PrEvention of Posttraumatic Joint contractuRes With Ketotifen 2 (PERK2)

University of Calgary

Status and phase: Completed; Phase 3

Conditions: Elbow Dislocation; Elbow Fracture; Elbow Injury

Treatments: Drug: Ketotifen Fumarate 5mg; Drug: Lactose Placebo; Drug: Ketotifen Fumarate 2mg

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT03582176

CDMRP-OR160026 (Other Grant/Funding Number)

PERK2_KAH

Details and patient eligibility

About

PrEvention of posttraumatic contractuRes with Ketotifen 2 (PERK 2) is a Phase III randomized, controlled, double blinded multicenter trial with 3 parallel groups (Ketotifen 2 mg or 5 mg or lactose placebo twice daily orally for 6 weeks) and a primary endpoint of elbow extension-flexion range of motion (ROM) arc at 12 weeks post-randomization.

Full description

PrEvention of posttraumatic contractuRes with Ketotifen 2 (PERK2) is a Phase III randomized, controlled, double blinded multicenter trial with 3 parallel groups (Ketotifen 2 mg or 5 mg or lactose placebo twice daily orally for 6 weeks) and a primary endpoint of elbow extension-flexion range of motion (ROM) arc at 12 weeks post-randomization. The Research Hypothesis is that Ketotifen is superior to a lactose placebo in reducing joint contracture severity in adult participants with isolated elbow fractures or dislocations. The Primary Objective is to determine if Ketotifen given within 10 days of injury can reduce post-traumatic elbow joint contractures when compared to placebo. The Secondary Objectives are: 1) to ascertain the optimal dose of Ketotifen and 2) to compare adverse events in Ketotifen and placebo groups.

Inclusion criteria: age ≥ 18 years old and skeletally mature; distal humerus (AO/OTA type 13) and/or proximal ulna and/or proximal radius fractures (AO/OTA type 2U1/2R1) and/or elbow dislocations (open fractures with or without nerve injury may be included); injury ≤ 10 days; ability to give informed consent; able to comply with protocol and follow up; operative treatment of the elbow fracture or dislocation; participant has negative urine or blood serum pregnancy test.

Exclusion criteria: Pre-existing elbow contracture; elbow arthritis (osteoarthritis, inflammatory arthritis, or nonspecific monoarticular arthritis); inability to mobilize elbow within 21 days of injury; bilateral elbow injury; oral hypoglycemic medications; history of epilepsy; lactose intolerance; language or cognitive difficulties preventing completion of questionnaires; pregnancy; breast feeding; male or female unwilling to use 2 methods of contraception; total elbow replacement planned for treatment of fracture or dislocation; prior elbow injury or operation; concomitant musculoskeletal or visceral injuries preventing post-operative elbow therapy; severe renal and hepatic impairment.

Outcome Measures: Range of motion; Disability Arm, Shoulder, Hand; Oxford Elbow Score; Pain Catastrophizing Scale; standardized case report form; radiographic evaluation for fracture healing/non-union; and number of participants requiring reoperation for all elbow related causes, and post-traumatic joint contractures, 2 - 52 weeks post-randomization.

Safety Endpoints: The main safety endpoint for this study is the frequency of adverse events and serious adverse events, and radiographic assessment for non-union and heterotopic ossification (HO), 2 - 52 weeks post-randomization.

Ketotifen is the first and only agent demonstrating a significant decrease in contracture severity in preclinical trials that also has a wide safety profile. Ketotifen has been used in the treatment of chronic asthma for over 40 years in humans. Ketotifen is a medication that has anti-anaphylactic properties, due to the prevention of the synthesis and/or release of growth factors and mediators, as well as antihistamine affects due to H1 receptor antagonism. Post market surveillance has confirmed the safety of Ketotifen. A Phase II RCT comparing a single dose of Ketotifen (5 mg) to placebo in elbow fractures or dislocations in Calgary (ClinicalTrials.gov Identifier NCT01902017), demonstrated safety of Ketotifen and coupled with preclinical animal studies informed the need to increase the sample size, examine multiple doses, and narrow the study population to more severe injuries requiring an operation in the Phase III RCT.

Enrollment: 395 patients

Sex: All

Ages: 18 to 95 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age ≥ 18 years old; skeletally mature with no growth plates in the elbow
• Distal humerus (AO/OTA type 13) and/or proximal ulna and/or proximal radius fractures (AO/OTA type 2U1 or 2R1) and/or elbow dislocations (open fractures with or without nerve injury may be included)
• Operative treatment of the elbow fracture or dislocation
• Injury ≤ 10 days
• Participant has a negative urine or blood serum pregnancy test

Exclusion criteria

• Pre-existing elbow contracture
• Elbow arthritis (osteoarthritis, inflammatory arthritis, or nonspecific monoarticular arthritis)
• Inability to mobilize elbow within 21 days of injury
• Bilateral elbow injury
• Concomitant musculoskeletal or visceral injuries preventing post-operative elbow therapy
• Oral hypoglycemic medications
• History of epilepsy
• Lactose intolerance
• Language or Cognitive difficulties preventing reliable completion of questionnaires
• Females who are pregnant or breast feeding
• Females of reproductive age or males unwilling to use 2 effective methods of contraception
• Severe renal impairment
• Severe hepatic impairment
• Prior elbow injury or operation
• Total elbow replacement planned for treatment of injury
• Unlikely to maintain follow up (no fixed address, plans to move out of town in the next year, states unable to comply with protocol)
• Unwilling or unable to provide written informed consent for trial participation

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

---

395 participants in 3 patient groups, including a placebo group

Lactose Placebo

Placebo Comparator group

Description:

Lactose Placebo by mouth twice per day

Treatment:

Drug: Lactose Placebo

Ketotifen Fumarate - 2mg

Active Comparator group

Description:

Ketotifen Fumarate 2 mg by mouth twice per day

Treatment:

Drug: Ketotifen Fumarate 2mg

Drug: Ketotifen Fumarate 5mg

Ketotifen Fumarate - 5mg

Active Comparator group

Description:

Ketotifen Fumarate 5 mg by mouth twice per day

Treatment:

Drug: Ketotifen Fumarate 2mg

Drug: Ketotifen Fumarate 5mg