PrEvention of Posttraumatic Joint contractuRes With Ketotifen 2
PrEvention of Posttraumatic Joint contractuRes With Ketotifen 2
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.
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 7 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 ≤ 7 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; concomittant 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.
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 ≤ 7 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