| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hand eczema (HE) is a common condition with a 1-year period prevalence up to 10%. Systemic treatment with alitretinoin is registered for all clinical types of HE. However, it is especially effective in the hyperkeratotic subtype. Cyclosporine is often prescribed for HE in daily practice and has shown to be especially effective in patients with vesicular HE. The efficacy of cyclosporine in moderate to very severe HE could prove superior to that of alitretinoin. |
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| E.1.1.1 | Medical condition in easily understood language |
| To compare the efficacy of alitretinoin and cyclosporine in moderate to very severe hand eczema. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Primary objective: to compare the efficacy of alitretinoin and cyclosporine 24 weeks post planned start treatment in patients with moderate to very severe hand eczema. |
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| E.2.2 | Secondary objectives of the trial |
• to compare alitretinoin and cyclosporine in terms of health related quality of life
• to compare alitretinoin and cyclosporine in terms of improvement in severity of hand eczema), assessed by the patient (PaGA)
• to compare alitretinoin and cyclosporine in terms of improvement in objective severity of hand eczema (HECSI)
• to compare the number and nature of adverse events
• to compare alitretinoin and cyclosporine in terms of cost-utility and cost-effectiveness
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
- Age ≥ 18 years
- Moderate, severe or very severe hand eczema for a minimum duration of 3 months as defined by a Physician Global Assessment (PGA) using a validated Photoguide16
- Refractory to standard therapy, defined as:
o Patients received treatment with topical corticosteroids of class II or higher for at least 8 weeks within 3 months before enrolment, with either no response or a transient response
o Patients had also received standard skin care, including emollients and barrier protection as appropriate, without significant improvement
o Patients had avoided irritants and contact allergens, if identified, without significant improvement
• Women of childbearing potential are required to use at least two forms of contraception for at least 1 month before starting treatment, during treatment, and for at least 1 month after finishing treatment; these women are required to take monthly pregnancy tests
• Able to provide written Informed Consent
• Able to speak and read the Dutch language
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| E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study:
General criteria prior to randomization
• Patients with predominantly atopic dermatitis, in which the hands are also involved. Patients with controlled atopic dermatitis, in which the hands are mainly affected, are eligible for inclusion.
• Patients with known clinically relevant allergic contact dermatitis of the hands unless they had made a reasonable effort to avoid the contact allergen.
• Psoriasis
• Active bacterial, fungal, or viral infection of the hands
• Pregnant/lactating or planning to become pregnant during the study period
• Treatment with systemic medication or UV radiation within the previous 4 weeks. For systemic prednisolone; patients with treatment within the previous 2 weeks will be excluded
• Treated with alitretinoin or cyclosporine in the previous 3 months
• Mentally incompetent
• Currently active depression
• Immunocompromised status
• Known or suspected allergy to ingredients in the study medications
• Inclusion in a study of an investigational drug within 60 days prior to start of treatment
• Current malignancy (other than successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and⁄or localized carcinoma in situ of the cervix)
• Current active pancreatitis
• Evidence of alcohol abuse or drug addiction
• Chronic or recurrent infectious diseases
• Impaired renal function as indicated by a clinically relevant abnormal creatinine value (to be determined by investigator or treating physician)
• Alanine aminotransferase (ALAT) and ⁄or aspartate aminotransferase (ASAT) values > 200% of the upper limit of normal
• Contact sensitizations with clinical relevance to the hands, in which avoidance of exposure is unclear
• Hypervitaminosis A due to the use of vitamin A supplements containing >2000 IU
• Use of drugs with potential to change the effective dosis of study drugs within the previous 2 weeks
Cyclosporine specific:
• Uncontrolled arterial hypertension
• Renal insufficiency prior to start treatment
• Contraindicated co-medication (see SPC text)
• Living vaccine (including bacillus Calmette-Guérin (BCG), varicella, measles, mumps, rubella, yellow fever, oral polio and oral typhoid) in the last 2 weeks or the planned application of such a vaccine during the study period
Alitretinoin specific
• Triglycerides > 200% of the upper limit of normal,
• Cholesterol or low density lipoprotein (LDL) cholesterol values > 200% of the upper limit of normal
• Uncontrolled hypothyroidism (to be determined by investigator or treating physician)
• Contraindicated co-medication of alitretinoin (see SPC text). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Main endpoint: severity of hand eczema.
