Trial Outcomes & Findings for Efficacy and Safety of a Retinoid in the Treatment of Severe Chronic Hand Eczema (NCT NCT00817063)

NCT ID: NCT00817063

Last Updated: 2020-04-27

Results Overview

The investigator assigned PGA grades according to a 5-point scale (clear \[not detectable\], almost clear \[less than 10% of affected hand surface\], mild disease \[less than 10% of affected hand surface\], moderate disease \[10% to 30% of affected hand surface\], severe disease \[\>30% of affected hand surface\]). PGA ratings were based on an integrated clinical picture of signs, symptoms, and the extent of disease. Symptoms included erythema, scaling, hyperkeratosis/lichenification, vesiculation, edema, fissures, and pruritus/pain. The PGA scale ranges from 0 (no symptom) to 4 (severe disease). Participants were considered as responders when they had a PGA of clear or almost clear.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 599 participants
• Primary outcome timeframe: Week 24 (end-of-treatment)
• Results posted on: 2020-04-27

Participant Flow

A total of 599 participants were randomized, out of these 3 participants did not receive study medication, hence Intent-to-treat (ITT) population consisted of 596 participants which included all randomized participants who were dispensed medication.

A total of 942 participants entered the run-in period for a maximum of 16 weeks who received class 1 corticosteroids for 2 weeks followed by corticosteroids of any potency. Out of 942 participants, 343 participants were run-in failures and hence 599 were randomized in the study.

Participant milestones

Measure	Alitretinoin 30 mg Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 milligrams (mg) of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Overall Study STARTED	298	298
Overall Study COMPLETED	161	128
Overall Study NOT COMPLETED	137	170

Reasons for withdrawal

Measure	Alitretinoin 30 mg Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 milligrams (mg) of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Overall Study Adverse Event	32	13
Overall Study Death	1	1
Overall Study Lack of Efficacy	33	86
Overall Study Failure to Return	13	12
Overall Study Violation of Selection at Entry	7	4
Overall Study Protocol Violation	3	8
Overall Study Withdrawal by Subject	17	37
Overall Study Early Improvement	19	4
Overall Study Administrative	10	4
Overall Study Abnormality of Laboratory Test	2	1

Baseline Characteristics

Efficacy and Safety of a Retinoid in the Treatment of Severe Chronic Hand Eczema

Baseline characteristics by cohort

Measure	Alitretinoin 30 mg n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.	Total n=596 Participants Total of all reporting groups
Age, Continuous	47.1 Years STANDARD_DEVIATION 12.55 • n=5 Participants	47.5 Years STANDARD_DEVIATION 12.96 • n=7 Participants	47.3 Years STANDARD_DEVIATION 12.75 • n=5 Participants
Sex: Female, Male Female	133 Participants n=5 Participants	149 Participants n=7 Participants	282 Participants n=5 Participants
Sex: Female, Male Male	165 Participants n=5 Participants	149 Participants n=7 Participants	314 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants	15 Participants n=7 Participants	21 Participants n=5 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
Race (NIH/OMB) Black or African American	19 Participants n=5 Participants	35 Participants n=7 Participants	54 Participants n=5 Participants
Race (NIH/OMB) White	263 Participants n=5 Participants	238 Participants n=7 Participants	501 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 24 (end-of-treatment)

Population: ITT Population.

The investigator assigned PGA grades according to a 5-point scale (clear [not detectable], almost clear [less than 10% of affected hand surface], mild disease [less than 10% of affected hand surface], moderate disease [10% to 30% of affected hand surface], severe disease [>30% of affected hand surface]). PGA ratings were based on an integrated clinical picture of signs, symptoms, and the extent of disease. Symptoms included erythema, scaling, hyperkeratosis/lichenification, vesiculation, edema, fissures, and pruritus/pain. The PGA scale ranges from 0 (no symptom) to 4 (severe disease). Participants were considered as responders when they had a PGA of clear or almost clear.

Outcome measures

Measure	Alitretinoin 30 mg n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants Who Responded as Per Physician's Global Assessment (PGA) at Week 24 Clear	58 Participants	14 Participants
Number of Participants Who Responded as Per Physician's Global Assessment (PGA) at Week 24 Almost clear	60 Participants	30 Participants
Number of Participants Who Responded as Per Physician's Global Assessment (PGA) at Week 24 Total	118 Participants	44 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 24 (end-of-treatment)

Population: ITT population.

A 4-point scale (0=none, 1=mild, 2=moderate, 3=severe) was used to grade 7 signs or symptoms of CHE. The mTLSS was calculated as sum of assigned scores for the symptoms of erythema, scaling, lichenification/hyperkeratosis, vesiculation, edema, fissures and Pruritus/Pain. The total score ranged from 0 (best) to 21 (worst). Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the individual post-baseline values. Percentage change from Baseline = (change from Baseline / Baseline value) * 100. Data for Week 24 last observation carried forward (LOCF) has been presented.

Outcome measures

Measure	Alitretinoin 30 mg n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Percentage Change From Baseline in Modified Total Lesion Symptom Score (mTLSS) at the End-of-treatment	-53.99 Percent change Standard Deviation 40.160	-29.86 Percent change Standard Deviation 37.830

SECONDARY outcome

Timeframe: Week 24 (end-of-treatment)

Population: ITT Population.

At Week 24 or at the end-of-treatment participants were asked by the investigator to grade their overall change from Baseline by selecting one of the following descriptions, which best matched their perception of overall treatment effect: cleared or almost cleared (at least 90% clearing), marked improvement (at least 75% clearing), moderate improvement (at least 50% clearing), mild improvement (at least 25% clearing), no change and worsening. Participants were considered as responders when the PaGa was cleared or almost cleared.

Outcome measures

Measure	Alitretinoin 30 mg n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants Who Responded as Per Patient Global Assessment (PaGA) at End-of-treatment	117 Participants	41 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 24 (end-of-treatment)

Population: ITT Population. Only those participants available at the indicated time points were analyzed.

The extent of disease was estimated as the percentage of hand area (with 100% defined as the palmar and dorsal aspects) affected by eczema at Baseline, and at the end of treatment). Extent of disease was estimated separately for the left and right hands, and the overall extent of disease for both hands was calculated as (Left+Right)/2. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the individual post-baseline values. Percentage change from Baseline = (change from Baseline / Baseline value) * 100.

Outcome measures

Measure	Alitretinoin 30 mg n=271 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=269 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Percentage Change From Baseline in Extent of Disease at End-of-treatment	-46.56 Percent change Standard Deviation 53.746	-24.20 Percent change Standard Deviation 48.214

SECONDARY outcome

Timeframe: Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up)

Population: ITT population.

Response Duration was defined as time from the end-of-therapy to the first diagnosis of mild, moderate, or severe CHE. Median and inter-quartile range has been presented.

Outcome measures

Measure	Alitretinoin 30 mg n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Response Duration for Responding Participants at the End-of-therapy	8.3 Weeks Interval 4.7 to 16.7	16.9 Weeks Interval 5.1 to 50.3

SECONDARY outcome

Timeframe: Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up)

Population: ITT population.

Time to relapse was defined as the time from end-of-therapy to the first diagnosis of severe CHE. Median and inter-quartile range has been presented. The median was based on the very last participant having a follow-up period longer than expected, those explaining the high median.

Outcome measures

Measure	Alitretinoin 30 mg n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Time to Relapse for Responding Participants at the End-of-therapy	83.0 Weeks Interval 18.1 to 83.0	NA Weeks Interval 39.6 to An analysis of the time to relapse from the End-of-therapy did not have sufficient data to yield a good estimate of median time to relapse as well as for Q3.

SECONDARY outcome

Timeframe: Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up)

Population: ITT population. Only those participant who responded to PGA assessment at the end of therapy was analyzed.

Time to response was defined as time from start of treatment to first PGA assessment of "clear" or "almost clear". Median and inter-quartile range has been presented.

Outcome measures

Measure	Alitretinoin 30 mg n=118 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=44 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Time to Response for Responding Participants at End-of-therapy	65.0 Days Interval 54.0 to 112.0	117.0 Days Interval 85.0 to 167.0

SECONDARY outcome

Timeframe: Up to Week 24 (end-of-treatment)

Population: Safety Population included all randomized participants who received at least one dose of study medication.

