Randomized, Placebo- and Active-Controlled Crossover Study of the Safety and Efficacy of THVD-102, a Fixed-dose Combination of Oxybutynin and Pilocarpine, in Subjects With Primary Focal Hyperhidrosis

February 2017 | Volume 16 | Issue 2 | Original Article | 127 | Copyright © 2017

David M. Pariser MD FACP FAAD,a Janakan Krishnaraja MD,b Thomas M. Tremblay RN,d R. Michael Rubison PhD,c Ted W. Love MD,d and Benjamin F. McGraw III PharmDd

aEastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA bLinear Clinical Research, Perth, Western Australia cFlint Hills Consulting, LLC, Lake Forest, IL dTheraVida, Inc., San Mateo, CA

Abstract

BACKGROUND: While muscarinic antagonists (anticholinergics) have shown efficacy in treating primary focal hyperhidrosis (PFH), side effects - most commonly dry mouth - are intolerable for most patients. THVD-102, a fixed-dose combination product has been developed combining oxybutynin, a muscarinic antagonist, and pilocarpine, a muscarinic agonist. The pilocarpine is at a dose level and release profile optimized to correct salivary flow impaired by oxybutynin yet not interfere with the therapeutic muscarinic antagonist effect of oxybutynin upon the sweat glands. OBJECTIVES: This study evaluated safety, efficacy, dry mouth and quality of life with THVD-102 (oxybutynin 7.5 mg / pilocarpine 7.5 mg) in subjects with axillary and / or palmar PFH. METHODS: After a 21-day open label treatment period with oxybutynin 5 mg twice daily to determine susceptibility of subjects to develop dry mouth, eligible subjects were randomized to 1 of 6 sequences of 3 study treatments (THVD-102, oxybutynin 7.5 mg, and placebo) in sequential 21day double-blind crossover treatment periods, each preceded by a washout period of at least 7 days. RESULTS: A total of 24 subjects were randomized and 19 finished all crossover treatments. Changes from baseline to end of treatment in symptoms associated with PFH were statistically significant for both THVD-102 versus placebo and for oxybutynin versus placebo as assessed by multiple measures. Beneficial trends, not statistically significant, for gravimetric measurements were also observed. There were no statistically significant differences between THVD-102 and oxybutynin in PFH efficacy. Fewer subjects reported moderate to severe dry mouth while receiving THVD-102 compared to oxybutynin and more subjects categorized their dry mouth as none or mild while receiving THVD-102 compared to oxybutynin. Differences in reported dry mouth were statistically significant. CONCLUSION: THVD-102 was generally well-tolerated. Both THVD-102 and oxybutynin 7.5 mg twice daily were effective in treating PFH. THVD-102 was associated with significantly reduced dry mouth compared to oxybutynin. J Drugs Dermatol. 2017;16(2):127-132.

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INTRODUCTION

Primary focal hyperhidrosis (PFH) is a condition of bilateral, relatively symmetrical excessive sweating without apparent cause that can occur in one or more locations including the axillae, palms of the hands, soles of the feet, and/ or craniofacial region. While a precise estimate of prevalence is not available, estimates range from 4% to 12% of populations worldwide with a projected US prevalence of 2.8% (more than 9.5 million) based on a survey sample reported in 2004.1Treatment options for PFH include topical aluminum chloride hexahydrate, iontophoresis, intradermal injections of botulinum toxin A (approved for axillary hyperhidrosis), microwave thermolysis (approved and used only for axillary hyperhidrosis), and surgery (including local sweat gland resection or endoscopic thoracic sympathectomy).2 Although not approved for PFH, published studies (mostly uncontrolled) and case reports have shown that some systemic therapies, including muscarinic antagonists (topical and oral), may be effective for PFH. However, the clinical utility of muscarinic antagonists has been limited by side effects, particularly dry mouth.2, 3Oxybutynin is a muscarinic antagonist approved for treating overactive bladder (OAB) at 5 to 20 mg/day. A major dose-limiting side effect is dry mouth, with an incidence of 72.4%.4 Oxybutynin acts on muscarinic receptors throughout the body, including sweat glands, and has been shown to be a

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