Trial Outcomes & Findings for Study to Evaluate Safety & Efficacy of d-Amphetamine Transdermal System vs Placebo in Children & Adolescents With ADHD (NCT NCT01711021)

Last Updated: 2023-12-21

Results Overview

The SKAMP total score comprises all 13 items. The SKAMP was designed for independent observers to rate 13 items representing 2 factors of classroom behavior: attention (SKAMP-A) and deportment (SKAMP-D), as well as quality of work. Items are specific to place (classroom setting) \& time (during a typical classroom period), \& the scale is used to assess multiple ratings taken within a day. The SKAMP-D subscale evaluates deportment, including interacting with other children, interacting with adults, remaining quiet according to classroom rules, \& staying seated according to classroom rules. The SKAMP-A subscale is a measure of attention \& evaluates getting started on assignments, sticking with tasks, attending to an activity, and making activity transitions. The SKAMP quality of work subscale includes 3 items: completing assigned work, performing work accurately, and being careful and neat while writing or drawing. Scores range from 0-78 with higher scores indicating worse impairment.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

110 participants

Primary outcome timeframe

Mean SKAMP Total Score of SKAMP Total Scores from 9 different time points including (1, 2, 3, 4.5, 6, 7, 9, 10, 12 hours post-dose)

Results posted on

2023-12-21

Participant Flow

The study consisted of 2 study periods. Period 1 is a 5-week open-label Dose Optimization Study with only one arm, Period 2 is a randomized, cross-over, double-blind treatment study (2 weeks). A total of 110 subjects were enrolled into the Dose Optimization Treatment (Period 1). 4 subjects did not complete the Dose Optimization Period. 106 subjects were randomized into the Double-Blind Treatment Period (Period 2).

Participant milestones

Participant milestones
Measure	d-Amphetamine Transdermal Patch The study consisted of 2 study periods. Period 1 is a 5-week open-label Dose Optimization Study with only one arm, Period 2 is a randomized, cross-over, double-blind treatment study (2 weeks). A total of 110 subjects were enrolled into the Dose Optimization Treatment (Period 1). 4 subjects did not complete the Dose Optimization Period. 106 subjects were randomized into the Double-Blind Treatment Period (Period 2). Arm Titles are defined for Period 2 (Open-Label Dose Optimization Treatment). For Period 1 study, there is only 1 arm. All participants started with the lowest dose of d-Amphetamine Transdermal System. Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied. Patients return for a visit every week to evaluate whether to increase the dose next week for 5 weeks until an optimized dose was identified. For Period 2 study, participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment.	Placebo Patch Period 1 is open-label, Dose Optimization Treatment Period and has only one treatment arm. No placebo patch were used. Placebo Patch was used in Double-Blind Treatment Period, which has 2 arms.
Open-Label Dose Optimization Period STARTED	110	0
Open-Label Dose Optimization Period COMPLETED	106	0
Open-Label Dose Optimization Period NOT COMPLETED	4	0
Double-blind Cross-Over Treatment Period STARTED	53	53
Double-blind Cross-Over Treatment Period COMPLETED	46	46
Double-blind Cross-Over Treatment Period NOT COMPLETED	7	7

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study to Evaluate Safety & Efficacy of d-Amphetamine Transdermal System vs Placebo in Children & Adolescents With ADHD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Baseline Characteristics for All Subjects Enrolled n=110 Participants Baseline Characteristics are presented for all subjects that were enrolled (n=110).
Age, Categorical <=18 years	110 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	10.5 years STANDARD_DEVIATION 3.09 • n=5 Participants
Age, Customized Median Age	10 years n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants
Sex: Female, Male Male	76 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	70 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	15 Participants n=5 Participants
Race (NIH/OMB) White	84 Participants n=5 Participants
Race (NIH/OMB) More than one race	7 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
BMI	18.68 kg/m^2 STANDARD_DEVIATION 3.369 • n=5 Participants