An AE was defined as any adverse change from the participant's Baseline (pretreatment) clinical condition, including intercurrent illness, which occurred during the course of the clinical study after written informed consent had been given, whether considered related to treatment or not. A treatment-emergent AE was defined as any adverse change that occurred after treatment started and up to 7 days after last treatment. An SAE was any experience that suggested a significant hazard, contradiction, side effect or precaution. It was any adverse event that at any dose resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Treatment Period Any AEs	216 Participants	155 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Treatment Period Any SAEs	7 Participants	3 Participants

SECONDARY outcome

Timeframe: Up to Week 28

Population: Safety Population. Only those participants available at the indicated time points were analyzed.

Blood samples were collected for the assessment of laboratory parameters hemoglobin, hematocrit, erythrocytes, mean corpuscular volume, mean corpuscular hemoglobin concentration, reticulocytes, platelets, white blood cell, lymphocytes, neutrophils, monocytes, eosinophils, basophils, total bilirubin, bilirubin conjugated (direct), aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), alkaline phosphatase (ALP), total protein, serum albumin, glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, sodium, potassium, chloride, serum calcium, serum phosphate, serum creatinine, blood urea nitrogen (BUN)/urea, uric acid, Free thyroxin and thyroid stimulating hormone (TSH) at Baseline and every 4 weeks of treatment period and Week 28 of follow up period. Data for participants with values outside the marked reference range are reported.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Reticulocyte, maximum post Baseline	8 Participants	6 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Reticulocyte Count, Absolute,maximum post Baseline	17 Participants	8 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range White Blood Cells, maximum post Baseline	1 Participants	1 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Lymphocytes, maximum post Baseline	1 Participants	0 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Lymphocytes,Absolute, maximum post Baseline	0 Participants	1 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Eosinophils, maximum post Baseline	29 Participants	39 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Eosinophils, Absolute, maximum post Baseline	12 Participants	20 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Bilirubin Total, maximum post Baseline	0 Participants	3 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range ALP, maximum post Baseline	1 Participants	1 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range AST, maximum post Baseline	6 Participants	6 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range ALT, maximum post Baseline	7 Participants	11 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range LDH, maximum post Baseline	0 Participants	1 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range CPK, maximum post Baseline	28 Participants	27 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Cholesterol, Total, maximum post Baseline	17 Participants	4 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Triglyceride, maximum post Baseline	16 Participants	2 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Glucose, maximum post Baseline	5 Participants	4 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Potassium, maximum post Baseline	1 Participants	0 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Calcium, maximum post Baseline	0 Participants	1 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Creatinine, maximum post Baseline	1 Participants	1 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range BUN, maximum post Baseline	1 Participants	0 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range Free T4 - Thyroxine, maximum post Baseline	1 Participants	3 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range TSH, maximum post Baseline	6 Participants	10 Participants
Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range LDL Calculated, maximum post Baseline	102 Participants	62 Participants

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety population. Only those participants meeting the criteria of referring to psychiatrist were analyzed.

The BSI is a 53 item self-report scale used to measure nine primary symptom dimensions (somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism). Respondents rank each feeling item (e.g., "your feelings being easily hurt") on a 5-point scale where, 0=not at all, 1=a little bit, 2=moderately, 3=quite a bit, 4=extremely (0 indicates best outcome and 4 indicates worst outcome). The total score ranged from 0 (best outcome) to 212 (worse outcome). Participants with an increase above Baseline of 25% or more on any domain subscore in BSI-53, or with an increase above Baseline of >=2 points or a score >=3 on any BSI-53 item that reflects depression, suicidality, psychotic symptoms, and hostility/aggression, were to be referred to a psychiatrist within 2 weeks.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 4, Referred to a Psychiatrist	47 Participants	34 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 4, Not Referred to a Psychiatrist	14 Participants	24 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 8, Referred to a Psychiatrist	19 Participants	10 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 8, Not Referred to a Psychiatrist	23 Participants	15 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 12, Referred to a Psychiatrist	10 Participants	9 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 12, Not Referred to a Psychiatrist	21 Participants	12 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 16, Referred to a Psychiatrist	11 Participants	4 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 16, Not Referred to a Psychiatrist	11 Participants	9 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 20, Referred to a Psychiatrist	6 Participants	1 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 20, Not Referred to a Psychiatrist	10 Participants	6 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 24, Referred to a Psychiatrist	10 Participants	9 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 24, Not Referred to a Psychiatrist	25 Participants	30 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 28, Referred to a Psychiatrist	2 Participants	1 Participants
Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks Week 28, Not Referred to a Psychiatrist	8 Participants	16 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24, 28

