Trial Outcomes & Findings for A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis (NCT NCT03738800)

Last Updated: 2023-08-14

Results Overview

The percentage of subjects in each treatment group who experienced successful resolution of LI where "success" is defined as clear/almost clear on treated areas and at least a 2-grade change from Baseline at Day 90/end-of-treatment (EOT) in the Double-blind Period on the 5-point IGA full body scale.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

65 participants

Primary outcome timeframe

90 Days

Results posted on

2023-08-14

Participant Flow

Participant milestones

Participant milestones
Measure	CD5789 Cream 200 µg/g CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA
Double-blind Treatment Period STARTED	23	21	21
Double-blind Treatment Period COMPLETED	14	18	17
Double-blind Treatment Period NOT COMPLETED	9	3	4
Open Label Extension STARTED	49	0	0
Open Label Extension COMPLETED	39	0	0
Open Label Extension NOT COMPLETED	10	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	CD5789 Cream 200 µg/g CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA
Double-blind Treatment Period Withdrawal by Subject	2	0	0
Double-blind Treatment Period Study Discontinued By Sponsor	5	3	3
Double-blind Treatment Period Lack of Efficacy	2	0	1

Baseline Characteristics

A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CD5789 Cream 200 µg/g n=23 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=21 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=21 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Total n=65 Participants Total of all reporting groups
Age, Categorical <=18 years	8 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants	13 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	15 Participants n=5 Participants	14 Participants n=7 Participants	19 Participants n=5 Participants	48 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Age, Continuous	32.1 years STANDARD_DEVIATION 17.08 • n=5 Participants	35.1 years STANDARD_DEVIATION 20.70 • n=7 Participants	31.5 years STANDARD_DEVIATION 13.34 • n=5 Participants	32.9 years STANDARD_DEVIATION 17.09 • n=4 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	16 Participants n=7 Participants	14 Participants n=5 Participants	41 Participants n=4 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants	24 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=5 Participants	17 Participants n=7 Participants	20 Participants n=5 Participants	60 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	8 Participants n=4 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	15 Participants n=7 Participants	13 Participants n=5 Participants	46 Participants n=4 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
5-point Investigator's Global Assessment [IGA]	3.5 units on a scale STANDARD_DEVIATION 0.51 • n=5 Participants	3.5 units on a scale STANDARD_DEVIATION 0.51 • n=7 Participants	3.3 units on a scale STANDARD_DEVIATION 0.48 • n=5 Participants	3.4 units on a scale STANDARD_DEVIATION 0.50 • n=4 Participants

PRIMARY outcome

Timeframe: 90 Days

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=15 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=17 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=17 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream Intent-to-treat population, secondary outcome
The Percentage of Subjects in Each Treatment Group Who Experienced Successful Resolution of LI.	0 Participants	2 Participants	0 Participants	—

SECONDARY outcome

Timeframe: 90 Days

Population: Intent-to-treat population

5-point Visual Index for Ichthyosis Severity (VIIS) for scaling (overall 16 points) for scaling, i.e. 0-4 points for 4 body areas: chest/abdomen, back, arms and legs) where minimum is 0 and maximum is 16 (e.g. 4 points for each of the four body parts). 0 (Clear) No scaling 1. (Almost Clear) Very fine, non-coalescent scales 2. (Mild) Small and thin, non-coalescent scales 3. (Moderate) Large and rather thick scales starting to coalesce 4. (Severe) Very large, adherent, coalescent and very thick scales

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=15 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=17 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=32 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream n=17 Participants Intent-to-treat population, secondary outcome
Total 16-point Visual Index for Ichthyosis Severity (VIIS)	10.9 units on a scale Standard Deviation 4.24	10.9 units on a scale Standard Deviation 3.51	10.9 units on a scale Standard Deviation 3.86	11.4 units on a scale Standard Deviation 2.94

SECONDARY outcome

Timeframe: 90 Days

Population: Intent-to-treat population

The amount of roughness of the skin will be measured on a 5-point scale. 0 (Clear) Smooth skin 1. (Almost Clear) Hardly palpably roughness 2. (Mild) Mild roughness (fine sand paper-like) 3. (Moderate) Moderate, coarse roughness (coarse sand paper-like) 4. (Severe) Very coarse skin (broken cornflakes-like)

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=15 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=17 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=32 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream n=17 Participants Intent-to-treat population, secondary outcome
The Difference in Mean Scores Using Individual Score for Roughness	2.7 score on a scale Standard Deviation 1.10	2.7 score on a scale Standard Deviation 0.99	2.7 score on a scale Standard Deviation 1.02	3.1 score on a scale Standard Deviation 0.78

SECONDARY outcome

Timeframe: 90 Days

Population: Intent-to-treat population, secondary endpoint

Thickening of the skin on the palms and soles will be measured on a 5-point scale: 0 (Clear) No thickening, no roughness, no fissure 1. (Almost Clear) Only slight thickening, minimal to no roughness, no fissures 2. (Mild) Some thickening, mild roughness on palpation, few fissures may be present 3. (Moderate) Substantial and diffuse thickening, coarse roughness on palpation may be present, fissures may be present 4. (Severe) Very thickened and rough skin, numerous fissures

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=15 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=17 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=32 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream n=17 Participants Intent-to-treat population, secondary outcome
The Difference in Mean Scores Using Palm Sole Assessment	2.1 score on a scale Standard Deviation 1.06	1.6 score on a scale Standard Deviation 1.27	1.9 score on a scale Standard Deviation 1.18	2.6 score on a scale Standard Deviation 1.06

SECONDARY outcome

Timeframe: 90 Days

Population: Intent-to-treat population, secondary outcome

Fissuring will be assessed by recording the presence or absence of fissures, the number of fissures present, and the pain associated with each fissure. The subject will assess pain associated with fissures as ranging from 0-3 (none, mild, moderate, severe) at day 90 between the active trifarotene cream HE1 and vehicle groups

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=15 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=16 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=31 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream n=17 Participants Intent-to-treat population, secondary outcome
The Difference in Proportion of Subjects With Presence of Fissures on Palms Between the Active and Vehicle Groups Number of participants with no fissures present at day 90	10 Participants	12 Participants	22 Participants	10 Participants
The Difference in Proportion of Subjects With Presence of Fissures on Palms Between the Active and Vehicle Groups Number of participants with Fissures Present at Day 90	5 Participants	4 Participants	9 Participants	7 Participants

SECONDARY outcome

Timeframe: 90 Days

Population: Intent-to-treat population, secondary endpoint

The DLQI, or the Dermatology Quality of Life Index, is a dermatology-specific Quality of Life instrument. It is a simple 10-question validated questionnaire with 6 domains (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment); higher scores indicate poorer quality of life. Responses collected are on a scale of 0-3 depending on the question relevance to the subject. Response (Score) Very much (scored 3) A lot (scored 2) A little (scored 1) Not at all (scored 0) Not relevant (scored 0) A minimum score of 0 and maximum score of 30 is obtained by summing the score of each question. The higher the score, the more quality of life is impaired. 0-1 = no effect at all on patient's life 2-5 = small effect on patient's life 6-10 = moderate effect on patient's life 11-20 = very large effect on patient's life 21-30 = extremely large effect on patient's life

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=11 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=16 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=27 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream n=17 Participants Intent-to-treat population, secondary outcome
Quality of Life Measurement Per Dermatology Life Quality Index (DLQI)	6.1 score on a scale Standard Deviation 5.22	5.9 score on a scale Standard Deviation 5.21	6.0 score on a scale Standard Deviation 5.11	6.2 score on a scale Standard Deviation 5.78

SECONDARY outcome

Timeframe: 90 Days

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=15 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=16 Participants CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=31 Participants CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream n=17 Participants Intent-to-treat population, secondary outcome
The Difference in Proportion of Subjects With Presence of Fissures on Soles Between the Active and Vehicle Groups Numer of participants with fissures on soles present at day 90	5 Participants	4 Participants	9 Participants	7 Participants
The Difference in Proportion of Subjects With Presence of Fissures on Soles Between the Active and Vehicle Groups Numer of participants with no fissures on soles present at day 90	10 Participants	12 Participants	22 Participants	10 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 180 Days

Population: Intent-to-treat population, open label extension

The Ectropion Severity Score (ESS), is a proven system to be reliable and sensitive to the presence of ectropion and has a maximum score of 8 points (0-8). A higher score indicates a worse ectropion. The score takes the severity of ectropion in terms of lateral and medial apposition, scleral show, conjunctival show, and roundness of the eye into account and gives an indication of the functional aspects involved in ectropion by scoring redness, excess tear film, and the position of the lacrimal punctum A point scale of 0=Nonaffected, 0.5=Emerging, 1= Affected is assigned to 8 observations. * Lateral apposition * Medial apposition * Sceral show * Conjunctival show * Excess team film * Redness of the eye * Round canthus * Punctum lacrimale

Outcome measures

Outcome measures
Measure	CD5789 Cream 200 µg/g n=38 Participants CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA	Vehicle Cream Intent-to-treat population, secondary outcome
The Difference in Mean Ectropion Scores Between the Active and Vehicle Groups	2.82 score on a scale Standard Deviation 3.077	—	—	—

Adverse Events

CD5789 Cream 200 µg/g

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

CD5789 Cream 100 µg/g

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

CD5789 Cream Vehicle

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Mayne Pharma

Phone: 1 252 752 3800

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	CD5789 Cream 200 µg/g n=23 participants at risk CD5789 200 µg/g, topical, 50g CD5789 Cream 200 µg/g: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream 100 µg/g n=21 participants at risk CD5789 100 µg/g, topical, 50g CD5789 Cream 100 µg/g: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA	CD5789 Cream Vehicle n=21 participants at risk CD5789 Cream Vehicle, topical, 50g CD5789 Cream Vehicle: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA
Infections and infestations Nasopharyngitis	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	9.5% 2/21 • The maximum study duration for each subject was approximately 291 days.
Infections and infestations Dermatophytosis	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Infections and infestations Rhinitis	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Infections and infestations Urinary tract infection	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Nervous system disorders Headache	13.0% 3/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	9.5% 2/21 • The maximum study duration for each subject was approximately 291 days.
Nervous system disorders Paraesthesia	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Nervous system disorders Tension headache	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
General disorders Application site pain	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
General disorders Chest pain	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
General disorders Feeling abnormal	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
General disorders Feeling hot	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
General disorders Temperature intolerance	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Injury, poisoning and procedural complications Arthropod bite	8.7% 2/23 • The maximum study duration for each subject was approximately 291 days.	9.5% 2/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Injury, poisoning and procedural complications Fall	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Injury, poisoning and procedural complications Overdose	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Reproductive system and breast disorders Dysmenorrhoea	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	14.3% 3/21 • The maximum study duration for each subject was approximately 291 days.
Gastrointestinal disorders Abdominal pain	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Gastrointestinal disorders Abdominal pain upper	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Gastrointestinal disorders Diarrhoea	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Gastrointestinal disorders Nausea	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Congenital, familial and genetic disorders Gilbert's syndrome	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Ear and labyrinth disorders Ear discomfort	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Eye disorders Dry eye	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Respiratory, thoracic and mediastinal disorders Nasal discomfort	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Skin and subcutaneous tissue disorders Pruritus	8.7% 2/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Skin and subcutaneous tissue disorders Dermatitis	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Skin and subcutaneous tissue disorders Dermatitis contact	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Skin and subcutaneous tissue disorders Papule	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Skin and subcutaneous tissue disorders Skin fissures	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Skin and subcutaneous tissue disorders Skin irritation	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Musculoskeletal and connective tissue disorders Back pain	8.7% 2/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	9.5% 2/21 • The maximum study duration for each subject was approximately 291 days.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/23 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.
Infections and infestations Ear infection	4.3% 1/23 • The maximum study duration for each subject was approximately 291 days.	0.00% 0/21 • The maximum study duration for each subject was approximately 291 days.	4.8% 1/21 • The maximum study duration for each subject was approximately 291 days.