PRIMARY outcome

Timeframe: Mean SKAMP Total Score of SKAMP Total Scores from 9 different time points including (1, 2, 3, 4.5, 6, 7, 9, 10, 12 hours post-dose)

Population: Full Analysis Set: included all consented and randomized subjects who took at least 1 dose of study of medication

Outcome measures

Outcome measures
Measure	d-Amphetamine Transdermal Patch n=100 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.	Placebo Patch n=101 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Mean Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Total Score During the Double-Blind Treatment Period	12.81 score on a scale Standard Error .32	18.67 score on a scale Standard Error .322

SECONDARY outcome

Timeframe: Onset of efficacy defined as the time of the first assessment time showing statistical significance between d-ATS and placebo. 2 hours post-dose in Double-Blind Treatment Period

Population: Full Analysis Set: included all consented and randomized subjects who took at least 1 dose of study of medication.

Onset of efficacy defined as the time of the first assessment time showing statistical significance between d-ATS and placebo. The time point for the reported data are SKAMP scores (LS mean) from 2 hours post-dose. The SKAMP total score comprises all 13 items. The SKAMP was designed for independent observers to rate 13 items representing 2 factors of classroom behavior: attention (SKAMP-A) and deportment (SKAMP-D), as well as quality of work. Items are specific to place (classroom setting) \& time (during a typical classroom period), \& the scale is used to assess multiple ratings taken within a day. Scores range from 0-78 with higher scores indicating worse impairment.

Outcome measures

Outcome measures
Measure	d-Amphetamine Transdermal Patch n=103 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.	Placebo Patch n=101 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Onset of Efficacy Measured by Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Total Score	12.2 score on a scale Standard Error 1.01	19.0 score on a scale Standard Error 1.02

SECONDARY outcome

Timeframe: Duration of Effect was from onset (2 hours post-dose) and up to 12 hours post-dose (p<0.001)

Population: Full Analysis Set: included all consented and randomized subjects who took at least 1 dose of study of medication.

Duration of Effect is the difference between the End of Effect and Onset of Effect in hours, where End of Effect is the first time point after Onset of Effect at which the 50% reduction in SKAMP total score from pre-dose is not observed.

Outcome measures

Outcome measures
Measure	d-Amphetamine Transdermal Patch n=61 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.	Placebo Patch n=20 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Duration of Effect for d-Amphetamine and Placebo Treatment	2.6 Hours Standard Error 2.08	1.7 Hours Standard Error 0.96

SECONDARY outcome

Timeframe: 1,2, 3, 4.5,6,7,9,10 and 12 hours post-dose from double-blind treatment period

Population: Full Analysis Set: included all consented and randomized subjects who took at least 1 dose of study of medication

To assess efficacy of d-ATS compared to placebo as measured by the PERMP-C (number of correct answers) and PERMP-A (number of attempted answers) score. The PERMP is an age-adjusted written math test, of 10 minutes' duration administered at multiple time points. Subjects are given 5 pages of 80 math problems (400 total problems) and are instructed to work at their desks and to complete as many problems as possible in 10 minutes. Performance is measured as the number of problems attempted (PERMP-A) and the number of problems worked correctly (PERMP-C). The scores range from 0-800 with higher scores indicating better performance.