Response to treatment is defined as achieving ‘clear’/’almost clear’ in the PGA (Physician Global Assessment) score, based on a validated Photographic Guide developed by Coenraads et al. at 24 weeks of treatment. In this study the main endpoint is the between-group difference in response to treatment between baseline and 24 weeks of treatment.
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| In this study the main endpoint is the between-group difference in response to treatment between baseline and 24 weeks of treatment. Response to treatment is defined as achieving ‘clear’/’almost clear’ in the PGA (Physician Global Assessment) score, based on a validated Photographic Guide developed by Coenraads et al. at 24 weeks of treatment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The main end point is at 24 weeks. |
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| E.5.2 | Secondary end point(s) |
Severity of hand eczema
• Between-group difference in ≥ 2 steps of PGA improvement between baseline and 24 weeks
• Between-group difference in mean change in PGA between baseline and 12 and 24 weeks.
• Between-group difference in response to treatment between baseline and 12 weeks of treatment.
•Between-group difference in mean change between baseline and week 4, 8, 12 and 24, assessed by the Hand Eczema Severity Index (HECSI) score.24 The HECSI is an objective severity assessment based on clinical symptoms only. It includes erythema, fissures, vesicles, scaling, oedema, papules and measurement of the affected area. The score ranges from 0-360, with a score > 28 indicating severe hand eczema.
• Between-group difference in time to response (time to first PGA improvement of ≥ 2 steps). This is only measured at control visits so possible outcome is limited to 4, 8, 12 and 24 weeks.
Patient rated outcome measures (PROMs)
Quality of life
• Between-group mean change in quality of life between baseline and 12 and 24 weeks, assessed by the Quality Of Life in Hand Eczema Questionnaire (QOLHEQ). The QOLHEQ is a multi domain disease specific instrument for hand eczema assessing impairments in quality of life. The score ranges from 0-120, with 120 indicating worst quality of life.
Patient reported improvement
• Between-group difference in patients reporting improvement as ‘clear or almost clear’ at week 12 and 24, assessed by Patient Global Assessment (PaGA). The PaGA takes signs and symptoms into account. It covers 6 degrees of improvement: ‘clear or almost clear’ (at least 90% clearing of disease signs and symptoms compared to baseline), ‘marked improvement’ (at least 75% clearing), ‘moderate improvement’ (at least 50% clearing), ‘mild improvement’ (at least 25% clearing), ‘no change’, or ‘worsening’.
Safety and tolerability
• Adverse events in both groups will be registered.
Cost-utility and cost-effectiveness
• Between-group difference in mean Quality Adjusted Life Years (QALY’s) will be measured by the EQ-5D-5L score at baseline, week 12 and week 24. The EQ-5D-5L is a measure for HRQoL and utility values. The EQ-5D-5L questionnaire includes a visual analog scale (VAS), which records the respondent's self-rated health status on a graduated (0–100) scale. Moreover it includes a descriptive system, which comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
• Direct medical costs will be determined using standardized prices for consultation, treatment, diagnostic tests, laboratory measurements, visits to the general practitioner for hand eczema and hospital admissions (in patient and/or daycare). Included patients will be asked to keep track of how much they spend on over-the-counter medication and other products for their hand eczema (out-of-pocket costs). Direct non-medical costs, consisting of travel costs, will be determined using average travel costs to the hospital as determined by relevant Dutch guidelines on cost-studies in healthcare.
• Indirect costs, consisting mainly of productivity loss, will be also be calculated using tables from the guidelines with average income of Dutch workers stratified by age and gender, corrected for shift working / irregular working hours.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Most time points were evaluated at 8, 12 and 24 weeks.
Evaluation of adverse events will be done every visit. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of the trial is at 24 weeks. In case of early drop out there will be a end of study visit.
When subjects withdrawn from treatment they will continue treatment at our center, outside the study. All efforts will be made to report the observations for the reason(s) for premature withdrawal and the time of occurrence. If an adverse event is the reason for withdrawal, the physicians will administer therapy as clinically indicated. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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