Clinical trial NCT02563899: Pharmacokinetic, Safety, Tolerability, and Clinical Effect of Topical Umeclidinium in Primary Axillary Hyperhidrosis
Official title: A Phase 2a Study to Evaluate the Pharmacokinetic, Safety, Tolerability and Clinical Effect of Topically Applied Umeclidinium/GSK573719 in Subjects With Primary Axillary Hyperhidrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hyperhidrosis
Keywords: Primary Axillary Hyperhidrosis
GSK573719
Hyperhidrosis Disease Severity Scale (HDSS)
Topical
PRO
Hyperhidrosis Symptom Severity Measure (HSSM)
Umeclidinium
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2015-09-30
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Mean Plasma Concentration After Repeat Dosing of Umeclidinium
timeFrame: Day 12 to Day 16
measure: Maximum Observed Concentration (Cmax) and Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) After Repeat Dosing of Umeclidinium
timeFrame: Day 14 (pre-dose), Day 15 (3 h, 6 h, 9 h, 10 h, 12 h, 16 h, and 24 h following the Day 14 dose), Day 16 (36 h and 48 h following the Day 14 dose)
measure: Mean Time to Reach Cmax (Tmax) of Umeclidinium After Repeat Dosing
timeFrame: Day 14 to Day 16
measure: Mean Terminal Plasma Elimination Rate Constant (Lambda Z) of Umeclidinium After Repeat Dosing
timeFrame: Day 14 to Day 16
measure: Terminal Phase Half-life (t1/2) of Umeclidinium After Repeat Dosing
timeFrame: Day 14 to Day 16
measure: Mean Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Across All Treatments (0-t) and AUC Over the Dosing Interval (0-tau) of Umeclidinium After Repeat Dosing
timeFrame: Day 14 to Day 16
measure: Composite Population Pharmacokinetics Parameter: Volume of Distribution in Central Compartment (V1) and Volume of Distribution in Peripheral Compartment (V2)
timeFrame: Day 12 to Day 16
measure: Composite Population Pharmacokinetics Parameter: Elimination Clearance (CL) and Inter-compartmental Clearance (Q)
timeFrame: Day 12 to Day 16
measure: Composite Population Pharmacokinetics Parameter: Absorption Rate Constant (Ka)
timeFrame: Day 12 to Day 16
measure: Composite Population Pharmacokinetics Parameter: Absolute Plasma Bioavailability Following Administration to Axilae (FA) Fraction of the Bioavailable Drug Absorbed Through a Zero Order Process (F2 [FIXED])
timeFrame: Day 12 to Day 16
measure: Composite Population Pharmacokinetics Parameter: Duration of the Zero Order Process and Lag Time for the First Order Absorption Process (ALAG1)
timeFrame: Day 12 to Day 16
measure: Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Event (SAE)
timeFrame: Over a period of 28 days
measure: Number of Participants With Abnormal Values of Potential Clinical for Electrocardiogram (ECG)
timeFrame: Up to Day 28
measure: Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance at Any Time on Treatment
timeFrame: Up to day 28
measure: Number of Participants With Clinical Hematology Abnormalities of Potential Clinical Importance at Any Time on Treatment.
timeFrame: Up to Day 28
measure: Number of Participants With Urinalysis Abnormalities of Potential Clinical Importance at Any Time on Treatment
timeFrame: Up to Day 28
measure: Number of Participants With Abnormal Values of Potential Clinical for Vital Signs
timeFrame: Up to 28 days
measure: Number of Participants With Local Tolerability Assessment Score Over 28 Days
timeFrame: Days 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, and 23
Secondary outcomes:
measure: Change From Baseline in Amount of Sweat Produced at Day 15
timeFrame: Baseline (Pre-dose, Day 1) and Day 15
measure: Percentage of Participants With Cut-points for Percent Change From Baseline in Sweat Production at Day 15
timeFrame: Baseline (Pre-dose, Day 1) and Day 15
measure: Change in Hyperhidrosis Disease Severity Scale (HDSS) at Day 15
timeFrame: Baseline (Pre-dose, Day 1) and Day 15
measure: Percentage of Participants With 2-point Decrease From Baseline to Day 15 in HDSS Score
timeFrame: Baseline (Pre-dose, Day 1) and Day 15
Other outcomes:
Locations:
city: Raleigh
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: