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

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ClinicalTrials.gov Identifier: NCT00817063
Recruitment Status : Completed
First Posted : January 6, 2009
Results First Posted : November 9, 2017
Last Update Posted : November 9, 2017
Sponsor:
Collaborator:
Basilea Pharmaceutica
Information provided by (Responsible Party):
GlaxoSmithKline ( Stiefel, a GSK Company )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Eczema
Interventions Drug: alitretinoin
Drug: Placebo
Enrollment 599
Recruitment Details 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.
Pre-assignment Details 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.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 298 298
Completed 161 128
Not Completed 137 170
Reason Not Completed
Adverse Event             32             13
Death             1             1
Lack of Efficacy             33             86
Failure to Return             13             12
Violation of Selection at Entry             7             4
Protocol Violation             3             8
Withdrawal by Subject             17             37
Early Improvement             19             4
Administrative             10             4
Abnormality of Laboratory Test             2             1
Arm/Group Title Alitretinoin 30 mg Placebo Total
Hide Arm/Group Description 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. 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 of all reporting groups
Overall Number of Baseline Participants 298 298 596
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 298 participants 298 participants 596 participants
47.1  (12.55) 47.5  (12.96) 47.3  (12.75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 298 participants 298 participants 596 participants
Female
133
  44.6%
149
  50.0%
282
  47.3%
Male
165
  55.4%
149
  50.0%
314
  52.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 298 participants 298 participants 596 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
6
   2.0%
15
   5.0%
21
   3.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
19
   6.4%
35
  11.7%
54
   9.1%
White
263
  88.3%
238
  79.9%
501
  84.1%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
10
   3.4%
10
   3.4%
20
   3.4%
1.Primary Outcome
Title Number of Participants Who Responded as Per Physician's Global Assessment (PGA) at Week 24
Hide Description 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.
Time Frame Week 24 (end-of-treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 298 298
Measure Type: Count of Participants
Unit of Measure: Participants
Clear
58
  19.5%
14
   4.7%
Almost clear
60
  20.1%
30
  10.1%
Total
118
  39.6%
44
  14.8%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.78
Confidence Interval (2-Sided) 95%
2.55 to 5.62
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value 24.8
Confidence Interval (2-Sided) 95%
18.0 to 31.7
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage Change From Baseline in Modified Total Lesion Symptom Score (mTLSS) at the End-of-treatment
Hide Description 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.
Time Frame Baseline (Week 0) and Week 24 (end-of-treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 298 298
Mean (Standard Deviation)
Unit of Measure: Percent change
-53.99  (40.160) -29.86  (37.830)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Kruskal-Wallis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -24.13
Confidence Interval (2-Sided) 95%
-30.40 to -17.85
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants Who Responded as Per Patient Global Assessment (PaGA) at End-of-treatment
Hide Description 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.
Time Frame Week 24 (end-of-treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 298 298
Measure Type: Count of Participants
Unit of Measure: Participants
117
  39.3%
41
  13.8%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.05
Confidence Interval (2-Sided) 95%
2.71 to 6.07
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value 25.5
Confidence Interval (2-Sided) 95%
18.7 to 32.3
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage Change From Baseline in Extent of Disease at End-of-treatment
Hide Description 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.
Time Frame Baseline (Week 0) and Week 24 (end-of-treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 271 269
Mean (Standard Deviation)
Unit of Measure: Percent change
-46.56  (53.746) -24.20  (48.214)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Kruskal-Wallis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -22.36
Confidence Interval (2-Sided) 95%
-31.00 to -13.73
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Response Duration for Responding Participants at the End-of-therapy
Hide Description 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.
Time Frame Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 298 298
Median (Inter-Quartile Range)
Unit of Measure: Weeks
8.3
(4.7 to 16.7)
16.9
(5.1 to 50.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.047
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
6.Secondary Outcome
Title Time to Relapse for Responding Participants at the End-of-therapy
Hide Description 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.
Time Frame Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 298 298
Median (Inter-Quartile Range)
Unit of Measure: Weeks
83.0
(18.1 to 83.0)
NA [1] 
(39.6 to NA)
[1]
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.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.068
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
7.Secondary Outcome
Title Time to Response for Responding Participants at End-of-therapy
Hide Description 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.
Time Frame Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population. Only those participant who responded to PGA assessment at the end of therapy was analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 118 44
Median (Inter-Quartile Range)
Unit of Measure: Days
65.0
(54.0 to 112.0)
117.0
(85.0 to 167.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
8.Secondary Outcome
Title Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Treatment Period
Hide Description 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.
Time Frame Up to Week 24 (end-of-treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population included all randomized participants who received at least one dose of study medication.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Measure Type: Count of Participants
Unit of Measure: Participants
Any AEs
216
  73.0%
155
  52.0%
Any SAEs
7
   2.4%
3
   1.0%
9.Secondary Outcome
Title Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range
Hide Description 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.
Time Frame Up to Week 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Measure Type: Count of Participants
Unit of Measure: Participants
Reticulocyte, maximum post Baseline Number Analyzed 288 participants 293 participants
8
   2.8%
6
   2.0%
Reticulocyte Count, Absolute,maximum post Baseline Number Analyzed 288 participants 293 participants
17
   5.9%
8
   2.7%
White Blood Cells, maximum post Baseline Number Analyzed 289 participants 293 participants
1
   0.3%
1
   0.3%
Lymphocytes, maximum post Baseline Number Analyzed 287 participants 292 participants
1
   0.3%
0
   0.0%
Lymphocytes,Absolute, maximum post Baseline Number Analyzed 287 participants 292 participants
0
   0.0%
1
   0.3%
Eosinophils, maximum post Baseline Number Analyzed 287 participants 292 participants
29
  10.1%
39
  13.4%
Eosinophils, Absolute, maximum post Baseline Number Analyzed 287 participants 292 participants
12
   4.2%
20
   6.8%
Bilirubin Total, maximum post Baseline Number Analyzed 289 participants 293 participants
0
   0.0%
3
   1.0%
ALP, maximum post Baseline Number Analyzed 289 participants 294 participants
1
   0.3%
1
   0.3%
AST, maximum post Baseline Number Analyzed 289 participants 294 participants
6
   2.1%
6
   2.0%
ALT, maximum post Baseline Number Analyzed 289 participants 294 participants
7
   2.4%
11
   3.7%
LDH, maximum post Baseline Number Analyzed 287 participants 293 participants
0
   0.0%
1
   0.3%
CPK, maximum post Baseline Number Analyzed 288 participants 294 participants
28
   9.7%
27
   9.2%
Cholesterol, Total, maximum post Baseline Number Analyzed 275 participants 278 participants
17
   6.2%
4
   1.4%
Triglyceride, maximum post Baseline Number Analyzed 275 participants 278 participants
16
   5.8%
2
   0.7%
Glucose, maximum post Baseline Number Analyzed 277 participants 280 participants
5
   1.8%
4
   1.4%
Potassium, maximum post Baseline Number Analyzed 288 participants 294 participants
1
   0.3%
0
   0.0%
Calcium, maximum post Baseline Number Analyzed 288 participants 294 participants
0
   0.0%
1
   0.3%
Creatinine, maximum post Baseline Number Analyzed 288 participants 294 participants
1
   0.3%
1
   0.3%
BUN, maximum post Baseline Number Analyzed 288 participants 294 participants
1
   0.3%
0
   0.0%
Free T4 - Thyroxine, maximum post Baseline Number Analyzed 289 participants 294 participants
1
   0.3%
3
   1.0%
TSH, maximum post Baseline Number Analyzed 289 participants 294 participants
6
   2.1%
10
   3.4%
LDL Calculated, maximum post Baseline Number Analyzed 274 participants 278 participants
102
  37.2%
62
  22.3%
10.Secondary Outcome
Title Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks
Hide Description 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.
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population. Only those participants meeting the criteria of referring to psychiatrist were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Measure Type: Count of Participants
Unit of Measure: Participants
Week 4, Referred to a Psychiatrist Number Analyzed 61 participants 58 participants
47
  77.0%
34
  58.6%
Week 4, Not Referred to a Psychiatrist Number Analyzed 61 participants 58 participants
14
  23.0%
24
  41.4%
Week 8, Referred to a Psychiatrist Number Analyzed 42 participants 25 participants
19
  45.2%
10
  40.0%
Week 8, Not Referred to a Psychiatrist Number Analyzed 42 participants 25 participants
23
  54.8%
15
  60.0%
Week 12, Referred to a Psychiatrist Number Analyzed 31 participants 21 participants
10
  32.3%
9
  42.9%
Week 12, Not Referred to a Psychiatrist Number Analyzed 31 participants 21 participants
21
  67.7%
12
  57.1%
Week 16, Referred to a Psychiatrist Number Analyzed 22 participants 13 participants
11
  50.0%
4
  30.8%
Week 16, Not Referred to a Psychiatrist Number Analyzed 22 participants 13 participants
11
  50.0%
9
  69.2%
Week 20, Referred to a Psychiatrist Number Analyzed 16 participants 7 participants
6
  37.5%
1
  14.3%
Week 20, Not Referred to a Psychiatrist Number Analyzed 16 participants 7 participants
10
  62.5%
6
  85.7%
Week 24, Referred to a Psychiatrist Number Analyzed 35 participants 39 participants
10
  28.6%
9
  23.1%
Week 24, Not Referred to a Psychiatrist Number Analyzed 35 participants 39 participants
25
  71.4%
30
  76.9%
Week 28, Referred to a Psychiatrist Number Analyzed 10 participants 17 participants
2
  20.0%
1
   5.9%
Week 28, Not Referred to a Psychiatrist Number Analyzed 10 participants 17 participants
8
  80.0%
16
  94.1%
11.Secondary Outcome
Title Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks
Hide Description 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.
Time Frame Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24, 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Mean (Standard Deviation)
Unit of Measure: Score on scale
Week 4 Number Analyzed 265 participants 274 participants
-0.3  (2.23) -0.2  (2.32)
Week 8 Number Analyzed 252 participants 236 participants
-0.6  (2.35) -0.6  (2.18)
Week 12 Number Analyzed 226 participants 173 participants
-0.9  (2.27) -0.9  (2.39)
Week 16 Number Analyzed 188 participants 141 participants
-0.9  (2.25) -0.9  (2.79)
Week 20 Number Analyzed 167 participants 130 participants
-1.0  (2.38) -1.2  (2.66)
Week 24 Number Analyzed 258 participants 266 participants
-0.8  (2.56) -0.6  (2.59)
Week 28 Number Analyzed 79 participants 85 participants
-0.6  (2.65) -0.6  (2.03)
12.Secondary Outcome
Title Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks
Hide Description 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.
Time Frame Up to 28 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Measure Type: Count of Participants
Unit of Measure: Participants
Week 4, PHQ-9 Score >=15 Number Analyzed 273 participants 278 participants
2
   0.7%
0
   0.0%
Week 4, Two Subsequent Scores of >=10 Number Analyzed 273 participants 278 participants
3
   1.1%
2
   0.7%
Week 4, PHQ-9 Question 9 >=1 Number Analyzed 273 participants 278 participants
3
   1.1%
3
   1.1%
Week 4, Referred to a Psychiatrist Number Analyzed 273 participants 278 participants
3
   1.1%
2
   0.7%
Week 4, Not Referred to a Psychiatrist Number Analyzed 273 participants 278 participants
1
   0.4%
2
   0.7%
Week 8, Two Subsequent Scores of >=10 Number Analyzed 252 participants 241 participants
1
   0.4%
2
   0.8%
Week 8, PHQ-9 Question 9 >=1 Number Analyzed 252 participants 241 participants
4
   1.6%
1
   0.4%
Week 8, Referred to a Psychiatrist Number Analyzed 252 participants 241 participants
1
   0.4%
1
   0.4%
Week 8, Not Referred to a Psychiatrist Number Analyzed 252 participants 241 participants
3
   1.2%
1
   0.4%
Week 12, Two Subsequent Scores of >=10 Number Analyzed 228 participants 177 participants
0
   0.0%
1
   0.6%
Week 12, PHQ-9 Question 9 >=1 Number Analyzed 228 participants 177 participants
2
   0.9%
0
   0.0%
Week 12, Not Referred to a Psychiatrist Number Analyzed 228 participants 177 participants
2
   0.9%
1
   0.6%
Week 16, PHQ-9 Score >=15 Number Analyzed 190 participants 144 participants
1
   0.5%
0
   0.0%
Week 16, PHQ-9 Question 9 >=1 Number Analyzed 190 participants 144 participants
2
   1.1%
0
   0.0%
Week 16, Not Referred to a Psychiatrist Number Analyzed 190 participants 144 participants
2
   1.1%
0
   0.0%
Week 20, PHQ-9 Question 9 >=1 Number Analyzed 168 participants 131 participants
1
   0.6%
0
   0.0%
Week 20, Not Referred to a Psychiatrist Number Analyzed 168 participants 131 participants
1
   0.6%
0
   0.0%
Week 24, PHQ-9 Score >=15 Number Analyzed 262 participants 270 participants
1
   0.4%
0
   0.0%
Week 24, Two Subsequent Scores of >=10 Number Analyzed 262 participants 270 participants
0
   0.0%
1
   0.4%
Week 24, PHQ-9 Question 9 >=1 Number Analyzed 262 participants 270 participants
1
   0.4%
2
   0.7%
Week 24, Not Referred to a Psychiatrist Number Analyzed 262 participants 270 participants
2
   0.8%
2
   0.7%
Week 28, PHQ-9 Score >=15 Number Analyzed 79 participants 86 participants
2
   2.5%
0
   0.0%
Week 28, Two Subsequent Scores of >=10 Number Analyzed 79 participants 86 participants
2
   2.5%
0
   0.0%
Week 28, PHQ-9 Question 9 >=1 Number Analyzed 79 participants 86 participants
2
   2.5%
0
   0.0%
Week 28, Not Referred to a Psychiatrist Number Analyzed 79 participants 86 participants
3
   3.8%
0
   0.0%
13.Secondary Outcome
Title Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks
Hide Description 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.
Time Frame Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Mean (Standard Deviation)
Unit of Measure: Score on scale
Week 4 Number Analyzed 83 participants 88 participants
-0.0  (0.96) -0.2  (0.86)
Week 8 Number Analyzed 77 participants 74 participants
-0.1  (1.14) -0.1  (0.69)
Week 12 Number Analyzed 70 participants 55 participants
-0.2  (1.01) -0.1  (0.52)
Week 16 Number Analyzed 58 participants 39 participants
-0.1  (0.79) -0.1  (0.32)
Week 20 Number Analyzed 51 participants 35 participants
-0.2  (0.78) -0.1  (0.34)
Week 24 Number Analyzed 79 participants 81 participants
-0.2  (1.02) -0.2  (1.10)
14.Secondary Outcome
Title Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks
Hide Description 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.
Time Frame Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Mean (Standard Deviation)
Unit of Measure: Score on scale
Week 4 Number Analyzed 82 participants 86 participants
-0.3  (2.65) 0.3  (1.26)
Week 8 Number Analyzed 74 participants 74 participants
-0.5  (2.68) -0.1  (1.02)
Week 12 Number Analyzed 70 participants 54 participants
-0.2  (3.78) -0.1  (0.38)
Week 16 Number Analyzed 57 participants 38 participants
0.1  (1.38) -0.1  (1.18)
Week 20 Number Analyzed 49 participants 35 participants
0.2  (2.34) -0.1  (1.24)
Week 24 Number Analyzed 78 participants 78 participants
0.7  (5.72) 0.2  (2.41)
15.Secondary Outcome
Title Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks
Hide Description 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.
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Measure Type: Count of Participants
Unit of Measure: Participants
Persistent TInnitus since treatment, yes Number Analyzed 131 participants 114 participants
16
  12.2%
5
   4.4%
Type of Tinnitus, Ringing Number Analyzed 15 participants 5 participants
11
  73.3%
2
  40.0%
Type of Tinnitus, Buzzing Number Analyzed 15 participants 5 participants
3
  20.0%
0
   0.0%
Type of Tinnitus, Hissing Number Analyzed 15 participants 5 participants
1
   6.7%
0
   0.0%
Type of Tinnitus, Whistle Number Analyzed 15 participants 5 participants
1
   6.7%
1
  20.0%
Type of Tinnitus, Hum Number Analyzed 15 participants 5 participants
3
  20.0%
0
   0.0%
Type of Tinnitus, Other Number Analyzed 15 participants 5 participants
0
   0.0%
2
  40.0%
Tinnitus - Pulsing Quality, Yes Number Analyzed 15 participants 5 participants
3
  20.0%
0
   0.0%
Tinnitus Location, Left Ear only Number Analyzed 15 participants 5 participants
2
  13.3%
0
   0.0%
Tinnitus Location, Right Ear only Number Analyzed 15 participants 5 participants
4
  26.7%
1
  20.0%
Tinnitus Location, Both ears Number Analyzed 15 participants 5 participants
7
  46.7%
1
  20.0%
Tinnitus Location, Inside head Number Analyzed 15 participants 5 participants
2
  13.3%
2
  40.0%
Tinnitus Location, Other Number Analyzed 15 participants 5 participants
0
   0.0%
1
  20.0%
Tinnitus Louder on right side of head Number Analyzed 14 participants 4 participants
5
  35.7%
1
  25.0%
Tinnitus Louder on left side of head Number Analyzed 14 participants 4 participants
2
  14.3%
0
   0.0%
Tinnitus Equal on both side of head Number Analyzed 14 participants 4 participants
7
  50.0%
3
  75.0%
Slightly loud tinnitus Number Analyzed 16 participants 4 participants
3
  18.8%
0
   0.0%
Moderately loud tinnitus Number Analyzed 16 participants 4 participants
6
  37.5%
1
  25.0%
How much of Time Tinnitus Present, Occasionally Number Analyzed 15 participants 4 participants
4
  26.7%
3
  75.0%
How much of Time Tinnitus Present,Some of the Time Number Analyzed 15 participants 4 participants
3
  20.0%
0
   0.0%
How much of Time Tinnitus Present,Most of the Time Number Analyzed 15 participants 4 participants
5
  33.3%
0
   0.0%
How much of Time Tinnitus Present,Always Number Analyzed 15 participants 4 participants
3
  20.0%
1
  25.0%
How much of a Problem is Tinnitus, Slight Number Analyzed 16 participants 4 participants
5
  31.3%
1
  25.0%
How much of a Problem is Tinnitus, Moderate Number Analyzed 16 participants 4 participants
2
  12.5%
0
   0.0%
How much of a Problem is Tinnitus, Big Number Analyzed 16 participants 4 participants
1
   6.3%
0
   0.0%
Has the Sound of Tinnitus Changed, Yes Number Analyzed 15 participants 4 participants
1
   6.7%
0
   0.0%
Has Loudness of Tinnitus Changed,Yes,Louder Now Number Analyzed 15 participants 4 participants
1
   6.7%
0
   0.0%
Has Loudness of Tinnitus Changed,Yes,Quieter Now Number Analyzed 15 participants 4 participants
1
   6.7%
0
   0.0%
Amount of TimeTinnitus PresentChanged,Yesmoreoften Number Analyzed 15 participants 4 participants
1
   6.7%
0
   0.0%
Amount of TimeTinnitus PresentChanged,Yeslessoften Number Analyzed 15 participants 4 participants
1
   6.7%
1
  25.0%
16.Secondary Outcome
Title Percent Change From Baseline in Bone Mineral Density (BMD) by Dual Energy X-ray Absorptiometry (DXA) Over 72 Weeks
Hide Description 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.
Time Frame Baseline (Week 0) and Week 72
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 296 298
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent change
Lumbar Spine BMD Number Analyzed 182 participants 164 participants
0.385
(-0.403 to 1.173)
-0.104
(-0.827 to 0.618)
Femur BMD Number Analyzed 179 participants 158 participants
0.435
(-0.196 to 1.065)
-0.063
(-0.644 to 0.519)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments Lumbar Spine BMD
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.179
Comments The analysis of covariance model includes treatment, age at Baseline, gender, menopausal status of females, baseline BMD score and duration of treatment exposure (<12weeks, >=12 weeks) as covariates.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.489
Confidence Interval (2-Sided) 95%
-0.226 to 1.204
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alitretinoin 30 mg, Placebo
Comments Femur BMD
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.089
Comments The analysis of covariance model includes treatment, age at Baseline, gender, menopausal status of females, baseline BMD score and duration of treatment exposure (<12weeks, >=12 weeks) as covariates.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.497
Confidence Interval (2-Sided) 95%
-0.077 to 1.071
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones
Hide Description 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.
Time Frame Up to Week 72
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants who had X-ray evaluations were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 244 243
Measure Type: Count of Participants
Unit of Measure: Participants
Baseline,Lateral C-Spine, Optimal
73
  29.9%
85
  35.0%
Baseline,Lateral C-Spine,Readable
171
  70.1%
158
  65.0%
Baseline,Lateral T-Spine,Readable
229
  93.9%
234
  96.3%
Baseline,Lateral T-Spine,Not Readable
15
   6.1%
9
   3.7%
Baseline, Calcaneous, Optimal
195
  79.9%
191
  78.6%
Baseline, Calcaneous, Readable
48
  19.7%
51
  21.0%
Baseline, Calcaneous, Not Readable
1
   0.4%
1
   0.4%
End of Therapy,Lateral C-Spine,Optimal
80
  32.8%
87
  35.8%
End of Therapy,Lateral C-Spine,Readable
162
  66.4%
146
  60.1%
End of Therapy,Lateral C-Spine, Not Readable
2
   0.8%
10
   4.1%
End of Therapy, Lateral T-Spine, Readable
232
  95.1%
229
  94.2%
End of Therapy, Lateral T-Spine, Not Readable
12
   4.9%
14
   5.8%
End of Therapy, Calcaneous, Optimal
196
  80.3%
182
  74.9%
End of Therapy, Calcaneous, Readable
40
  16.4%
44
  18.1%
End of Therapy, Calcaneous, Not Readable
8
   3.3%
17
   7.0%
Week 72, Lateral C-Spine, Optimal
39
  16.0%
38
  15.6%
Week 72, Lateral C-Spine, Readable
151
  61.9%
134
  55.1%
Week 72, Lateral C-Spine, Not Readable
0
   0.0%
1
   0.4%
Week 72, Lateral C-Spine, Missing
54
  22.1%
70
  28.8%
Week 72, Lateral T-Spine, Readable
183
  75.0%
168
  69.1%
Week 72, Lateral T-Spine, Not Readable
7
   2.9%
5
   2.1%
Week 72, Lateral T-Spine, Missing
54
  22.1%
70
  28.8%
Week 72, Calcaneous, Optimal
141
  57.8%
119
  49.0%
Week 72, Calcaneous, Not Readable
6
   2.5%
4
   1.6%
Week 72, Calcaneous, Missing
54
  22.1%
70
  28.8%
Week 72, Calcaneous, Readable
43
  17.6%
50
  20.6%
18.Secondary Outcome
Title Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure
Hide Description 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.
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants who had ophthalmological evaluations were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 180 186
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with an Adverse Change, No Number Analyzed 180 participants 186 participants
152
  84.4%
146
  78.5%
Participants with an Adverse Change, Yes Number Analyzed 180 participants 186 participants
0
   0.0%
1
   0.5%
Participants with an Adverse Change, Missing Number Analyzed 180 participants 186 participants
28
  15.6%
39
  21.0%
Baseline, Normal Number Analyzed 180 participants 186 participants
177
  98.3%
183
  98.4%
Baseline, Abnormal Number Analyzed 180 participants 186 participants
3
   1.7%
1
   0.5%
Baseline, Missing Number Analyzed 180 participants 186 participants
0
   0.0%
2
   1.1%
End of Therapy, Normal Number Analyzed 180 participants 186 participants
152
  84.4%
146
  78.5%
End of Therapy, Abnormal Number Analyzed 180 participants 186 participants
1
   0.6%
1
   0.5%
End of Therapy, Missing Number Analyzed 180 participants 186 participants
27
  15.0%
39
  21.0%
Worsened from Baseline, No Number Analyzed 3 participants 1 participants
2
  66.7%
1
 100.0%
Worsened from Baseline, Missing Number Analyzed 3 participants 1 participants
1
  33.3%
0
   0.0%
19.Secondary Outcome
Title Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency
Hide Description 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.
Time Frame Up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population. Only those participants who had audiologic evaluations were analyzed.
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 149 147
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with adverse change, No
131
  87.9%
125
  85.0%
Participants with adverse change, Yes
4
   2.7%
10
   6.8%
Participants with adverse change, Missing
14
   9.4%
12
   8.2%
Baseline, Normal
57
  38.3%
69
  46.9%
Baseline, Abnormal
91
  61.1%
75
  51.0%
Baseline, Missing
1
   0.7%
3
   2.0%
End of Therapy, Normal
48
  32.2%
55
  37.4%
End of Therapy, Abnormal
75
  50.3%
71
  48.3%
End of Therapy, Missing
26
  17.4%
21
  14.3%
Time Frame AEs were collected up to follow up period (up to Week 28). Treatment emergent SAEs and nSAEs (up to Week 24) has been presented.
Adverse Event Reporting Description Safety Population was used for the analysis of safety data.
 
Arm/Group Title Alitretinoin 30 mg Placebo
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Alitretinoin 30 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   1/296 (0.34%)   2/298 (0.67%) 
Show Serious Adverse Events Hide Serious Adverse Events
Alitretinoin 30 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   7/296 (2.36%)   3/298 (1.01%) 
Blood and lymphatic system disorders     
Lymphadenopathy  1  0/296 (0.00%)  1/298 (0.34%) 
Gastrointestinal disorders     
Pancreatitis  1  2/296 (0.68%)  0/298 (0.00%) 
General disorders     
Granuloma  1  1/296 (0.34%)  0/298 (0.00%) 
Infections and infestations     
Arthritis Bacterial  1  1/296 (0.34%)  0/298 (0.00%) 
CELLULITIS  1  1/296 (0.34%)  0/298 (0.00%) 
STAPHYLOCOCCAL INFECTION  1  1/296 (0.34%)  0/298 (0.00%) 
Injury, poisoning and procedural complications     
ACCIDENT AT HOME  1  0/296 (0.00%)  1/298 (0.34%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
NON-HODGKIN'S LYMPHOMA  1  0/296 (0.00%)  1/298 (0.34%) 
Nervous system disorders     
HAEMORRHAGIC STROKE  1  1/296 (0.34%)  0/298 (0.00%) 
Psychiatric disorders     
ALCOHOL ABUSE  1  0/296 (0.00%)  1/298 (0.34%) 
COMPLETED SUICIDE  1  1/296 (0.34%)  0/298 (0.00%) 
Renal and urinary disorders     
HYDRONEPHROSIS  1  0/296 (0.00%)  1/298 (0.34%) 
Vascular disorders     
DEEP VEIN THROMBOSIS  1  0/296 (0.00%)  1/298 (0.34%) 
1
Term from vocabulary, MedDRA 15.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Alitretinoin 30 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   108/296 (36.49%)   36/298 (12.08%) 
Gastrointestinal disorders     
Nausea  1  22/296 (7.43%)  4/298 (1.34%) 
Infections and infestations     
Upper respiratory tract infection  1  20/296 (6.76%)  13/298 (4.36%) 
Nervous system disorders     
Headache  1  87/296 (29.39%)  24/298 (8.05%) 
Vascular disorders     
Flushing  1  17/296 (5.74%)  1/298 (0.34%) 
1
Term from vocabulary, MedDRA 15.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
Responsible Party: GlaxoSmithKline ( Stiefel, a GSK Company )
ClinicalTrials.gov Identifier: NCT00817063     History of Changes
Other Study ID Numbers: 117183
BAP01346 ( Other Identifier: Basilea Pharmaceutica )
First Submitted: January 5, 2009
First Posted: January 6, 2009
Results First Submitted: July 17, 2017
Results First Posted: November 9, 2017
Last Update Posted: November 9, 2017