologic; Viscosupplements; Hyaluronic Acid; Amobarbital
• Other Study ID Numbers: 201911366

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified radiographic and clinical data will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No