Randomized Pilot Clinical Trial of Tofacitinib Solution for Plaque Psoriasis: Challenges of the Intra-Subject Study Design
August 2015 | Volume 14 | Issue 8 | Original Article | 777 | Copyright © 2015
William C. Ports DVM,a Steven R. Feldman MD PhD,b Pankaj Gupta PhD,a Huaming Tan PhD,a Theodore R. Johnson PhD,c and Robert Bissonnette MDd
aPfizer Inc, Groton, CT
bWake Forest Baptist Medical Center, Winston-Salem, NC
cPharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, San Diego, CA
dInnovaderm Research, Montreal, QC, Canada
Intra-subject, left-right, randomized, controlled study designs are often used for proof-of-concept studies in dermatology. This design was used to evaluate the safety and efficacy of a topical solution of tofacitinib (NCT00678561), a small-molecule Janus kinase inhibitor under investigation for the topical and oral treatment of patients with chronic plaque psoriasis. Eighty-one patients, each with matched left and right target plaques, were randomized to 2%, 0.2%, or 0.02% tofacitinib or vehicle solution once or twice daily. Patients treated one plaque as per their randomization group (2%, 0.2%, 0.02% tofacitinib, or vehicle solution), and used vehicle to treat the contralateral plaque for 4 weeks. Except during clinic visits, study drug applications were performed unsupervised outside the clinical trial site. Intra-subject, vehicle-adjusted mean percent change from baseline in Target Plaque Severity Score at week 4 (primary efficacy endpoint) was not significantly different from baseline for any treatment group (P values of 0.28–0.68). However, skin biopsy analyses detected tofacitinib in both tofacitinib- and vehicle-treated plaques of some patients, suggesting cross-contamination or solution misapplication.
Lack of efficacy with tofacitinib relative to vehicle may be due to the intra-subject study design with unsupervised applications.
These findings have potential implications for future intra-subject studies of topical treatments.
J Drugs Dermatol. 2015;14(8):777-784.
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Psoriasis is a common, debilitating, immune-mediated disease; plaque psoriasis is the most common form, characterized by thickened, erythemato-squamous plaques.1 First-line treatment of mild to moderate plaque psoriasis involves topical therapies including corticosteroids and vitamin D analogs.2 However, as local and systemic adverse effects (AEs) can limit the use of topical therapies,3 additional treatment options that are effective and well-tolerated are needed.
Janus kinase (JAK) intracellular signaling has been implicated in the pathogenesis of psoriasis.4 Tofacitinib (CP-690,550) is a small-molecule JAK inhibitor being investigated for the topical and oral treatment of plaque psoriasis. When the clinical trial in this report was conducted, the potential therapeutic benefits of JAK inhibition in psoriasis had been demonstrated in a Phase 1 study of oral tofacitinib administered over 14 days.5 A proof-of-concept pilot study was designed to evaluate efficacy, safety, local tolerability, and pharmacokinetics of a topical tofacitinib solution in patients with chronic plaque psoriasis.
Proof-of-concept studies with topical formulations can be challenging; relatively few patients are enrolled and only a small surface area is typically treated, potentially restricting the generation of clinically meaningful results. The intra-subject design (also termed half body, left-right, or bilateral design) utilizes each patient as his/her own control to reduce the impact of variability between patients. However, few studies have been published on this strategy’s limitations. The outcomes reported here have implications for future intra-subject studies of investigational topical therapies.
MATERIALS AND METHODS
This study was performed in compliance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study protocol was approved by the institutional review board or independent ethics committee at each investigational center; all patients provided written, informed consent.
Study Design and Treatment
This was a Phase 2a, multicenter, randomized, double-blind, vehicle-controlled, eight-arm, parallel-group study (A3921038; ClinicalTrials.gov, NCT00678561) conducted at five centers in Canada and 13 centers in the United States between October 13, 2008 and July 24, 2009. The study employed a left-right, intra-subject design, whereby in each patient one psoriasis target plaque was randomly assigned to be treated with tofacitinib solution, and one with vehicle. For each patient, matched