Clinical trial NCT02673619: A Study to Evaluate Clinical Effect, Pharmacokinetics , Safety, and Tolerability of Umeclidinium in Palmar Hyperhidrosis Subjects
Official title: A Phase 2a Study to Evaluate the Clinical Effect, Pharmacokinetics, Safety and Tolerability of Topically Applied Umeclidinium in Subjects With Primary Palmar Hyperhidrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hyperhidrosis
Keywords: Topical
Palmar Hyperhidrosis
Umeclidinium
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2016-02-04
Enrollment: 58
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: Umeclidinium (UMEC) is a potent pan-active long-acting muscarinic antagonist (LAMA). It is anticipated that topical administration of UMEC will block stimulation of muscarinic receptors, thereby reducing the overproduction of sweat in subjects who suffer from hyperhidrosis. This study will assess the clinical effect, pharmacokinetics, safety and tolerability of topically applied UMEC following once daily topical administration, for 28 days, to the palms, in subjects with primary palmar hyperhidrosis. The study will also investigate if topically applied UMEC, at the highest possible concentration, will decrease palmar hyperhidrosis with a systemic anticholinergic adverse event profile similar to or below that observed with inhaled administration. This is a double blind (Sponsor unblind), repeat dose, randomized, parallel group, placebo controlled study. Study will enrol up to 55 subjects.


Eligibility criteria: Inclusion Criteria:

* Male or female subjects between 18 and 65 years of age inclusive, at the time of signing the informed consent may be considered for enrolment. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as, Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy OR Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and for 30 days after the last dose of study medication and completion of the follow-up visit.

The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

* The subject has a HDSS score of 3 or 4.
* The subject has a diagnosis of primary, palmar hyperhidrosis, defined as excessive, palmar sweating of at least 6 months duration without apparent cause and with at least one of the following characteristics: Positive family history of hyperhidrosis or Hyperhidrosis is bilateral and relatively symmetrical or First episode of hyperhidrosis before 25 years of age or Cessation of focal sweating during sleep.
* The subject has a Baseline/Day 1 gravimetric assessment of at least 150 mg sweat produced at rest, during a period of 5 minutes separately for each palm. (Measurements can be repeated up to two times on two different days, screening and/or Baseline/Day 1 visits, but subjects need to qualify on at least one occasion for each palm.)
* The subject agrees to avoid to use nicotine-containing products (including nicotine patches) during the treatment period
* The subject is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in protocol

Exclusion Criteria:

* The subject has an unstable or life threatening cardiac disease such as: Myocardial infarction or unstable angina in the last 6 months or Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months or New York Heart Association (NYHA) Class IV heart failure
* The subject has a diagnosis of Type 1 or Type 2 diabetes, or is receiving treatment for control of blood glucose levels.
* The subject has a diagnosis of hyperthyroidism, as confirmed by thyroid stimulating hormone (TSH), or is receiving treatment for hyperthyroidism.
* The subject has a diagnosis of narrow-angle glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction that in the opinion of the study Investigator or Medical Monitor would prevent use of an anticholinergic.
* The subject has irritation or active infection of palm area, including sweat glands.
* The subject has a 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 insignificant)
* The subject has an ALT\>2xUpper limit of normal (ULN) and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) at screening.
* The subject has QT interval corrected for heart rate (QTc) \> 450 milli second (msec) or QTc \> 480 msec in subjects with Bundle Branch Block.

The QTc 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 as specified in the Reporting and Analysis Plan (RAP).

* The subject has a history of allergy or hypersensitivity to anticholinergic/muscarinic receptor antagonist or any ingredient of the preparation.
* The subject has had a prior surgical procedure for palmar hyperhidrosis.
* The subject has had treatment with radiofrequency and/or microwave devices for palmar hyperhidrosis
* The subject has had botulinum toxin injections for palmar hyperhidrosis in the last year prior to Baseline/Day 1
* The subject has had treatment with iontophoresis for palmar hyperhidrosis within 4 weeks prior to Baseline/Day 1
* The subject used antiperspirant on the palms within 2 weeks of the Baseline/Day 1
* The subject is a menopausal female who has had symptoms of menopause such as sweating or flushing within 3 years of Baseline/Day 1
* The subject has used any prohibited medication within the indicated washout period
* The subject tested positive for any of the following at screening or within 3 months of the first scheduled dose of study medication: Hepatitis B surface antigen (HBsAg) and Hepatitis C antibody.
* The subject has a positive pre-study drug and/or alcohol test at screening
* The subject has 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). This does not apply to UMEC when a subject who participated in the 1.85% cohort participates in the 1.15% cohort
* The subject has had exposure to more than four investigational medicinal products within 12 months prior to the first dosing day.
* The subject has any other condition which, in the judgment of the Investigator, would put the subject at unacceptable risk from participation in the study (e.g., subjects with renal failure).
* The subject has clinically significant abnormalities in laboratory values which, according to the Investigator, would put the subject at undue risk due to study participation.
* The subject has abnormal findings on screening ECG deemed clinically significant by the Investigator.
* The subject is pregnant or lactating or is planning on becoming pregnant during the study.

