Treatment of Chronic Hand Eczema With Oral Roflumilast (HERO)

Study Overview
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Brief Summary
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This study is a multicentre, double-blinded, randomized, placebo-controlled, clinical trial with open-label extension. The purpose and aim of this study is to investigate the efficacy and safety of roflumilast (PDE4-inhibitor) in adult patients with chronic hand eczema (CHE). Patients will receive 16-week treatment with either roflumilast or placebo tablets. Hereafter, both groups continue in open-label treatment for 12 weeks where both groups will receive treatment with roflumilast.

Detailed Description
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This study will investigate the efficacy and safety of roflumilast in adult patients with CHE and it is hypothesized that patients treated with oral roflumilast (500 microgram once daily) will experience an improvement in their moderate-to-severe CHE (measured by hand eczema severity index (HECSI)) and alter the skin microbiome. Secondly, it is hypothesized that patients treated with oral roflumilast will experience improved lung function and weight loss. This study includes two phases: Phase 1: 20 patients will receive 500 microgram tablet of roflumilast once daily for 16 weeks while 20 patients will receive placebo once daily for 16 weeks. Phase 2: All 40 patients from phase 1 will receive 500 microgram tablet of roflumilast once daily for 12 weeks.

Official Title
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Treatment of Chronic Hand Eczema With Oral Roflumilast (HERO) - a Randomized Controlled Trial

Conditions
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Chronic Hand Eczema

Intervention / Treatment
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* Drug: Roflumilast 500 Mcg Oral Tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Age ≤ 75 years HECSI ≥ 18 (moderate to severe hand eczema) IGA-CHE ≥ 3 Body mass index (BMI) ≥ 20 kg/m2 Negative pregnancy test (only women of child-bearing potential (see section 2.8)) Willing to use safe anticonception during entire study and at least 1 week after end of treatment (-5 times plasma half-life of Roflumilast). This only account for women child-bearing potential Speaks, understands, and reads danish. Exclusion Criteria: Severe immunological disease, e.g. HIV, systemic lupus, and systemic sclerosis Diagnosis of current tuberculosis Current viral hepatitis History of heart failure (NYHA III-IV) History of moderate or severe liver failure (Child-Pugh B-C) Current or former depression with suicidal ideation Topical therapy (anti-inflammatory) for chronic hand eczema 14 days before randomization Topical therapy (anti-inflammatory) for chronic hand eczema during study Systemic therapy for chronic hand eczema 28 days before randomization Systemic therapy for chronic hand eczema during study Current treatment with oral dicloxacillin or macrolide Current treatment with topical antibiotics Diagnosis of contact eczema of clinical significance 3 months before randomization Previous treatment with apremilast (Otezla®) or roflumilast (Daxas®) Confirmed pregnancy Breast feeding Blood donation during study Allergy to roflumilast or any other PDE-4 inhibitor

