Abstract
BackgroundInjuries and resulting stiffness around joints, especially the elbow, have huge psychological effects by reducing quality of life through interference with normal daily activities such as feeding, dressing, grooming, and reaching for objects. Over the last several years and through numerous research results, the myofibroblast-mast cell-neuropeptide axis of fibrosis had been implicated in post-traumatic joint contractures. Pre-clinical models and a pilot randomized clinical trial (RCT) demonstrated the feasibility and safety of using Ketotifen Fumarate (KF), a mast cell stabilizer to prevent elbow joint contractures. This study aims to evaluate the efficacy of KF in reducing joint contracture severity in adult participants with operately treated elbow fractures and/or dislocations.Methods/designA Phase III randomized, controlled, double-blinded multicentre trial with 3 parallel groups (KF 2 mg or 5 mg or lactose placebo twice daily orally for 6 weeks). The study population consist of adults who are at least 18 years old and within 7 days of injury. The types of injuries are distal humerus (AO/OTA type 13) and/or proximal ulna and/or proximal radius fractures (AO/OTA type 2 U1 and/or 2R1) and/or elbow dislocations (open fractures with or without nerve injury may be included). A stratified randomization scheme by hospital site will be used to assign eligible participants to the groups in a 1:1:1 ratio. The primary outcome is change in elbow flexion-extension range of motion (ROM) arc from baseline to 12 weeks post-randomization. The secondary outcomes are changes in ROM from baseline to 6, 24 & 52 weeks, PROMs at 2, 6, 12, 24 & 52 weeks and impact of KF on safety including serious adverse events and fracture healing. Descriptive analysis for all outcomes will be reported and ANCOVA be used to evaluate the efficacy KF over lactose placebo with respect to the improvement in ROM.DiscussionThe results of this study will provide evidence for the use of KF in reducing post-traumatic joint contractures and improving quality of life after joint injuries.Trial registrationThis study was prospectively registered (July 10, 2018) with ClinicalTrials.gov reference: NCT03582176.
Highlights
Injuries and resulting stiffness around joints, especially the elbow, have huge psychological effects by reducing quality of life through interference with normal daily activities such as feeding, dressing, grooming, and reaching for objects
Through a preclinical rabbit model of post-traumatic joint contractures, we have shown that Ketotifen Fumarate (KF), decreased contracture severity concomitant with decreased numbers of myofibroblasts, mast cells, neuropeptide containing nerve fibres, and measures of fibrosis in the joint capsule in a dose-dependent fashion [12,13,14]
This trial follows from the feasibility PERK 1 randomized clinical trial (RCT) (Clinicaltrials.gov, NCT01902017) where a dose of 5 mg was used, which is larger than the recommended dose of Ketotifen for the treatment of chronic asthma (1–2 mg twice daily) [11]
Summary
Injuries and resulting stiffness around joints, especially the elbow, have huge psychological effects by reducing quality of life through interference with normal daily activities such as feeding, dressing, grooming, and reaching for objects. Joint contractures develop as a consequence of trauma, arthritis, or reconstructive procedures and can be functionally debilitating [1]. These injuries occur most commonly in the working age group (20–60 years), representing a significant societal burden in North America [2,3,4,5]. Analysis of the Calgary Health Region database revealed that approximately 1200 elbow fractures or dislocations occurred in 2002–2005 [2,3,4,5] These rates extrapolated to the Canadian population resulted in an estimated 20,000 elbow fractures or dislocations per year nationally. Extrapolated to the US, this would yield over 25,000 operative procedures annually
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