Pharmacokinetic, Safety, Tolerability, and Clinical Effect of Topical Umeclidinium in Primary Axillary Hyperhidrosis
Condition: Hyperhidrosis
MeSH terms: Hyperhidrosis
Intervention: Umeclidinium; Vehicle
Intervention description: Umeclidinium (GSK573719) 1.85% will be supplied as a clear, colorless solution, free from visible particulates, for topical application. This formulation will be available at a concentration of 18.5 milligrams (mg) umeclidinium parent per gram. 2 mg of this formulation will be applied per square centimeter of the axilla, once a day at night before going to bed for 14 days. The total amount of formulation applied daily to both axillae is expected to range between approximately 204 and 680 mg. Total daily dosage of the active pharmaceutical ingredient (umeclidinium parent) to both axillae will range between approximately 3.8 and 12.6 mg. If certain pre-specified criteria for safety and tolerability are met, consideration will be given to decreasing the dose by decreasing the concentration of the topical formulation to 1.15% for the remaining subjects. This lower strength formulation will contain 11.5 mg parent per gram.; The vehicle will be supplied as a clear, colorless solution, free from visible particulates, for topical application. This formulation will be similar to the umeclidinium formulation except that it will be devoid of the umeclidinium parent. 2 mg of the vehicle will be applied per square centimeter of the axilla, once a day at night before going to bed for 14 days. The total amount of vehicle applied daily to both axillae is expected to range between approximately 204 and 680 mg.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Primary Axillary Hyperhidrosis; GSK573719; Hyperhidrosis Disease Severity Scale (HDSS); Topical; PRO; Hyperhidrosis Symptom Severity Measure (HSSM); Umeclidinium

Summary:

      This is a double blind (sponsor unblind), repeat dose, randomized, parallel group, placebo
      controlled study to assess the pharmacokinetic parameters, safety, tolerability, and clinical
      effect of topically applied umeclidinium following once daily topical administration to
      axilla for 14 days in subjects with primary axillary hyperhidrosis. This study will determine
      whether topically applied umeclidinium can decrease hyperhidrosis without systemic
      anticholinergic effects (ie. in the range or lower to those obtained after inhaled route) at
      the highest possible concentration.

      Subjects will be dosed by site staff each night immediately before bedtime for 14 days.
      Subjects will complete gravimetric and Hyperhidrosis Disease Severity Scale (HDSS)
      measurements, patient reported outcomes (PRO), safety assessments, and/or pharmacokinetic
      sampling. Follow up visits will occur on days 15, 16, 19, 23 and 28. The total duration of
      the study will be approximately 6 to 8 weeks. The study is planned to enroll approximately 24
      subjects.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 65 years of age inclusive, at the time of signing the informed consent.

          -  A Hyperhidrosis Disease Severity Scale (HDSS) score of 3 or 4.

          -  A diagnosis of primary, axillary hyperhidrosis, defined as excessive, bilateral,
             axillary sweating of at least 6 months duration without apparent cause and with at
             least 1 of the following characteristics: subject has a positive family history of
             hyperhidrosis, hyperhidrosis is bilateral and relatively symmetrical, subject
             experienced first episode of hyperhidrosis before 25 years of age, subject experiences
             cessation of focal sweating during sleep.

          -  A baseline gravimetric assessment of at least 50 milligrams sweat produced at rest by
             each axilla during a period of 5 minutes (measurements can be repeated up to 2 times
             on two different days, screening and baseline visits, but subjects need to qualify on
             at least one occasion).

          -  Male.

          -  A female is eligible to enter and participate in the study if she is of:

        Non-child bearing potential (i.e., physiologically incapable of becoming pregnant,
        including any female who is post-menopausal or surgically sterile). Surgically sterile
        females are defined as those with a documented hysterectomy and/or bilateral oophorectomy
        or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater
        than 1 year with an appropriate clinical profile, e.g., age appropriate, > 45 years, in the
        absence of hormone replacement therapy. In questionable cases for women < 60 years of age,
        a blood sample with simultaneous follicle stimulating hormone and estradiol falling into
        the central laboratory's postmenopausal reference range is confirmatory.

        OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one
        of the following acceptable contraceptive methods used consistently and correctly (i.e., in
        accordance with the approved product label and the instructions of the physician) for the
        duration of the study: abstinence; oral contraceptive, either combined or progestogen
        alone; injectable progestogen; implants of levonorgestrel; estrogenic vaginal ring;
        percutaneous contraceptive patches; intrauterine device (IUD) or intrauterine system (IUS)
        that meets the standard operating procedure effectiveness criteria as stated in the product
        label; male partner sterilization (vasectomy with documentation of azoospermia) prior to
        the female subject's entry into the study, and this male is the sole partner for that
        subject; double barrier method: condom and an occlusive cap (diaphragm or cervical/vault
        caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository

          -  If subjects have shaved axilla or removed hair by other means within the last 2 weeks,
             there should be minimal to no irritation.

          -  Capable of giving signed informed consent which includes compliance with the
             pre-specified requirements and restrictions.

        Exclusion Criteria:

          -  Unstable or life threatening cardiac disease. In the opinion of the investigator, use
             should only be considered if the benefit is likely to outweigh the risk in conditions
             such as: myocardial infarction or unstable angina in the last 6 months, unstable or
             life threatening cardiac arrhythmia requiring intervention in the last 3 months, New
             York Heart Association (NYHA) Class IV heart failure.

          -  Diagnosis of narrow-angle glaucoma, urinary retention, prostatic hypertrophy or
             bladder neck obstruction that in the opinion of the study investigator or
             GlaxoSmithKline (GSK) Medical Monitor would prevent use of an anticholinergic and
             therefore study participation.

          -  Irritation or active infection of axillary area, including sweat glands.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones that the
             investigator deems clinically significant).

          -  Alanine aminotransferase (ALT) > 2 x Upper Limit of Normal (ULN) and bilirubin
             >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and
             direct bilirubin < 35%) at screening.

          -  Corrected QT Interval (QTc) > 450 milliseconds (ms) or QTc > 480 ms in subjects with
             Bundle Branch Block.

        The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB),
        Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.

        The specific formula that will be used to determine eligibility and discontinuation for an
        individual subject should be determined prior to initiation of the study. In other words,
        several different formulae cannot be used to calculate the QTc for an individual subject
        and then the lowest QTc value used to include or discontinue the subject from the trial.

        For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of
        available values of QTc will be used.

          -  Prior surgical procedure for hyperhidrosis.

          -  Axillary treatment with radiofrequency and microwave devices.

          -  Treatment with axillary iontophoresis within 4 weeks prior to Baseline/Day 1.

          -  Menopausal women who have had symptoms of menopause such as sweating or flushing
             within 3 years of the study.

          -  Used any prohibited medication within the indicated washout period.

          -  Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor
             antagonist, sympathomimetic.

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment.

          -  A positive pre-study drug/alcohol screen at screening.

          -  A positive test for Human Immunodeficiency Virus (HIV) antibody at screening.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time periods prior to the first dosing day in the current
             study: 30 days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than 4 investigational medicinal products within 12 months prior to
             the first dosing day.

          -  Any other condition which, in the judgment of the investigator, would put the subject
             at unacceptable risk for participation in the study (e.g., subjects with renal
             failure).

          -  Subjects with clinically significant abnormalities in laboratory values for which,
             according to the investigator, study participation would put the subject at undue
             risk.

          -  Abnormal findings on screening electrocardiogram (ECG) deemed clinically significant
             by the Investigator.

          -  Women who are pregnant or lactating or are planning on becoming pregnant during the
             study.