Study protocol and statistical analysis plan for a randomized controlled trial evaluating the safety and feasibility of the recombinant human platelet-derived growth factor B (rhPDGF-BB)-enhanced collagen plug for complex perianal fistula healing

Background

A drug-repurposing-specific phenome-wide association study (PheWAS) demonstrated that patients with a single nucleotide variant that decreases expression of platelet-derived growth factor receptor beta (PDGFRβ) have a higher prevalence of fistulas, suggesting that PDGFRβ signaling is important for tissue repair. Recombinant human platelet derived growth factor B (rhPDGF) is an FDA-approved protein-based therapeutic that signals through PDGFRβ to heal and regenerate cutaneous skin wounds, periodontal tissue, and orthopedic bone with a strong safety profile. We hypothesize that rhPDGF will benefit other conditions identified by PheWAS with a similar physiological mechanism as the existing indications, such as complex perianal fistulas that are ineligible for a fistulotomy.

Methods and analysis

This prospective, blinded, single-site study aims to enroll 12 participants, randomized at a ratio of 2:1, comparing implantation of rhPDGF-enhanced collagen to routine care procedures, and stratified by fistula etiology, idiopathic versus Crohn’s disease (CD)-related. The primary outcome of this study will evaluate the technical performance of the rhPDGF-enhanced collagen implant for treatment of complex perianal fistulas as measured by the proportion of participants with successful implantation of the intervention without any intervention-related serious adverse events. The secondary outcomes will assess the preliminary safety and efficacy of the intervention based on all intervention-related adverse events, total fistulas healed, rate of fistula recurrence, and change in patient-reported symptoms. Complex perianal fistulas, idiopathic or CD-related, remain a major clinical challenge in need of new multimodal treatments aimed at tissue repair and regeneration. Pharmaceutical rhPDGF stimulation of PDGFRβ signaling promotes healing of skin, bone, and soft tissue. PheWAS revealed fistulas as a novel indication for repurposing rhPDGF. This protocol aims to evaluate the technical performance, preliminary safety and efficacy, and feasibility of rhPDGF-enhanced collagen for healing and remission of complex perianal fistulas.

Ethics and dissemination

This trial was approved by the Vanderbilt University Medical Center institutional review board (IRB#240585). Results will be submitted for publication in a peer-reviewed journal.

Clinical trial registration

This trial is registered at ClinicalTrials.gov ( NCT06632418 ).

STRENGTHS AND LIMITATIONS OF THIS STUDY

• In this trial we utilized a novel drug repurposing approach, PheWAS, to identify fistulas as a novel pathophysiological phenotype which may benefit from a pharmacological intervention targeting the PDGF signaling pathway.

• A crossover design was employed to improve recruitment and retention, allowing patients within the control group the opportunity to receive the intervention if their fistula fails to heal.

• Our secondary outcomes will include stratified subgroup analyses for idiopathic and CD-related fistulas allowing us to determine if PDGF may benefit one fistula etiology over the other.

• Due to the complexity of perianal fistula etiology, stringent exclusion criteria were required to establish a study population who might benefit the most and the small sample size restricts the ability to perform subgroup analyses and limits statistical power for efficacy outcomes.

• The control procedures differ based on disease etiology (idiopathic vs CD-related) yet all patients undergoing treatment receive the same procedure, as such, the interpretation of the secondary outcomes may be difficult due to the lack of a true placebo.