Outcome measures

Outcome measures
Measure	d-Amphetamine Transdermal Patch n=106 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.	Placebo Patch n=106 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 3 hours	141.2 score on a scale Standard Error 6.02	93.7 score on a scale Standard Error 6.07
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 4.5 hours	141.5 score on a scale Standard Error 6.02	97.9 score on a scale Standard Error 6.07
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 7 hours	139.7 score on a scale Standard Error 6.02	96.2 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 9 hours	139.0 score on a scale Standard Error 6.07	102.9 score on a scale Standard Error 6.07
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 10 hours	132.4 score on a scale Standard Error 6.07	98.9 score on a scale Standard Error 6.07
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 3 hours	144.0 score on a scale Standard Error 6.04	97.4 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 6 hours	139.7 score on a scale Standard Error 6.02	94.3 score on a scale Standard Error 6.07
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 12 hours	135.3 score on a scale Standard Error 6.07	96.4 score on a scale Standard Error 6.07
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 1 hour	126.6 score on a scale Standard Error 6.07	116.3 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 2 hours	142.7 score on a scale Standard Error 6.04	106.3 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 4.5 hours	144.0 score on a scale Standard Error 6.04	100.9 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 6 hours	142.0 score on a scale Standard Error 6.04	96.8 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 7 hours	142.3 score on a scale Standard Error 6.04	98.9 score on a scale Standard Error 6.13
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 9 hours	141.7 score on a scale Standard Error 6.10	106.8 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 10 hours	134.7 score on a scale Standard Error 6.10	102.1 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-A at 12 hours	137.4 score on a scale Standard Error 6.10	100.1 score on a scale Standard Error 6.10
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 2 hours	139.8 score on a scale Standard Error 6.02	103.8 score on a scale Standard Error 6.07
Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose PERMP-C at 1 hour	124.0 score on a scale Standard Error 6.04	113.1 score on a scale Standard Error 6.07

SECONDARY outcome

Timeframe: Averaged from week 6 and week 7 results during the Double-Blind Cross-Over treatment period.

Population: Full Analysis Set

The ADHD-RS-IV is based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria to assess efficacy of d-ATS compared to placebo. The ADHD-RS-IV scale was developed to measure the behaviors of children with ADHD, and it consists of 18 items designed to reflect current symptomatology of ADHD based on DSM-IV criteria. Each item is scored from a range of 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0 to 54. Note: Week 6 is the first week of the double-blind treatment period, week 7 is the second week of the double-blind treatment period.

Outcome measures

Outcome measures
Measure	d-Amphetamine Transdermal Patch n=104 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.	Placebo Patch n=106 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Change in the Clinician-rated Scale of ADHD Symptoms Based on DSM-IV-TR Criteria (ADHD-RS-IV).	-23.4 score on a scale Standard Deviation 1.02	-10.3 score on a scale Standard Deviation 1.02

SECONDARY outcome

Timeframe: Combined analysis by treatment groups from week 6 and week 7 (averaged)

Population: Full Analysis Set Double-Blind period Week 6 and Week 7

The CPRS-R:S evaluates problem behaviors as reported by the parent or alternative caregivers. The CPRS-R:S total score comprises 27 items and covers a subset of the subscales and items on the long parent form. The score ranges from 0-81 calculated from summed subscales scores. Higher score is considered a worse outcome for ADHD patients. Note: Week 6 is the first week of the double-blind treatment period, week 7 is the second week of the double-blind treatment period.

Outcome measures

Outcome measures
Measure	d-Amphetamine Transdermal Patch n=100 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.	Placebo Patch n=100 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Conners Parent Rating Scale Revised Short Form (CPRS-R:S) Total Scores From Week 6 and Week 7	23.5 score on a scale Standard Error 1.75	39.5 score on a scale Standard Error 1.75

SECONDARY outcome

Timeframe: the double-blind treatment period

Population: Responder includes the categories "Very Much Improved" and "Much Improved"; "Non-Responder" includes all other categories, with the exception of "not assessed" which has been considered missing data. Note: the Full Analysis Set is 106 (N)

The CGI scale permits a global evaluation of the subject's improvement over time. During the Dose Optimization Period and the Double-Blind Treatment Period, the investigator assessed the subject's improvement relative to symptoms prior to dosing, using the CGI-I Scale. For CGI-I scale, the responders are defined as subjects achieving a score of 1. Very much improved or 2. Much improved or The non-responders are defined as subjects achieving a score of 3. Minimally improved on the clinician-rated CGI global improvement item or 4. No change or 5. Minimally worse or 6. Much worse or 7. Very much worse Then the number of responders are calculated by treatment arms. Note: Week 6 is the first week of the double-blind treatment period, week 7 is the second week of the double-blind treatment period.

