Trial Outcomes & Findings for A Study to Evaluate Clinical Effect, Pharmacokinetics , Safety, and Tolerability of Umeclidinium in Palmar Hyperhidrosis Subjects (NCT NCT02673619)

This was a double blind, repeat dose, randomized, parallel group, placebo controlled study to examine the clinical effect, pharmacokinetics, safety and tolerability of topically applied umeclidinium (UMEC) for 28 days, to the palms, in participants with primary palmar hyperhidrosis. The study was conducted at six centers.

Participants were randomized in 4:1 ratio (UMEC: vehicle) to receive UMEC 1.85 percent or vehicle in higher dose cohort and UMEC 1.15 percent or vehicle in lower dose cohort. A total of 140 participants were screened, of which 82 failed screening and 58 participants were randomized into the study.

Age has been presented in two different tables to provide total for higher and lower dose seperately

A response rate is defined as percentage of participants who achieved at least 30 percent decrease from Baseline in gravimetric sweat production at Day 29. Baseline was latest assessment prior to first dosing. A response rate of greater than 50 percent was considered to be clinically meaningful (greater than 50 percent of participants achieving at least 30 percent decrease from Baseline in gravimetric sweat production at Day 29). The posterior probability that response rate in sweat production is greater than 50 percent was analyzed. The evaluation was performed using Bayesian analysis, in which latest pre-dose value was used as Baseline.

Percentage of participants at Day 29 post-treatment with at least a 30 percent reduction from Baseline in sweat production measured by gravimetry. Participants remained at rest for at least 20-30 min before the measurements in order to reduce external interference. The latest pre-dose value was considered as Baseline value. The summary of percentage of participants from both the cohorts with at least 30 percent reduction from Baseline in sweat production was presented for the average of both palms.

Percentage of participants at Day 29 post-treatment with at least a 50 percent reduction from Baseline in sweat production was measured by gravimetric analysis. Participants remained at rest for at least 20-30 min before the measurements in order to reduce external interference. The latest pre-dose value was considered as Baseline value. The summary of percentage of participants from both the cohorts with at least 50 percent reduction from Baseline in sweat production was presented for the average of both palms.

The amount of sweat produced was assessed by gravimetric measurement . Participants remained at rest for at least 20-30 min before the measurements in order to reduce external interference. Baseline value was the latest assessment prior to first dosing. The latest pre-dose value was considered as Baseline value.Change from Baseline value was calculated by post-dose visit value minus Baseline value. The summary of change from Baseline in sweat production has been presented for the average of both palms.

The amount of sweat produced was assessed by gravimetric measurement . Participants remained at rest for at least 20-30 min before the measurements in order to reduce external interference. Baseline value was the latest assessment prior to first dosing. The latest pre-dose value was considered as Baseline value. Percentage change from Baseline was calculated with post-dose visit value minus Baseline value, divided by Baseline value and multiplied by 100. The summary of percentage change from Baseline in sweat production was presented for the average of both palms.

The HDSS was assessed based on a score 1 to 4 .The HDSS is a 4-point scale ranging from 1 (sweating never noticeable and never interferes daily activities), 2 (sweating tolerable but sometimes interferes daily activities), 3(sweating barely tolerable and frequently interferes daily activities) and 4 (sweating intolerable and always interferes daily activities s). A shift table describing change in response in participants from 1.85 percent cohort to 1.15 percent cohort has been presented for weekly average HDSS scores.

The HDSS was assessed based on a score 1 to 4. The HDSS is a 4-point scale ranging from 1 (sweating never noticeable and never interferes daily activities), 2 (sweating tolerable but sometimes interferes daily activities), 3 (sweating barely tolerable and frequently interferes daily activities) and 4 (sweating intolerable and always interferes daily activities). Baseline value was the latest assessment prior to first dosing. The summary of percentage of participants from both the cohorts with at least 2-point decrease from Baseline in HDDS scores was presented.

Blood samples were collected at indicated time points. Samples were collected at nominal times relative to the proposed time of UMEC dosing. NA represents that the values were not available for specific arm or category. The participants with data available at specified time points were represented by n=x in the category titles.

Blood samples were collected to measure Cmax at Day 28. Cmax is the maximum observed concentration, determined directly from the concentration-time data. The geometric mean and geometric coefficient were presented for all log transformed Cmax values.

Blood samples were collected to measure Tmax at indicated time-points. Tmax is the time to reach Cmax, determined directly from the concentration-time data. Mean and standard deviation has been presented for Tmax values.

