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

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

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.

Study Overview

• Status: Completed
• Conditions: Eczema
• Intervention / Treatment: Drug: alitretinoin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 599
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama, Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85710
      • Radiant Research Inc.
  • Arkansas
    • Fort Smith, Arkansas, United States, 72916
      • Johnson Dermatology
    • Little Rock, Arkansas, United States, 72205
      • Dermatology Research of Arkansas
    • Rogers, Arkansas, United States, 72758
      • Hull Dermatology
  • California
    • Encino, California, United States, 91436
      • Shahram Jacobs, MD, Inc.
    • La Jolla, California, United States, 92037
      • University of California, San Diego Dermatology Clinical Trials Unit
    • Los Angeles, California, United States, 90045
      • Dermatology Research Associates
    • Marina Del Rey, California, United States, 90292
      • Laser and Dermatology Center
    • Riverside, California, United States, 92506
      • Integrated Research Group
    • Sacramento, California, United States, 95816
      • University of California, Davis
    • San Diego, California, United States, 92123
      • Therapeutics Clinical Research
    • San Ramon, California, United States, 94583
      • East Bay Psoriasis Treatment Center
    • Stanford, California, United States, 94305
      • Stanford University Dept of Dermatology
    • Vallejo, California, United States, 94589
      • Solano Clinical Research, Dow Pharmaceutical Sciences
  • Colorado
    • Longmont, Colorado, United States, 80501
      • Longmont Clinic, P.C.
    • Wheat Ridge, Colorado, United States, 80033
      • Western State Clinical Research Inc.
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University - Medical Faculty Associates
  • Florida
    • Orange Park, Florida, United States, 32073
      • Park Avenue Dermatology, PA
    • West Palm Beach, Florida, United States, 33409
      • Palm Beach Research Center
  • Georgia
    • Toccoa, Georgia, United States, 30577
      • Toccoa Clinic Medical Associates
  • Idaho
    • Nampa, Idaho, United States, 83687
      • Saltzer Medical Group
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Michael Bukhalo MD
    • Belleville, Illinois, United States, 62226
      • Dermassociates, Ltd
    • Schaumburg, Illinois, United States, 60194
      • Schaumburg Dermatology
    • West Dundee, Illinois, United States, 60118
      • Dundee Dermatology
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Deaconess Clinic, Inc.
    • Indianapolis, Indiana, United States, 37660
      • Indiana University Dermatology
    • New Albany, Indiana, United States, 47150
      • The Dermatology Center
    • Plainfield, Indiana, United States, 46168
      • Dermatology Center of Indiana/Indiana Clinical Trials Center
  • Kansas
    • Overland Park, Kansas, United States, 66215
      • Kansas City Dermatology, PA
    • Shawnee Mission, Kansas, United States, 66216
      • American Dermatology Association
    • Topeka, Kansas, United States, 66614
      • Kansas Medical Clinic
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Dermatology Specialists
    • Louisville, Kentucky, United States, 40217
      • Derm Research, PLLC
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences, Dermatology Dept
  • Michigan
    • Fort Gratiot, Michigan, United States, 48059
      • Hamzavi Dermatology Clinic
    • Grand Blanc, Michigan, United States, 48439
      • Silverton Skin Institute
    • Warren, Michigan, United States, 48088
      • Grekin Skin Institute
  • Minnesota
    • Edina, Minnesota, United States, 55435
      • MAPS Applied Research Center
    • Fridley, Minnesota, United States, 55432
      • Minnesota Clinical Studies Research Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Dermatology Research
  • Nebraska
    • Lincoln, Nebraska, United States, 68502
      • South Lincoln Dermatology
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Somerset, New Jersey, United States, 08873
      • UMDNJ - Robert Wood Johnson School of Medicine, Dermatology
  • New York
    • New York, New York, United States, 10025
      • St.Luke's/Roosevelt Hospital Center
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine Clinical Dermatology
    • Rochester, New York, United States, 14609
      • Helendale Dermatology and Medical Spa
    • Stony Brook, New York, United States, 11790
      • Derm Research Center of New York Inc.
  • North Carolina
    • Chapel Hill, North Carolina, United States, 918-843-9447
      • University of North Carolina, Dermatology Department
    • Wilmington, North Carolina, United States, 28403
      • Azalea Research Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forrest University School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Bernstein Clinical Research Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97210
      • Oregon Dermatology and Research Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19103
      • Paddington Testing Co.Inc
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Dermatology Associates of Kingsport
    • Nashville, Tennessee, United States, 37215
      • Tennessee Clinical Research Center
  • Texas
    • Arlington, Texas, United States, 76011
      • Academy of Clinical Research
    • Dallas, Texas, United States, 75231
      • Modern Research Associates
    • Houston, Texas, United States, 77030
      • Center for Clinical Studies
    • San Antonio, Texas, United States, 77056
      • Dermatology Clinical Research Center of San Antonio
    • Webster, Texas, United States, 77598
      • Center for Clinical Studies
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Virginia Clinical Research Inc.
  • Washington
    • Bellingham, Washington, United States, 98281
      • Dermatology and Laser Center NW
    • Seattle, Washington, United States, 99204
      • Premier Clinical Research
  • Wisconsin
    • Madison, Wisconsin, United States, 53719
      • Madison Skin & Research Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alitretinoin; Patients will receive alitretinoin 30mg capsule for up to 24 weeks	Drug: alitretinoin; Patients receive alitretinoin 30mg one capsule daily for up to 24 weeks
Experimental: Placebo; Patients will receive placebo 30mg capsule for up to 24 weeks	Drug: Placebo; Patients receive matching placebo for up to 24 weeks

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

Collaborators and Investigators

• Sponsor: Stiefel, a GSK Company
• Collaborators: Basilea Pharmaceutica

Publications and helpful links

General Publications

• Diepgen TL, Agner T, Aberer W, Berth-Jones J, Cambazard F, Elsner P, McFadden J, Coenraads PJ. Management of chronic hand eczema. Contact Dermatitis. 2007 Oct;57(4):203-10. doi: 10.1111/j.1600-0536.2007.01179.x.
• Ruzicka T, Larsen FG, Galewicz D, Horvath A, Coenraads PJ, Thestrup-Pedersen K, Ortonne JP, Zouboulis CC, Harsch M, Brown TC, Zultak M. Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial. Arch Dermatol. 2004 Dec;140(12):1453-9. doi: 10.1001/archderm.140.12.1453.
• Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, Kaszuba A, Bissonnette R, Varjonen E, Hollo P, Cambazard F, Lahfa M, Elsner P, Nyberg F, Svensson A, Brown TC, Harsch M, Maares J. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol. 2008 Apr;158(4):808-17. doi: 10.1111/j.1365-2133.2008.08487.x. Epub 2008 Feb 21.
• Fowler JF, Graff O, Hamedani AG. A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of alitretinoin (BAL4079) in the treatment of severe chronic hand eczema refractory to potent topical corticosteroid therapy. J Drugs Dermatol. 2014 Oct;13(10):1198-204.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2009
• Primary Completion (Actual): April 26, 2012
• Study Completion (Actual): April 26, 2012

Study Registration Dates

• First Submitted: January 5, 2009
• First Submitted That Met QC Criteria: January 5, 2009
• First Posted (Estimate): January 6, 2009

Study Record Updates

• Last Update Posted (Actual): April 27, 2020
• Last Update Submitted That Met QC Criteria: April 10, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: retinoid treatment; fingertip dermatitis; hyperkeratotic hand eczema; vesicular hand eczema; pompholyx
• Additional Relevant MeSH Terms: Skin Diseases; Dermatitis; Skin Diseases, Eczematous; Eczema; Antineoplastic Agents; Dermatologic Agents; Alitretinoin
• Other Study ID Numbers: 117183; BAP01346 (Other Identifier: Basilea Pharmaceutica); NCT00817063 (Registry Identifier: Clinicaltrials.gov)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Access Criteria: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)