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

NCT04589611 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 201911366
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Osteoarthritis; Post-traumatic Osteoarthritis

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (9)

• Patient Reported Outcome Measurement Information Systems (PROMIS) - Pain Interference

  3, 6, 12, and 24 months

• Patient Reported Outcome Measurement Information Systems (PROMIS) Physical Function

  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.

  3, 6, 12, and 24 months

• American Orthopaedic Foot and Ankle Society (AOFAS) Score.

  3, 6, 12, and 24 months

• Foot and Ankle Disability Index (FADI).

  3, 6, 12, and 24 months

Study Arms (5)

Phase I single amobarbital/Gel-One dose

EXPERIMENTAL

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)

Phase IIa Part 1 amobarbital/Gel-One dose

ACTIVE COMPARATOR

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

Drug: amobarbital/Gel-One (one dose)

Phase IIa Part 1 Placebo

PLACEBO COMPARATOR

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

Drug: Placebo (single dose)

Phase IIa Part 2 amobarbital/Gel-One dose

ACTIVE COMPARATOR

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)

Phase IIa Part 2 placebo

PLACEBO COMPARATOR

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)

Interventions

amobarbital/Gel-One (one dose) DRUG

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

Phase I single amobarbital/Gel-One dose; Phase IIa Part 1 amobarbital/Gel-One dose

Placebo (single dose) DRUG

One dose of placebo during the initial surgical intervention

Phase IIa Part 1 Placebo

amobarbital/Gel-One (two doses) 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 amobarbital/Gel-One dose

Placebo (two doses) DRUG

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

Phase IIa Part 2 placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• J L Marsh: lead
• United States Department of Defense: collaborator

Study Sites (1)

University of Iowa

Iowa City, Iowa, 52240, United States

Location

MeSH Terms

Conditions

Osteoarthritis

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: June 23, 2020
• First Posted: October 19, 2020
• Study Start: July 20, 2022
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: March 26, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)