Population: Safety population. Only those participants available at the indicated time points were analyzed.

The PHQ-9 was a standardized tests of mood/depression. This was a nine item measure with a response for each item between 0-3 where, 0=not at all, 1= several days, 2= more than half the days, 3= nearly every day. Total scores on this measure range from 0-27, with 0 being a minimum indicating no depressive symptoms, and 27 being the maximum number and severity of depressive symptoms. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the individual post-baseline values.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks Week 4	-0.3 Score on scale Standard Deviation 2.23	-0.2 Score on scale Standard Deviation 2.32
Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks Week 8	-0.6 Score on scale Standard Deviation 2.35	-0.6 Score on scale Standard Deviation 2.18
Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks Week 12	-0.9 Score on scale Standard Deviation 2.27	-0.9 Score on scale Standard Deviation 2.39
Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks Week 16	-0.9 Score on scale Standard Deviation 2.25	-0.9 Score on scale Standard Deviation 2.79
Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks Week 20	-1.0 Score on scale Standard Deviation 2.38	-1.2 Score on scale Standard Deviation 2.66
Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks Week 24	-0.8 Score on scale Standard Deviation 2.56	-0.6 Score on scale Standard Deviation 2.59
Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks Week 28	-0.6 Score on scale Standard Deviation 2.65	-0.6 Score on scale Standard Deviation 2.03

SECONDARY outcome

Timeframe: Up to 28 Weeks

Population: Safety Population. Only those participants available at the indicated time points were analyzed.

Participants meeting any of the following criteria were to be referred for specialist psychiatric evaluation within 2 weeks: PHQ-9 Score >=15, Two Subsequent Scores of >=10 and PHQ-9 Question 9 >=1. The PHQ -9 was a standardized tests of mood/depression. This was a nine item measure with a response for each item between 0-3 where, 0=not at all, 1= several days, 2= more than half the days, 3= nearly everyday. Total scores on this measure range from 0-27, with 0 being a minimum indicating no depressive symptoms, and 27 being the maximum number and severity of depressive symptoms. Only categories with data available at the indicated time points have been presented. Categories with null values for all the arms have not been presented.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 12, Not Referred to a Psychiatrist	2 Participants	1 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 16, PHQ-9 Score >=15	1 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 16, PHQ-9 Question 9 >=1	2 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 16, Not Referred to a Psychiatrist	2 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 20, PHQ-9 Question 9 >=1	1 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 20, Not Referred to a Psychiatrist	1 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 24, PHQ-9 Score >=15	1 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 24, Two Subsequent Scores of >=10	0 Participants	1 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 24, PHQ-9 Question 9 >=1	1 Participants	2 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 24, Not Referred to a Psychiatrist	2 Participants	2 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 28, PHQ-9 Score >=15	2 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 28, Two Subsequent Scores of >=10	2 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 28, PHQ-9 Question 9 >=1	2 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 28, Not Referred to a Psychiatrist	3 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 4, PHQ-9 Score >=15	2 Participants	0 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 4, Two Subsequent Scores of >=10	3 Participants	2 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 4, PHQ-9 Question 9 >=1	3 Participants	3 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 4, Referred to a Psychiatrist	3 Participants	2 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 4, Not Referred to a Psychiatrist	1 Participants	2 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 8, Two Subsequent Scores of >=10	1 Participants	2 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 8, PHQ-9 Question 9 >=1	4 Participants	1 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 8, Referred to a Psychiatrist	1 Participants	1 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 8, Not Referred to a Psychiatrist	3 Participants	1 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 12, Two Subsequent Scores of >=10	0 Participants	1 Participants
Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks Week 12, PHQ-9 Question 9 >=1	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24

Population: Safety Population. Only those participants available at the indicated time points were analyzed.

HHIE-S assessed participants by handicap category: no handicap (0 to 8 points); mild/moderate handicap (10 to 24 points); severe handicap (26-40 points). Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the individual post-baseline values.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks Week 4	-0.0 Score on scale Standard Deviation 0.96	-0.2 Score on scale Standard Deviation 0.86
Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks Week 8	-0.1 Score on scale Standard Deviation 1.14	-0.1 Score on scale Standard Deviation 0.69
Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks Week 12	-0.2 Score on scale Standard Deviation 1.01	-0.1 Score on scale Standard Deviation 0.52
Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks Week 16	-0.1 Score on scale Standard Deviation 0.79	-0.1 Score on scale Standard Deviation 0.32
Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks Week 20	-0.2 Score on scale Standard Deviation 0.78	-0.1 Score on scale Standard Deviation 0.34
Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks Week 24	-0.2 Score on scale Standard Deviation 1.02	-0.2 Score on scale Standard Deviation 1.10

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24

Population: Safety Population. Only those participants available at the indicated time points were analyzed.

DHI assessed participants by handicap category: no handicap (0 to 14 points); mild handicap (16 to 34 points); moderate handicap (36 to 52 points); severe handicap (54 points). Increase from Baseline of <6 points, 6 to <12 points and 12 points. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the individual post-baseline values.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks Week 4	-0.3 Score on scale Standard Deviation 2.65	0.3 Score on scale Standard Deviation 1.26
Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks Week 8	-0.5 Score on scale Standard Deviation 2.68	-0.1 Score on scale Standard Deviation 1.02
Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks Week 12	-0.2 Score on scale Standard Deviation 3.78	-0.1 Score on scale Standard Deviation 0.38
Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks Week 16	0.1 Score on scale Standard Deviation 1.38	-0.1 Score on scale Standard Deviation 1.18
Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks Week 20	0.2 Score on scale Standard Deviation 2.34	-0.1 Score on scale Standard Deviation 1.24
Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks Week 24	0.7 Score on scale Standard Deviation 5.72	0.2 Score on scale Standard Deviation 2.41

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety Population. Only those participants available at the indicated time points were analyzed.

Participants who developed tinnitus were monitored by use of the TOMI. The numbers of participants with pre-existing tinnitus, new tinnitus, increased/decreased loudness of tinnitus, or increased/decreased duration of tinnitus, pulsing quality of tinnitus were assessed.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Has Loudness of Tinnitus Changed,Yes,Louder Now	1 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Persistent TInnitus since treatment, yes	16 Participants	5 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Type of Tinnitus, Ringing	11 Participants	2 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Type of Tinnitus, Buzzing	3 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Type of Tinnitus, Hissing	1 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Type of Tinnitus, Whistle	1 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Type of Tinnitus, Hum	3 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Type of Tinnitus, Other	0 Participants	2 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus - Pulsing Quality, Yes	3 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Location, Left Ear only	2 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Location, Right Ear only	4 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Location, Both ears	7 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Location, Inside head	2 Participants	2 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Location, Other	0 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Louder on right side of head	5 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Louder on left side of head	2 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Tinnitus Equal on both side of head	7 Participants	3 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Slightly loud tinnitus	3 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Moderately loud tinnitus	6 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks How much of Time Tinnitus Present, Occasionally	4 Participants	3 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks How much of Time Tinnitus Present,Some of the Time	3 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks How much of Time Tinnitus Present,Most of the Time	5 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks How much of Time Tinnitus Present,Always	3 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks How much of a Problem is Tinnitus, Slight	5 Participants	1 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks How much of a Problem is Tinnitus, Moderate	2 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks How much of a Problem is Tinnitus, Big	1 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Has the Sound of Tinnitus Changed, Yes	1 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Has Loudness of Tinnitus Changed,Yes,Quieter Now	1 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Amount of TimeTinnitus PresentChanged,Yesmoreoften	1 Participants	0 Participants
Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks Amount of TimeTinnitus PresentChanged,Yeslessoften	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 72

Population: Safety Population. Only those participants available at the indicated time points were analyzed.

