A Phase 2a Study to Evaluate the Pharmacokinetic, Safety, Tolerability and Clinical Effect of Topically Applied Umeclidinium/GSK573719 in Subjects With Primary Axillary Hyperhidrosis
Overview
- Phase
- Phase 2
- Intervention
- Umeclidinium
- Conditions
- Hyperhidrosis
- Sponsor
- GlaxoSmithKline
- Enrollment
- 28
- Locations
- 1
- Primary Endpoint
- Mean Plasma Concentration After Repeat Dosing of Umeclidinium
- Status
- Completed
- Last Updated
- 7 years ago
Overview
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.
Investigators
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
- •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).
- •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.
Arms & Interventions
Umeclidinium
Subjects will receive umeclidinium once daily before bedtime for 14 days.
Intervention: Umeclidinium
Vehicle
Subjects will receive vehicle once daily before bedtime for 14 days.
Intervention: Vehicle
Outcomes
Primary Outcomes
Mean Plasma Concentration After Repeat Dosing of Umeclidinium
Time Frame: Day 12 to Day 16
Pharmacokinetic blood sampling was done at the following time points: Day 12 (pre-dose), Day 13 (pre-dose), Day 14 (pre-dose), Day 15 (3 hours \[h\], 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). Approximately 3 ml of blood was taken at each timepoint. Mean and standard deviation of the umeclidinium concentration was reported. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
Maximum Observed Concentration (Cmax) and Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) After Repeat Dosing of Umeclidinium
Time Frame: 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)
Pharmacokinetic blood sampling was done at 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). Cmax and Ctau was determined directly from the concentration-time data.
Composite Population Pharmacokinetics Parameter: Absorption Rate Constant (Ka)
Time Frame: Day 12 to Day 16
Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for Ka was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) X 100.
Number of Participants With Local Tolerability Assessment Score Over 28 Days
Time Frame: Days 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, and 23
The investigator or designated evaluator assessed skin tolerability at each visit using the 5-point tolerability scale. Tolerability of the topical application was assessed and scored as, 0- none (no evidence of local intolerance), 1-mild (minimal erythema and/or edema, slight glazed appearance), 2-moderate (definite erythema and/or edema with peeling and/or cracking but needs no adaptation of posology), 3-severe (erythema, edema glazing with fissures, few vesicles or papules), 4- very severe (strong reaction spreading beyond the treated area, bullous reaction, erosions).
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
Time Frame: Day 14 to Day 16
Pharmacokinetic blood sampling was done at 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). Calculated using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. Geometric mean of log-transformed values of AUC were reported.
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])
Time Frame: Day 12 to Day 16
Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for FA and F2 (FIXED) was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) x 100.
Composite Population Pharmacokinetics Parameter: Duration of the Zero Order Process and Lag Time for the First Order Absorption Process (ALAG1)
Time Frame: Day 12 to Day 16
Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for ALAG1 was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) x 100.
Mean Time to Reach Cmax (Tmax) of Umeclidinium After Repeat Dosing
Time Frame: Day 14 to Day 16
Pharmacokinetic blood sampling was done at 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). Tmax was determined directly from the concentration-time data.
Mean Terminal Plasma Elimination Rate Constant (Lambda Z) of Umeclidinium After Repeat Dosing
Time Frame: Day 14 to Day 16
Pharmacokinetic blood sampling was done at 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). Derivation of lambda-Z was planned. However, the parameter could not be derived for any of the participant included in the study because of insufficient data in the elimination phase (\< 3 data points, coefficient of determination (R\^2) was not adequate).
Terminal Phase Half-life (t1/2) of Umeclidinium After Repeat Dosing
Time Frame: Day 14 to Day 16
Pharmacokinetic blood sampling was done at 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). Derivation of t1/2 was planned. However, the parameter could not be derived for any of the participant included in the study because of insufficient data in the elimination phase (\< 3 data points, coefficient of determination (R\^2) was not adequate).
Composite Population Pharmacokinetics Parameter: Volume of Distribution in Central Compartment (V1) and Volume of Distribution in Peripheral Compartment (V2)
Time Frame: Day 12 to Day 16
Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for V1 and V2 was reported as mean (estimate) with relative standard error (RSE). RSE= (Standard error of the estimate/ Final parameter estimate) X 100.
Composite Population Pharmacokinetics Parameter: Elimination Clearance (CL) and Inter-compartmental Clearance (Q)
Time Frame: Day 12 to Day 16
Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for CL and Q was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) X 100.
Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance at Any Time on Treatment
Time Frame: Up to day 28
The clinical chemistry parameters analyzed were albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, gamma glutamyl transferase, glucose, potassium, sodium, total and direct bilirubin, total protein, uric acid. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important clinical chemistry findings at any visit were reported.
Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Event (SAE)
Time Frame: Over a period of 28 days
AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Number of Participants With Abnormal Values of Potential Clinical for Electrocardiogram (ECG)
Time Frame: Up to Day 28
Single 12-lead ECGs was obtained at Day 1, Day 14 and Day 28 during the study. The standard ECG criteria of potential clinical importance were 1) absolute QTc Interval, \> 450 milliseconds (msec), 2) absolute PR Interval, \<110 msec, 3) absolute QRS Interval, \< 75 msec and 4) increase from baseline in QTc \> 60 msec. The number of participants with potentially clinically significant ECG findings at any visit were reported.
Number of Participants With Urinalysis Abnormalities of Potential Clinical Importance at Any Time on Treatment
Time Frame: Up to Day 28
The urinalysis parameters analyzed were specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important urinalysis findings at any visit were reported.
Number of Participants With Abnormal Values of Potential Clinical for Vital Signs
Time Frame: Up to 28 days
The potential clinical importance ranges (low and high) of the vital sign parameters were for systolic blood pressure (\<85 and \>160 millimeter of mercury \[mmHg\]), diastolic blood pressure (\<45 and \>100 mmHg) and heart rate (\<40 and \>110 beats per minute). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important vital parameter findings at any visit were reported.
Number of Participants With Clinical Hematology Abnormalities of Potential Clinical Importance at Any Time on Treatment.
Time Frame: Up to Day 28
The hematology parameters analyzed were basophils, eosinophils, erythrocyte mean corpuscular hemoglobin concentration, erythrocyte mean corpuscular hemoglobin, erythrocyte mean corpuscular volume, erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, neutrophils, platelets, and reticulocytes. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important hematology findings at any visit were reported.
Secondary Outcomes
- Percentage of Participants With Cut-points for Percent Change From Baseline in Sweat Production at Day 15(Baseline (Pre-dose, Day 1) and Day 15)
- Change From Baseline in Amount of Sweat Produced at Day 15(Baseline (Pre-dose, Day 1) and Day 15)
- Change in Hyperhidrosis Disease Severity Scale (HDSS) at Day 15(Baseline (Pre-dose, Day 1) and Day 15)
- Percentage of Participants With 2-point Decrease From Baseline to Day 15 in HDSS Score(Baseline (Pre-dose, Day 1) and Day 15)