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    Summary
    EudraCT Number:2015-003488-12
    Sponsor's Protocol Code Number:54659
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-06-01
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-003488-12
    A.3Full title of the trial
    Efficacy of oral alitretinoin versus oral cyclosporine in patients with moderate to very severe hand eczema. A randomized prospective open-label trial with blinded outcome assessment.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of alitretinoin versus cyclosporine in patients with moderate to very severe hand eczema.
    A.3.2Name or abbreviated title of the trial where available
    Alitretinoin versus cyclosporine in hand eczema
    A.4.1Sponsor's protocol code number54659
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Medical Center Groningen
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportZonMW
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointFieke Rosenberg
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713GZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31355256116
    B.5.5Fax number+31503619247
    B.5.6E-mailf.m.rosenberg@umcg.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Toctino/alitretinoin
    D.2.1.1.2Name of the Marketing Authorisation holderStiefel
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameToctino/alitretinoin
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Neoral/cyclosporine
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNeoral/cyclosporine
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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.
    E.1.1.1Medical condition in easily understood language
    To compare the efficacy of alitretinoin and cyclosporine in moderate to very severe hand eczema.
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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).
    E.5 End points
    E.5.1Primary 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.
    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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The main end point is at 24 weeks.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 53
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state78
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the trial has ended subjects will continue treatment in the hospital as standard care. If necessary subject will continue alitretinoin or cyclosporine.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-08-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-23
    P. End of Trial
    P.End of Trial StatusOngoing
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