Outcome measures

Outcome measures
Measure	d-Amphetamine Transdermal Patch n=106 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.	Placebo Patch n=106 Participants Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.
Number of Responders Evaluated by Clinical Global Impression (CGI-I) Scale by Treatments From the Double-blind Treatment Period	89 Participants	25 Participants

Adverse Events

All d-ATS Treatment During the Dose-Optimization Phase

Serious events: 0 serious events

Other events: 108 other events

Deaths: 0 deaths

d-ATS Patch Treated Arm During the Double Blind Phase

Serious events: 0 serious events

Other events: 44 other events

Deaths: 0 deaths

Placebo Treated Arm During the Double Blind Phase

Serious events: 0 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Study Director

Noven Pharmaceuticals, Inc.

Phone: (305) 253-5099

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	All d-ATS Treatment During the Dose-Optimization Phase n=110 participants at risk This includes subjects that started the one arm Dose-Optimization Study in Period 1 and continued into Double-Blind, Cross-Over, Placebo-Controlled Treatment study in Period 2. The adverse events are reported for adverse events including all d-ATS doses during Dose-Optimization Study Phase (Period 1).	d-ATS Patch Treated Arm During the Double Blind Phase n=106 participants at risk This includes subjects that started the one arm Dose-Optimization Study in Period 1 and continued into Double-Blind, Cross-Over, Placebo-Controlled Treatment study in Period 2. The adverse events are reported from subjects who received d-ATS patch treatment during the double blind phase.	Placebo Treated Arm During the Double Blind Phase n=106 participants at risk This includes subjects that started the one arm Dose-Optimization Study in Period 1 and continued into Double-Blind, Cross-Over, Placebo-Controlled Treatment study in Period 2. The adverse events are reported from subjects who received placebo patch treatment.
Metabolism and nutrition disorders Decreased appetite	58.2% 64/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	12.3% 13/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	1.9% 2/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Metabolism and nutrition disorders Hyperkalemia	8.2% 9/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	3.8% 4/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	4.7% 5/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Psychiatric disorders Insomnia	26.4% 29/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	5.7% 6/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	4.7% 5/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Psychiatric disorders Affect lability	12.7% 14/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	2.8% 3/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.00% 0/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Psychiatric disorders Initial insomnia	9.1% 10/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.00% 0/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
General disorders Irritability	19.1% 21/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	1.9% 2/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
General disorders Application site pain	10.9% 12/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.00% 0/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.00% 0/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
General disorders Fatigue	9.1% 10/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
General disorders Application site pruritis	8.2% 9/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
General disorders Pyrexia	6.4% 7/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Nervous system disorders Headache	29.1% 32/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	5.7% 6/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	3.8% 4/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Nervous system disorders Dizziness	5.5% 6/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	1.9% 2/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Infections and infestations Upper respiratory tract infection	11.8% 13/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	1.9% 2/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Infections and infestations Nasopharyngitis	10.0% 11/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	2.8% 3/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	1.9% 2/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Respiratory, thoracic and mediastinal disorders Cough	25.5% 28/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	1.9% 2/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	2.8% 3/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Respiratory, thoracic and mediastinal disorders Nasal congestion	15.5% 17/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.00% 0/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	2.8% 3/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Gastrointestinal disorders Abdominal upper pain	14.5% 16/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	2.8% 3/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Gastrointestinal disorders Nausea	11.8% 13/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	2.8% 3/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Gastrointestinal disorders Vomiting	7.3% 8/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	3.8% 4/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.00% 0/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.
Gastrointestinal disorders Abdominal Pain	6.4% 7/110 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	2.8% 3/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.	0.94% 1/106 • From beginning of Dose-Optimization Phase (5-week) through double blind treatment phase (2-week), up to 7 weeks total.