Blood samples were planned to be collected to measure Lambda Z. The outcome measure was not analyzed due to lack of data availability.

Blood samples were planned to be collected to measure t1/2. The outcome measure was not analyzed due to lack of data availability.

Blood samples were collected to measure AUC(0-t) at indicated time-points. AUC(0-t) and AUC(0-tau) was calculated by the linear up and log down trapezoidal method. Samples were collected at nominal times relative to the proposed time of UMEC dosing. The participants with data available at specified time points were represented by n=x in the category titles.

Trough (pre-dose at the end of each dosing interval) plasma concentration (Ctau) was analyzed at indicated time-points. Trough concentration samples were used for the assessment/attainment of steady state (ss). Samples were collected at nominal times relative to the proposed time of UMEC dosing. NA represents the data was not available for specific arm or category.

Population pharmacokinetic profiling was planned to characterize the population pharmacokinetics of UMEC administered topically to both palms in participants with palmar hyperhidrosis. Due to the fact that the majority of the pharmacokinetic samples were below the limit of quantitation, a population pharmacokinetic analysis could not be performed.

An AE was any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE was defined as any untoward medical occurrence that, that results in death, life-threatening, requires hospitalization or prolongation of existing hospitalization, disability/incapacity, any a congenital anomaly/birth defect or other situations at any dose.

Single measurements of 12-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. ECG values were recorded as abnormal not clinically significant (NCS) and abnormal clinically significant (CS). The participants with data available at specified time points were represented by n=x in the category titles.

Blood samples were collected from participants for evaluation of hematology parameters by Potential Clinical Chemistry Criteria. The data was presented for only those hematology parameters for which abnormal values were found (neutrophils and hemoglobin) . During the analysis, no participant in the higher dose cohort- vehicle group, nor in the lower dose cohort (for both UMEC and vehicle groups) had abnormal hematology values that met the pre-specified criteria for potential clinical importance. Hence, the data for only higher dose cohort was presented. The measurements taken at Day 29 were presented. Participants were counted in the category for their values greater than (\>) reference (ref) range high and less than (\<) ref range low. The participants with data available at specified time points were represented by n=x in the category titles.

Blood samples were collected to analyze the abnormal clinical chemistry parameters by Potential Clinical Importance Criteria. The data was presented for only those parameters for which abnormal values were found (calcium, alanine aminotransferase \[ALT\]). Participants in the higher dose cohort (UMEC group) had abnormal calcium values and for ALT, the abnormal values were found in lower dose cohort (UMEC group). Hence, data was presented only for these specific cohorts. Participants were counted in the category for their values \> ref range high and \< ref range low. The measurements taken at Day 1, Day 15 and Day 29 were presented. The participants with data available at specified time points were represented by n=x in the category titles. "n=0" in category titles represents that the data was not available for participants in respective category or arm.

Urine sample were taken to analyze glucose and protein levels, blood and ketones body.Urinalysis analytes were measured by dipstick test. Results have been reported in a semi-quantitative manner as negative, Trace, 1+, 2+, 3+ and 4+, indicating proportional concentrations of the analyte in the urine sample. Abnormal laboratory values have been presented in the table. The participants with data available at specified time points were represented by n=x in the category titles.

Body temperature was measured as a vital sign in seated position, after 5 min rest. Baseline value was the latest assessment prior to first dosing. Change from Baseline value was calculated by post-dose visit value minus Baseline value. The participants with data available at specified time points were represented by n=x in the category titles.

Vital signs including SBP and DBP were measured in a seated position, after 5 minutes rest. Baseline value was the latest assessment prior to first dosing. Change from Baseline value was calculated by post-dose visit value minus Baseline value. The participants with data available at specified time points were represented by n=x in the category titles.

Heart rate was measured in a seated position, after 5 minutes rest. Baseline value was the latest assessment prior to first dosing. Change from Baseline value was calculated by post-dose visit value minus Baseline value. The participants with data available at specified time points were represented by n=x in the category titles.

Weight measurement was performed as a measure of safety. Baseline value was the latest assessment prior to first dosing. Change from Baseline value was calculated by post-dose visit value minus Baseline value.

Skin tolerability was assessed by a 5-point tolerability scale ranging from 0 to 4; where 0 (no irritation), 1 (mild), 2 (moderate), 3 (severe) to 4 (Very Severe).The participants with data available at specified time points were represented by n=x in the category titles.