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentre, double-blinded, randomized, placebo-controlled, clinical trial with open-label extension
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Roflumilast<br>20 of the participating patients are randomized to the active arm where systemic roflumilast 500 microgram tablets are received. | Drug: Roflumilast 500 Mcg Oral Tablet<br>* Randomized to either systemic roflumilast or placebo in phase 1. All participating patients will receive roflumilast in phase 2.<br>* Other names: Daxas;|
| Placebo Comparator: Placebo<br>20 of the participating patients are randomized to the active arm where systemic placebo tablets are received. | Drug: Placebo<br>* Placebo tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving at least 75% reduction in hand eczema severity index (HECSI75) at week 16 when compared to HECSI at baseline. | HECSI is a measure of hand eczema disease severity considering the extent and intensity of the disease. Each hand is divided into five areas (fingertips, fingers (except the tips), palms, back of hands and wrists) and each area is graded on the intensity of six clinical signs: erythema, induration/papulation, vesicles, fissuring, scaling, and oedema. The grading scale used is: 0, no skin change; 1, mild disease; 2, moderate and 3, severe. The affected area for each location (total of both hands) are given a score from 0 to 4 (0, 0%; 1, 1-25%; 2, 26-50%; 3, 51-75% and 4, 76-100%) for the extent of clinical symptoms. Finally, the total sum of the intensity of the six clinical signs multiplied by the extent of each location is called HECSI score and it may vary from 0 to a maximum of 360 points, with higher scores reflecting greater disease severity. The score reflects HE severity as following: 1-16, mild HE; 17-37, moderate HE; 38-116 severe HE and 117-360, very severe HE. | Through study completion, an average of 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving at least 50% reduction in baseline HECSI (HECSI50) at assessments. | HECSI is a measure of hand eczema disease severity considering the extent and intensity of the disease. Each hand is divided into five areas (fingertips, fingers (except the tips), palms, back of hands and wrists) and each area is graded on the intensity of six clinical signs: erythema, induration/papulation, vesicles, fissuring, scaling, and oedema. The grading scale used is: 0, no skin change; 1, mild disease; 2, moderate and 3, severe. The affected area for each location (total of both hands) are given a score from 0 to 4 (0, 0%; 1, 1-25%; 2, 26-50%; 3, 51-75% and 4, 76-100%) for the extent of clinical symptoms. Finally, the total sum of the intensity of the six clinical signs multiplied by the extent of each location is called HECSI score and it may vary from 0 to a maximum of 360 points, with higher scores reflecting greater disease severity. The score reflects HE severity as following: 1-16, mild HE; 17-37, moderate HE; 38-116 severe HE and 117-360, very severe HE. | Through study completion, an average of 28 weeks | 
| Proportion of patients achieving at least 90% reduction in baseline HECSI (HECSI90) at assessments. | HECSI is a measure of hand eczema disease severity considering the extent and intensity of the disease. Each hand is divided into five areas (fingertips, fingers (except the tips), palms, back of hands and wrists) and each area is graded on the intensity of six clinical signs: erythema, induration/papulation, vesicles, fissuring, scaling, and oedema. The grading scale used is: 0, no skin change; 1, mild disease; 2, moderate and 3, severe. The affected area for each location (total of both hands) are given a score from 0 to 4 (0, 0%; 1, 1-25%; 2, 26-50%; 3, 51-75% and 4, 76-100%) for the extent of clinical symptoms. Finally, the total sum of the intensity of the six clinical signs multiplied by the extent of each location is called HECSI score and it may vary from 0 to a maximum of 360 points, with higher scores reflecting greater disease severity. The score reflects HE severity as following: 1-16, mild HE; 17-37, moderate HE; 38-116 severe HE and 117-360, very severe HE. | Through study completion, an average of 28 weeks | 
| Proportion of patients achieving at least 100% reduction in baseline HECSI (HECSI100) at assessments | HECSI is a measure of hand eczema disease severity considering the extent and intensity of the disease. Each hand is divided into five areas (fingertips, fingers (except the tips), palms, back of hands and wrists) and each area is graded on the intensity of six clinical signs: erythema, induration/papulation, vesicles, fissuring, scaling, and oedema. The grading scale used is: 0, no skin change; 1, mild disease; 2, moderate and 3, severe. The affected area for each location (total of both hands) are given a score from 0 to 4 (0, 0%; 1, 1-25%; 2, 26-50%; 3, 51-75% and 4, 76-100%) for the extent of clinical symptoms. Finally, the total sum of the intensity of the six clinical signs multiplied by the extent of each location is called HECSI score and it may vary from 0 to a maximum of 360 points, with higher scores reflecting greater disease severity. The score reflects HE severity as following: 1-16, mild HE; 17-37, moderate HE; 38-116 severe HE and 117-360, very severe HE. | Through study completion, an average of 28 weeks | 
| Percent change from baseline in HECSI score at assessments. | HECSI is a measure of hand eczema disease severity considering the extent and intensity of the disease. Each hand is divided into five areas (fingertips, fingers (except the tips), palms, back of hands and wrists) and each area is graded on the intensity of six clinical signs: erythema, induration/papulation, vesicles, fissuring, scaling, and oedema. The grading scale used is: 0, no skin change; 1, mild disease; 2, moderate and 3, severe. The affected area for each location (total of both hands) are given a score from 0 to 4 (0, 0%; 1, 1-25%; 2, 26-50%; 3, 51-75% and 4, 76-100%) for the extent of clinical symptoms. Finally, the total sum of the intensity of the six clinical signs multiplied by the extent of each location is called HECSI score and it may vary from 0 to a maximum of 360 points, with higher scores reflecting greater disease severity. The score reflects HE severity as following: 1-16, mild HE; 17-37, moderate HE; 38-116 severe HE and 117-360, very severe HE. | Through study completion, an average of 28 weeks | 
