| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe chronic hand eczema |
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| E.1.1.1 | Medical condition in easily understood language |
| Long term hand eczema that has not responded to treatment with steroids. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066558 |
| E.1.2 | Term | Chronic eczema |
| E.1.2 | System Organ Class | 100000004858 |
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| 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 |
| The primary objective is to compare alitretinoin (AL) and psoralen combined with ultraviolet A (PUVA) as first line therapy in terms of disease activity at 12 weeks post planned start of treatment. |
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| E.2.2 | Secondary objectives of the trial |
1. To compare Alitretinoin and PUVA in terms of disease activity over time with a focus on disease activity at 24 and 52 weeks post planned start of treatment.
2. To compare Alitretinoin and PUVA in terms of time to relapse.
3. To compare Alitretinoin and PUVA in terms of quality of life (QoL) and patient benefit over the 52 weeks duration post planned start of treatment.
4. To determine cost effectiveness of Alitretinoin compared to PUVA over the short and longer term.
5. To determine the educational need for individual patients.
6. To compare Alitretinoin and PUVA in terms of safety
Exploratory Objectives
1. To compare scoring systems HECSI, mTLSS, DLQI and PGA used to monitor response to treatment in patients with severe CHE.
2. To evaluate whether response to first line treatment is affected by the following parameters:
• duration of disease
• clinical phenotype
• disease severity
• presence of atopy
• filaggrin loss of function mutation (and other potential emerging mutations |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
For the ALPHA trial the sub study is incorporated within the main study. The main objective of the sub-study is to determine the treatment responses in patient sub-groups defined by molecular inflammatory mediators, which will be measured in skin samples obtained by either tape strips or washing solution.
An additional nail assessment sub-study has been included in the latest version of the protocol. This will take place exclusively at St Luke's hospital, Bradford.
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| E.3 | Principal inclusion criteria |
1. Patients aged ≥18 years at the time of signing the Informed Consent Form
2. Patients suffering from uncontrolled, severe CHE defined as the presence of both of the following criteria:
a) PGA score of severe
b) Resistance to treatment with potent topical corticosteroids for ≥ 4 weeks prior to the point of eligibility screening.
3. Patient has provided written informed consent.
4. Patient is expected to comply with treatment and protocol schedule.
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|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study for any of the following reasons:
Skin related:
1. Patients who have a clinically suspected infection (fungal, bacterial or viral) as cause for dermatitis of the hands.
2. Patients with known clinically relevant allergic contact dermatitis of the hands unless they had made a reasonable effort to avoid the contact allergen.
3. Patients suffering from atopic eczema covering more than 10% of body surface (excluding hands).
4. Patients who have skin conditions worsened by the sun i.e. do not tolerate UV-light (for example lupus erythematosus, porphyria).
Treatment related:
5. Patients who have received phototherapy/photochemotherapy in the last 3 months prior to randomisation
6. Patients who have received systemic vitamin A derivatives or other systemic immunosuppressants e.g. methotrexate or biologics treatment for HE in the last 3 months prior to randomisation
7. Patients who have received Ciclosporin A or systemic glucocorticoid steroid treatment for HE in the last 4 weeks prior to randomisation.
8. Patients receiving topical calcineurin antagonist treatment within 1 week prior to randomisation.
9. Patients receiving concomitant treatment with tetracyclines, or medication with potential for drug-drug interaction with Alitretinoin (e.g. CYP3A4 inhibitor ketoconazole) that cannot be suspended or switched to an acceptable alternative.
10. Patients receiving concomitant treatment with relevant photosensitisers, when this treatment cannot be suspended for the duration of the intervention or switched to an acceptable alternative
11. Patients with a history of melanoma skin cancer, or patients with a history of non-melanoma skin cancer depending on history, location and “severity” of the non-melanoma skin cancer based on experience from routine practice.
12. Patients who have received prior treatment with arsenic agents or ionising radiation in the treatment area (e.g. hands).
General:
13. If female:
a) Lactating
b) Of child bearing potential (WCBP, Appendix 1):
i. With positive pregnancy test (absence of pregnancy will be confirmed with a negative pregnancy test before randomisation)
ii. Unwilling to follow pregnancy prevention program measures* (see below) whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC
14. Patients with hepatic insufficiency (alanine aminotransferase and/or aspartate aminotransferase > 2.5 times the upper limit of normal), known severe renal insufficiency, uncontrolled hyperlipidaemia (for all of the following: triglycerides, cholesterol and/or LDL cholesterol) or uncontrolled hypothyroidism in the 12 week period prior to randomisation.
15. Patients with known hypersensitivity to peanut, soya or vitamin A derivatives or with rare hereditary fructose intolerance as determined by patient history.
16. Patients currently suffering from hypervitaminose A as directed by clinical symptoms or patient history
17. Patients previously participated in the ALPHA trial
Eligibility waivers to the eligibility criteria are not permitted.
*Rigorous contraception for women of childbearing potential,unless exempt according to standard of care practice, is required 1 month before treatment, during the treatment period and 1 month after cessation of treatment as per usual standard practice.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure for the study is the Log (HECSI score) at 12 weeks post planned start of treatment, where the HECSI score is obtained from the Hand Eczema Severity Index. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks post planned start of treatment. |
|
| E.5.2 | Secondary end point(s) |
1. Log(HECSI score) over the 52 weeks post planned start of treatment
2. mTLSS of the index hand and overall over the 52 weeks post planned start of treatment
3. PGA of the index hand and overall at over the 52 weeks post planned start of treatment
4. Time to relapse (HECSI score >75% baseline HECSI score of the index hand)
5. DLQI over the 52 weeks post planned start of treatment
6. PBI-HE over the 52 weeks post planned start of treatment
7. PeDeSi over the 52 weeks post planned start of treatment
8. Cost-effectiveness over the 52 weeks post planned start of treatment
9. AEs and SAEs reported throughout the reporting period
For the purposes of secondary analysis the index hand will be used in addition to overall. The index hand is defined as the worst affected hand based on the hand which interferes with their daily life the most.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline, and at 4,8,12, 16, 20, 24, 28, 32, 36, 44 and 52 weeks post planned start of treatment
2. Baseline, and at 12, 24, 36 and 52 weeks post planned start of treatment
3. Baseline, and at 4,8,12, 16, 20, 24, 28, 32, 36, 44 and 52 weeks post planned start of treatment
4. Over the 52 weeks post planned start of treatment
5. Baseline, and at 4,8,12, 16, 20, 24, 28, 32, 36, 44 and 52 weeks post planned start of treatment
6. Baseline, and at 12, 24, 36 and 52 weeks post planned start of treatment
7. Baseline, 12 and 52 weeks post planned start of treatment
8. Baseline, and at 12,24,36 and 52 weeks post planned start of treatment
9. over the 52 weeks post planned start of treatment |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| psoralen combined with ultraviolet A (PUVA) as first line therapy |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 35 |
| 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 | Yes |
| 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
|
| The end of the trial is defined as the date of receipt of the last participant’s last data item. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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