Clinical trial NCT03582176: PrEvention of Posttraumatic Joint contractuRes With Ketotifen 2
Official title: PrEvention of Posttraumatic Joint contractuRes With Ketotifen 2
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Elbow Fracture
Elbow Injury
Elbow Dislocation
Keywords: Acute elbow fractures and/or dislocations
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2018-07-10
Enrollment: 395
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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)
Primary purpose: PREVENTION

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Elbow Extension-Flexion Arc of Motion
timeFrame: 12 weeks post-randomization
Secondary outcomes:
measure: Range of Motion at other time points
timeFrame: 6 weeks, 24 weeks, 52 weeks
measure: Patient Reported Outcome Measures
timeFrame: Enrolment - 52 weeks
measure: Patient Reported Outcome Measures
timeFrame: Enrolment - 52 weeks
measure: Patient Reported Outcome Measures
timeFrame: Enrolment - 52 weeks
measure: Radiographs
timeFrame: Enrolment - 52 weeks
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland Medical Centre
state: Maryland
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Calgary
country: Canada
facility: South Health Campus
state: Alberta
city: St. Albert
country: Canada
facility: Sturgeon Community Hospital
state: Alberta
city: New Westminster
country: Canada
facility: Royal Columbia Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: London
country: Canada
facility: St. Joseph's Health Care London
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Civic Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
Study officials:
affiliation: University of Calgary and Alberta Health Services
name: Kevin A Hildebrand, MD, FRCSC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ademola A, Hildebrand KA, Schneider PS, Mohtadi NGH, White NJ, Bosse MJ, Garven A, Walker REA, Sajobi TT. PrEvention of posttraumatic contractuRes with Ketotifen 2 (PERK 2) - protocol for a multicenter randomized clinical trial. BMC Musculoskelet Disord. 2020 Feb 24;21(1):123. doi: 10.1186/s12891-020-3139-2.