Investigations of Mechanisms and Treatment in Post-traumatic Joint Contractures (Ketotifen)

Randomized, Double Blind, Placebo Controlled Trial of Ketotifen in Patients With Elbow Fractures or Dislocations

Injured joints, especially at the elbow, are at risk for permanent motion loss, also known as joint contractures. Joint contractures limit the function of an elbow and are a recognized complication that occurs often after a traumatic injury. The benefits of early motion after injury has helped in preventing joint contractures but there are still several patients that develop debilitating joint contractures. Current research suggests that mast cells, which are found in the joint, are key in causing joint contractures. Research has been done using a medication called Ketotifen. Ketotifen has been linked to stabilizing mast cells and preventing the joint contracture. It is hoped that short-term use of this medication after an injury will prevent the contracture from occurring.

Study Overview

• Status: Completed
• Conditions: Joint Contractures
• Intervention / Treatment: Drug: Ketotifen; Drug: Placebo

Detailed Description

Individuals ≥ 18 years old with isolated distal 1/3 humerus and/or proximal 1/3 ulna and/or proximal 1/3 radius fractures and/or elbow dislocations (open fractures with or without nerve injury may be included) and presented to Peter Lougheed Centre (PLC), Foothills Medical Center (FMC), or South Health Campus (SHC).

Participants were required to take Ketotifen 5mg by mouth twice a day for 6 weeks or placebo twice a day by mouth for 6 weeks. Neither the participant nor the physician knew if the participant was taking Ketotifen or placebo. Sometimes this type of injury requires surgery. This study invited both patients that do and do not require surgery to participate.

We took a sample of blood to measure tryptase (normally found in the body). We predicted people with high levels of tryptase were more likely to develop stiffening in the joint.

Participants were asked to return for follow up visits 2, 6, 12, 24, and 52 weeks after surgery or date of initial injury if surgery was not required. These visits were part of normal care for this type of injury.

At the visit participants were asked to do the following, some of which was not part of normal care.

At each visit: Range of motion of the elbow was assessed, DASH score was completed- form helping the research group understand the level of disability from this injury, X-rays until the fracture was considered healed (this was normal treatment), SF12 - questionnaire about how the patient was feeling and coping with their injury, Additional information was collected about how the injury was healing and weight was measured.

The participant was required to have physiotherapy which is normal treatment for this injury.

The participant was contacted by telephone at week 1, 3, 4 and 5 while taking the study medication. During these times:

The participant was asked about:

• any problems with the study medication
• any new conditions or concerns that have developed

The participant was reminded:

• of next visit
• to continue to take study drug as instructed

During these telephone contacts, if any problems were detected that could not be rectified or figured out during the telephone interview, then participant was asked to attend the Cast Clinic to see their doctor in person.

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Peter Lougheed Centre
    • Calgary, Alberta, Canada, T2N 1N4
      • Foothills Medical Centre
    • Calgary, Alberta, Canada
      • South Health Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years old
• Isolated distal 1/3 humerus fractures
• Proximal 1/3 ulna fractures
• Proximal 1/3 radial fractures
• Elbow dislocations
• Open fractures with or without nerve injury
• Presentation to Peter Lougheed Centre (PLC), Foothills Medical Centre (FMC) or South Health Campus (SHC).

Exclusion Criteria:

• Pre-existing elbow contracture
• Osteoarthritis of affected elbow
• Inflammatory arthritis of affected elbow
• Gout of affected elbow
• Nonspecific monoarticular arthritis of the affected elbow
• Inability to give informed consent due to irreversible cognitive disorder
• Inability to comply with post-operative physiotherapy
• Injury > 7 days at the time of presentation
• Inability to mobilize elbow injury within 2 weeks of injury or surgery
• Pregnancy
• Breast feeding
• Oral hypoglycemic medications
• History of epilepsy
• Lactose intolerance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Operative, Ketotifen; Ketotifen 5mg orally twice per day for 6 weeks.	Drug: Ketotifen; 5 mg PO bid; Other Names: Zaditen
Experimental: Non-operative, Ketotifen; Ketotifen 5mg orally twice per day for 6 weeks.	Drug: Ketotifen; 5 mg PO bid; Other Names: Zaditen
Placebo Comparator: Operative, Placebo; Placebo oral medication twice daily for 6 weeks.	Drug: Placebo; 5 mg placebo PO bid; Other Names: Lactose Placebo
Placebo Comparator: Non-operative, Placebo; Placebo oral medication twice daily for 6 weeks.	Drug: Placebo; 5 mg placebo PO bid; Other Names: Lactose Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Joint range of motion	Extension-flexion arc of motion	12 months post-injury

Secondary Outcome Measures

Outcome Measure	Time Frame
Range of motion	2,6,12,24 and 52 weeks post injury
Patients requiring (re)operation for elbow-related causes	12 months
Radiographic evaluation for fracture healing/non-union	12-52 weeks

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Canadian Institutes of Health Research (CIHR); American Society for Surgery of the Hand; Workers' Compensation Board, Alberta
• Investigators: Principal Investigator: Kevin Hildebrand, MD, University of Calgary

Publications and helpful links

General Publications

• Kopka M, Zhang M, Schneider PS, Fan C-Y, Liang X, Hart DA, Befus A Dean, Garven A, Salo P, Hildebrand KA. Human Serum Mast Cell Tryptase Levels in Elbow Fractures and Dislocations. Transactions of the Orthopaedic Research Society; 41:1190, 2016.
• Hildebrand KA, Schneider PS, Mohtadi NGH, Ademola A, White NJ, Garven A, Walker REA, Sajobi TT; PERK 1 Investigators. PrEvention of Posttraumatic contractuRes with Ketotifen 1 (PERK 1): A Randomized Clinical Trial. J Orthop Trauma. 2020 Dec 1;34(12):e442-e448. doi: 10.1097/BOT.0000000000001878.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: July 10, 2013
• First Submitted That Met QC Criteria: July 15, 2013
• First Posted (Estimate): July 17, 2013

Study Record Updates

• Last Update Posted (Actual): March 27, 2018
• Last Update Submitted That Met QC Criteria: March 25, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Fracture; Elbow; Joint; Contracture; Dislocation
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Contracture; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents; Anti-Allergic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Ketotifen
• Other Study ID Numbers: REB15-0081 (Other Identifier: Conjoint Health Research Ethics Board)