Bone mineral density scans of the left proximal femur (total hip) and anterior-posterior lumbar spine were obtained by use of DXA, at Baseline, at end of therapy, and 1 year (48 weeks) after end of therapy. In case of abnormality or surgery of the left hip, the right hip was to be used. If both hips were affected, the participant was not eligible for DXA. Vertebrae L1 to L4 had to be completely scanned. At least 3 vertebrae had to be free of any abnormalities potentially interfering with DXA analysis (eg, fractures, large osteophytes), otherwise the participant was not eligible for DXA. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the individual post-baseline values. Percentage change from Baseline = (change from Baseline / Baseline value) * 100. Least square means and 95% confidence interval has been presented.

Outcome measures

Measure	Alitretinoin 30 mg n=296 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Percent Change From Baseline in Bone Mineral Density (BMD) by Dual Energy X-ray Absorptiometry (DXA) Over 72 Weeks Lumbar Spine BMD	0.385 Percent change Interval -0.403 to 1.173	-0.104 Percent change Interval -0.827 to 0.618
Percent Change From Baseline in Bone Mineral Density (BMD) by Dual Energy X-ray Absorptiometry (DXA) Over 72 Weeks Femur BMD	0.435 Percent change Interval -0.196 to 1.065	-0.063 Percent change Interval -0.644 to 0.519

SECONDARY outcome

Timeframe: Up to Week 72

Population: Safety Population. Only those participants who had X-ray evaluations were analyzed.

X-ray evaluations was done at Baseline (Week 0), end of therapy and at follow up period (Week 72). X-ray evaluations was done for Lateral C-Spine, Lateral T-Spine and Calcaneous. The images were evaluated as optimal, readable (but not optimal) or not readable.

Outcome measures

Measure	Alitretinoin 30 mg n=244 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=243 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Baseline,Lateral C-Spine, Optimal	73 Participants	85 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Baseline,Lateral C-Spine,Readable	171 Participants	158 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Baseline,Lateral T-Spine,Readable	229 Participants	234 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Baseline,Lateral T-Spine,Not Readable	15 Participants	9 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Baseline, Calcaneous, Optimal	195 Participants	191 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Baseline, Calcaneous, Readable	48 Participants	51 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Baseline, Calcaneous, Not Readable	1 Participants	1 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy,Lateral C-Spine,Optimal	80 Participants	87 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy,Lateral C-Spine,Readable	162 Participants	146 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy,Lateral C-Spine, Not Readable	2 Participants	10 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy, Lateral T-Spine, Readable	232 Participants	229 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy, Lateral T-Spine, Not Readable	12 Participants	14 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy, Calcaneous, Optimal	196 Participants	182 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy, Calcaneous, Readable	40 Participants	44 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones End of Therapy, Calcaneous, Not Readable	8 Participants	17 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Lateral C-Spine, Optimal	39 Participants	38 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Lateral C-Spine, Readable	151 Participants	134 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Lateral C-Spine, Not Readable	0 Participants	1 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Lateral C-Spine, Missing	54 Participants	70 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Lateral T-Spine, Readable	183 Participants	168 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Lateral T-Spine, Not Readable	7 Participants	5 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Lateral T-Spine, Missing	54 Participants	70 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Calcaneous, Optimal	141 Participants	119 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Calcaneous, Not Readable	6 Participants	4 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Calcaneous, Missing	54 Participants	70 Participants
Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones Week 72, Calcaneous, Readable	43 Participants	50 Participants

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety Population. Only those participants who had ophthalmological evaluations were analyzed.

An adverse change was defined as a change from normal at Baseline to abnormal at end of therapy, or as a worsening from Baseline for either or both eyes. A missing adverse change was defined as missing results at Baseline and end of therapy, or missing result at Baseline and abnormal at end of therapy, or normal at Baseline and missing result at end of therapy, or abnormal at Baseline and missing result at end of therapy, for both eyes or one eye when the other eye was not concerned by an adverse change. Other changes from Baseline to end of therapy was considered as no adverse change. Optic disc, macula, and retinal periphery were assessed by fundoscopy after pupil dilation using tropicamide.