Primary outcomes:
measure: Posterior Probability That the Response Rate is Greater Than 50%
timeFrame: Baseline and Day 29
measure: Percentage of Participants With at Least 30 Percent Reduction From Baseline in Sweat Production at Day 29
timeFrame: Baseline and Day 29
Secondary outcomes:
measure: Percentage of Participants With at Least 50% Reduction From Baseline in Sweat Production at Day 29
timeFrame: Baseline and Day 29
measure: Change From Baseline in Amount of Sweat Produced at Day 29
timeFrame: Baseline and Day 29
measure: Percentage Change From Baseline/Day1 in Amount of Sweat Produced at Day 29
timeFrame: Baseline and Day 29
measure: Number of Participants With Shift of Response in HDSS Score at Day 29
timeFrame: Baseline and Day 29
measure: Percentage of Participants With at Least 2-point Decrease From Baseline to Day 29 in HDSS Score
timeFrame: Baseline and Day 29
measure: Plasma Concentration After Repeat Dosing of UMEC
timeFrame: Pre dose on Day 27 and 28; 3, 6, 9, 10, 12, 16, 24 hours post dose on Day 29; 36 and 48 hours post dose on Day 30
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Day 28
measure: Time of the Maximum Measured Plasma Concentration (Tmax) After Repeat Dosing of UMEC
timeFrame: Pre dose on Day 28; 3, 6, 9, 10, 12, 16, 24 hours post dose on Day 29; 36 and 48 hours post dose on Day 30
measure: The Terminal Plasma Elimination Rate Constant (Lambda z)
timeFrame: Day 28
measure: The Apparent Terminal Phase Half-life (t1/2) After Repeat Dosing of UMEC
timeFrame: Day 28
measure: The Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration [AUC(0-t)] and AUC Over the Dosing Interval Tau, [AUC(0-tau)] After Repeat Dosing of UMEC
timeFrame: Pre dose on Day 28; 3, 6, 9, 10, 12, 16, 24 hours post dose on Day 29; 36 and 48 hours post dose on Day 30
measure: Plasma Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau)
timeFrame: Pre dose on Day 27 and 28; 3, 6, 9, 10, 12, 16, 24 hours post dose on Day 29; 36 and 48 hours post dose on Day 30
measure: Population Pharmacokinetic Profile After Repeat Dosing of UMEC
timeFrame: Pre dose on Day 27 and 28; 3, 6, 9, 10, 12, 16, 24 hours post dose on Day 29; 36 and 48 hours post dose on Day 30
measure: Number of Participants With Adverse Event (AE) and Serious Adverse Events (SAE's)
timeFrame: Up to Day 43
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Day 1, 15 and 29
measure: Number of Participants With Abnormal Values of Hematological Parameters
timeFrame: Day 29
measure: Number of Participants With Abnormal Values of Chemistry Parameters Assessment as a Safety Measure
timeFrame: Day 1, 15 and 29
measure: Number of Participants With Abnormal Urine Analysis
timeFrame: Day 1, 15 and 29
measure: Change From Baseline in Body Temperature Assessment as a Safety Measure
timeFrame: Baseline, Day 15, 27, 28 and 29
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline, Day 15, 27, 28 and 29
measure: Change From Baseline in Heart Rate
timeFrame: Baseline, Day 15, 27, 28 and 29
measure: Change From Baseline in Weight
timeFrame: Baseline and Up to Day 29
measure: Number of Participants With Local Tolerability Assessments
timeFrame: Day 1, 8, 15, 22, 27, 28, 29, 30, 36 and 43
Other outcomes:
Locations:
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Raleigh
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: College Station
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
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: