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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate the safety and efficacy of alitretinoin in the treatment of severe chronic hand eczema that does not respond to treatment with potent topical steroids.

Detailed Description
-----------------
Chronic hand eczema (CHE)is a distressing disease that poses difficult problems for dermatologists. CHE leads to considerable work-absenteeism, disability and exclusion from labour market. Conventional treatments, including highly potent topical steroids, yield often unsatisfactory results. This study investigates the efficacy and safety of oral alitretinoin, a retinoid, in patients who have not responded to avoidance of causative factors, such as contact allergens and skin irritants, non-medicated skin care and highly potent topical steroids. Eligible patients are randomly assigned to receive alitretinoin or a placebo.

Official Title
-----------------
Efficacy and Safety of Alitretinoin in the Treatment of Severe Chronic Hand Eczema Refractory to Topical Therapy

Conditions
-----------------
Eczema

Intervention / Treatment
-----------------
* Drug: alitretinoin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: all types of chronic hand eczema, lasting for at least 6 months since initial diagnosis rated as severe by the physician unresponsive to highly potent topical corticosteroids, such as clobetasol Exclusion Criteria: patients whose disease is adequately controlled by standard non-medicated therapy, including potent topical steroids, skin moisturizers, and avoidance of allergens and irritants patients with known allergens and irritants, who have not made a reasonable effort to avoid the substances patients with psoriasis lesions active fungal, bacterial or viral infections of the hands female patients who are pregnant or breastfeeding female patients of childbearing potential who cannot use or will not commit to use two effective methods of contraception

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alitretinoin<br>Patients will receive alitretinoin 30mg capsule for up to 24 weeks | Drug: alitretinoin<br>* Patients receive alitretinoin 30mg one capsule daily for up to 24 weeks<br>|
| Experimental: Placebo<br>Patients will receive placebo 30mg capsule for up to 24 weeks | Drug: Placebo<br>* Patients receive matching placebo for up to 24 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Responded as Per Physician's Global Assessment (PGA) at Week 24 | 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. | Week 24 (end-of-treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in Modified Total Lesion Symptom Score (mTLSS) at the End-of-treatment | 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. | Baseline (Week 0) and Week 24 (end-of-treatment) | 
| Number of Participants Who Responded as Per Patient Global Assessment (PaGA) at End-of-treatment | 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. | Week 24 (end-of-treatment) | 
| Percentage Change From Baseline in Extent of Disease at End-of-treatment | 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. | Baseline (Week 0) and Week 24 (end-of-treatment) | 
| Response Duration for Responding Participants at the End-of-therapy | 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. | Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up) | 
| Time to Relapse for Responding Participants at the End-of-therapy | 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. | Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up) | 
| Time to Response for Responding Participants at End-of-therapy | 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. | Up to 72 Weeks (including 24 weeks of treatment and 48 weeks of follow-up) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Treatment Period | 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. | Up to Week 24 (end-of-treatment) | 
| Number of Participants With Maximum Post Baseline Laboratory Values Outside the Marked Reference Range | 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. | Up to Week 28 | 
| Number of Participants Referred or Not Referred to a Psychiatrist as Per Brief Summary Inventory (BSI) 53 Questionnaire up to 24 Weeks | 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. | Up to Week 24 | 
| Change From Baseline in Patient Health Questionnaire (PHQ-9) Score Over 28 Weeks | 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. | Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24, 28 | 
| Number of Participants Meeting the Referral Criteria of Psychiatric Evaluation Over 28 Weeks | 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. | Up to 28 Weeks | 
| Change From Baseline in Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) Over 24 Weeks | 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. | Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in Dizziness Handicap Inventory (DHI) Over 24 Weeks | 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. | Baseline (Week 0) and Week 4, 8, 12, 16, 20, 24 | 
| Number of Participants Responding to Tinnitus Ototoxicity Monitoring Interview (TOMI) Questionnaire Over 24 Weeks | 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. | Up to Week 24 | 
| Percent Change From Baseline in Bone Mineral Density (BMD) by Dual Energy X-ray Absorptiometry (DXA) Over 72 Weeks | 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. | Baseline (Week 0) and Week 72 | 
| Number of Participants With Adequecy of Images Assessed by X-ray Evaluation of Bones | 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. | Up to Week 72 | 
| Number of Participants With Adverse Ophthalmological Change as Assessed by Fundus Photography - Intraocular Pressure | 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. | Up to Week 24 | 
| Number of Participants With Adverse Audiological Change as Assessed by Puretone Audiogram at Highest Frequency | 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. | Up to Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
retinoid treatment, fingertip dermatitis, hyperkeratotic hand eczema, vesicular hand eczema, pompholyx