Outcome measures

Measure	Alitretinoin 30 mg n=180 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=186 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Participants with an Adverse Change, No	152 Participants	146 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Participants with an Adverse Change, Yes	0 Participants	1 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Participants with an Adverse Change, Missing	28 Participants	39 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Baseline, Normal	177 Participants	183 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Baseline, Abnormal	3 Participants	1 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Baseline, Missing	0 Participants	2 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure End of Therapy, Normal	152 Participants	146 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure End of Therapy, Abnormal	1 Participants	1 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure End of Therapy, Missing	27 Participants	39 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Worsened from Baseline, No	2 Participants	1 Participants
Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure Worsened from Baseline, Missing	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety Population. Only those participants who had audiologic evaluations were analyzed.

An adverse change was defined as a change from normal at Baseline to abnormal at end of therapy. A missing adverse change was defined as missing results at Baseline and end of therapy, or missing result at Baseline and abnormal at end of therapy, or normal at Baseline and missing result at end of therapy. Other changes from Baseline to end of therapy are considered as no adverse change. All puretone testing used a modified Hughson-Westlake procedure with 5 decibel (dB) step size.

Outcome measures

Measure	Alitretinoin 30 mg n=149 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=147 Participants Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency Participants with adverse change, No	131 Participants	125 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency Participants with adverse change, Yes	4 Participants	10 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency Participants with adverse change, Missing	14 Participants	12 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency Baseline, Normal	57 Participants	69 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency Baseline, Abnormal	91 Participants	75 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency Baseline, Missing	1 Participants	3 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency End of Therapy, Normal	48 Participants	55 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency End of Therapy, Abnormal	75 Participants	71 Participants
Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency End of Therapy, Missing	26 Participants	21 Participants

Adverse Events

Alitretinoin 30 mg

Serious events: 7 serious events

Other events: 108 other events

Deaths: 1 deaths

Placebo

Serious events: 3 serious events

Other events: 36 other events

Deaths: 2 deaths

Serious adverse events

Measure	Alitretinoin 30 mg n=296 participants at risk Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 participants at risk Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.34% 1/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Gastrointestinal disorders Pancreatitis	0.68% 2/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.00% 0/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
General disorders Granuloma	0.34% 1/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.00% 0/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Infections and infestations Arthritis Bacterial	0.34% 1/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.00% 0/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Infections and infestations CELLULITIS	0.34% 1/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.00% 0/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Infections and infestations STAPHYLOCOCCAL INFECTION	0.34% 1/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.00% 0/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Injury, poisoning and procedural complications ACCIDENT AT HOME	0.00% 0/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.34% 1/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) NON-HODGKIN'S LYMPHOMA	0.00% 0/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.34% 1/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Nervous system disorders HAEMORRHAGIC STROKE	0.34% 1/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.00% 0/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Psychiatric disorders ALCOHOL ABUSE	0.00% 0/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.34% 1/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Psychiatric disorders COMPLETED SUICIDE	0.34% 1/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.00% 0/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Renal and urinary disorders HYDRONEPHROSIS	0.00% 0/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.34% 1/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Vascular disorders DEEP VEIN THROMBOSIS	0.00% 0/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.34% 1/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.

Other adverse events

Measure	Alitretinoin 30 mg n=296 participants at risk Participants with severe CHE rated as refractory during the run-in period were randomized to receive 30 mg of alitretinoin oral soft capsule once daily up to 24 weeks.	Placebo n=298 participants at risk Participants with severe CHE rated as refractory during the run-in period were randomized to receive matching Placebo oral soft capsule once daily up to 24 weeks.
Infections and infestations Upper respiratory tract infection	6.8% 20/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	4.4% 13/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Nervous system disorders Headache	29.4% 87/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	8.1% 24/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Vascular disorders Flushing	5.7% 17/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	0.34% 1/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.
Gastrointestinal disorders Nausea	7.4% 22/296 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.	1.3% 4/298 • AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented. Safety Population was used for the analysis of safety data.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
• Publication restrictions are in place

Restriction type: OTHER