| Change (2 or more points) in physician global assessment for chronic hand eczema IGA-CHE) at assessments. | The IGA-CHE rates the severity of the patient's global disease assessed by the physician and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). | Through study completion, an average of 28 weeks | 
| Change from baseline in dermatology life quality index (DLQI) at assessments. | DLQI is a validated, self-administered, 10-item questionnaire that measure the impact of skin disease on patients' quality of life, based on recall over the past week. Domains include symptoms, feeling, daily activities, social, leisure, work or studying, personal relationships, and treatment. Each question is answered on a scale of 0 (not at all) to 3 (very much) and the total score may vary from 0 to 30. | Through study completion, an average of 28 weeks | 
| Change from baseline in patient's global assessment (PaGA) at assessments. | The PaGA rates the severity of the patient's global disease assessed by the patient and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). | Through study completion, an average of 28 weeks | 
| Change from baseline in numeric rating scale (NRS) - Peak skin pain on hands within the last 24 hours at assessments. | NRS is a simple and commonly used numeric scale in which the patient rates patient symptoms such as pain, itch and sleeplessness on a scale from 0 (no pain, no itch, no sleeplessness) to 10 (worst pain, worst itch, worst sleeplessness). | Through study completion, an average of 28 weeks | 
| Change from baseline in numeric rating scale (NRS) - Peak skin pain on hands within the last 7 days at assessments. | NRS is a simple and commonly used numeric scale in which the patient rates patient symptoms such as pain, itch and sleeplessness on a scale from 0 (no pain, no itch, no sleeplessness) to 10 (worst pain, worst itch, worst sleeplessness). | Through study completion, an average of 28 weeks | 
| Change from baseline in NRS - Peak itch on hands within the last 24 hours at assessments. | NRS is a simple and commonly used numeric scale in which the patient rates patient symptoms such as pain, itch and sleeplessness on a scale from 0 (no pain, no itch, no sleeplessness) to 10 (worst pain, worst itch, worst sleeplessness). | Through study completion, an average of 28 weeks | 
| Change from baseline in NRS - Peak itch on hands within the last 7 days at assessments. | NRS is a simple and commonly used numeric scale in which the patient rates patient symptoms such as pain, itch and sleeplessness on a scale from 0 (no pain, no itch, no sleeplessness) to 10 (worst pain, worst itch, worst sleeplessness). | Through study completion, an average of 28 weeks | 
| Change from baseline in NRS - sleeplessness within the last 24 hours at assessments. | NRS is a simple and commonly used numeric scale in which the patient rates patient symptoms such as pain, itch and sleeplessness on a scale from 0 (no pain, no itch, no sleeplessness) to 10 (worst pain, worst itch, worst sleeplessness). | Through study completion, an average of 28 weeks | 
| Change from baseline in NRS - sleeplessness within the last 7 at assessments. | NRS is a simple and commonly used numeric scale in which the patient rates patient symptoms such as pain, itch and sleeplessness on a scale from 0 (no pain, no itch, no sleeplessness) to 10 (worst pain, worst itch, worst sleeplessness). | Through study completion, an average of 28 weeks | 
| Change from baseline in NRS - Patient treatment satisfaction within the last 7 at assessments. | NRS is a simple and commonly used numeric scale in which the patient rates patient treatment satisfaction on a scale from 0 (very unsatisfied) to 10 (very satisfied). | Through study completion, an average of 28 weeks | 
| Change from baseline in quality of life hand eczema questionnaire (QOLHEQ) at assessments. | QOLHEQ is a validated, self-administered 30-question questionnaire that measures impairment of health-related quality of life (HRQoL) in patients with HE. Domains include symptoms, emotions, functioning and treatment/prevention. 0 (not at all) to 4 (all the time) and the total score may vary from 0 to 120. A QOLHEQ score greater than 86 is indicative of very strong impairment. | Through study completion, an average of 28 weeks | 
| Change from baseline in work productivity and activity impairment: CHE (WPAI:CHE) at assessments. | WPAI is a validated, self-administered questionnaire that measures the impact of CHE on work. Domains include time missed from work and impairment of work and regular activities due to CHE. | Through study completion, an average of 28 weeks | 
| Adverse events (AEs), serious adverse events (SAEs), serious adverse reactions (SARs), and suspected unexpected serious adverse reactions (SUSARS) documented at assessments. | AE are any unfavorable and/or unintended sign or incident, symptoms or disease, whether related to roflumilast or placebo. This also includes laboratory results outside the reference range, though only laboratory results with clinical relevance will be examined. Any AE from the first administration of the trial medication to 8 days after the last administration of the trial medicine will be recorded, though unfavorable event reported in questionnaires will not be recorded as AE. SAE and SAR are any AE or adverse reaction that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly of birth defect. | Through study completion, an average of 28 weeks |