PrEvention of Posttraumatic Joint contractuRes With Ketotifen 2

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; distal humerus (AO/OTA type 13) and/or proximal ulna
and/or proximal radius fractures (AO/OTA type 21) 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.

Exclusion criteria: Pre-existing elbow contracture; elbow arthritis (osteoarthritis,
inflammatory arthritis, or nonspecific monoarticular arthritis); inability to mobilize elbow
within 3 weeks of 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.
The common expected side effects of Ketotifen, weight gain and transient drowsiness, plus the
other noted serious adverse events in the Phase II randomized clinical trial (RCT) of
nausea/vomiting, pulmonary embolus, and dermatitis/extremity swelling will be monitored. The
radiographs will be assessed for non-union and to detect heterotopic ossification (HO).

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

- Distal humerus (AO/OTA type 13) and/or proximal ulna and/or proximal radius fractures
(AO/OTA type 21) 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

- Able to give informed consent

- Able to comply with protocol and follow up

Exclusion Criteria:

- Pre-existing elbow contracture

- Elbow arthritis (osteoarthritis, inflammatory arthritis, or nonspecific monoarticular
arthritis)

- Inability to mobilize elbow within 3 weeks of 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