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    Summary
    EudraCT Number:2015-001447-37
    Sponsor's Protocol Code Number:52232
    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:2015-06-12
    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 number2015-001447-37
    A.3Full title of the trial
    Efficacy of oral alitretinoin versus oral azathioprine in patients with severe chronic non-hyperkeratotic hand eczema. A randomized prospective open-label trial with blinded outcome assessment.
    Effectiviteit van oraal alitretinoine versus oraal azathioprine bij patienten met ernstig chronisch niet-hyperkeratotisch handeczeem. Een gerandomiseerde prospectieve open-label studie met geblindeerde meting van eindpunten.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effectivity of alitretinoin compared to azathioprine in patients with severe chronic non-hyperkeratotic hand eczema.
    Effectiviteit van alitretinoïne vergeleken met azathioprine bij patiënten met ernstig chronisch niet-hyperkeratotisch handeczeem.
    A.3.2Name or abbreviated title of the trial where available
    ALIAZ-trial
    ALIAZ-studie
    A.4.1Sponsor's protocol code number52232
    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 supportUniversity Medical Center Groningen
    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 pointDepartment of Dermatology
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9700RB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31503610795
    B.5.6E-mailj.a.f.oosterhaven@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 / 9-cis-retinoic acid
    D.2.1.1.2Name of the Marketing Authorisation holderStiefel Laboratories (Ireland) Limited
    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 nameAlitretinoin
    D.3.2Product code 9-cis-retinoic acid
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    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 Imuran / Azasan / Azathioprine
    D.2.1.1.2Name of the Marketing Authorisation holderAspen Pharma Trading Limited
    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 nameAzathioprine
    D.3.2Product code Azathioprine
    D.3.4Pharmaceutical form Film-coated tablet
    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
    Handeczeem
    E.1.1.1Medical condition in easily understood language
    Hand eczema
    Handeczeem
    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
    To compare the efficacy of alitretinoin and azathioprine in the treatment of severe chronic non-hyperkeratotic hand eczema.
    Het vergelijken van de effectiviteit van alitretinoïne en azathioprine bij de behandeling van ernstig chronisch niet-hyperkeratotisch handeczeem.
    E.2.2Secondary objectives of the trial
    To compare time to response, to compare health related quality of life, to compare improvement in severity of hand eczema assessed by the patient, to compare safety.
    Het vergelijken van tijd tot respons, vergelijken van gezondheid gerelateerde kwaliteit van leven, vergelijken van verbetering van ernst van handeczeem als gemeten door de patiënt, vergelijken van veiligheid.
    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 and ≤ 75 years

    - Severe chronic non-hyperkeratotic hand eczema for a minimum duration of 3 months as defined by a Physician Global Assessment (PGA) using a validated Photoguide

    - Refractory to standard therapy, defined as:
    -> 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
    -> Patients had also received standard skin care, including emollients and barrier protection as appropriate, without significant improvement
    -> Patients had avoided irritants and 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

    - Not previously treated with alitretinoin or azathioprine

    - Able to provide written informed consent

    - Able to speak and read the Dutch language
    - Leeftijd ≥ 18 jaar en ≤ 75 jaar

    - Ernstig chronisch niet-hyperkeratotisch handeczeem gedurende minimaal 3 maanden, gedefinieerd met een Physician Global Assessment (PGA) gebruik makend van een gevalideerde Photoguide

    - Refractair voor standaard therapie, gedefinieerd als:
    -> Patienten zijn gedurende minstens 8 weken in de afgelopen 3 maanden behandeld met topicale corticosteroiden van klasse II of hoger met ofwel geen respons ofwel een tijdelijke respons
    -> Patienten hebben standaard huidbehandeling gekregen, inclusief emollientia en bescherming van de huidbarrière, zonder significante verbetering
    -> Patienten hebben irritantia en allergenen vermeden wanneer deze zijn geïdentificeerd, zonder significante verbetering

    - Vrouwen in de vruchtbare leeftijd zijn verplicht om minstens 2 vormen van anticonceptie te gebruiken gedurende minstens 1 maand voorafgaand aan de behandeling, tijdens de behandeling en minstens 1 maand na staken van de behandeling. Deze vrouwen moeten maandelijks een zwangerschapstest doen

    - Niet eerder behandeld met alitretinoine of azathioprine

    - Geschreven informed consent kunnen verschaffen

    - De Nederlandse taal kunnen spreken en lezen
    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
    - Hyperkeratotic palmar eczema as defined by the Danish Contact Dermatitis Group
    - Patients with predominantly atopic dermatitis, in which the hands are also involved. Patients with mild atopic dermatitis, in which the hands are mainly affected are eligible for inclusion.
    - 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
    - Use of topical corticosteroids > class II within 1 week before enrolment
    - 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
    - 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
    - Evidence of alcohol abuse or drug addiction
    - Chronic or recurrent infectious diseases
    - 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

    Laboratory exclusion criteria post randomization
    - Alanine aminotransferase (ALAT) and ⁄or aspartate aminotransferase (ASAT) values > 200% of the upper limit of normal
    - Impaired renal function as indicated by a clinically relevant abnormal creatinine value (to be determined by investigator or treating physician)
    - Anemia as indicated by a clinically relevant lowered hemoglobin value (to be determined by investigator or treating physician)

    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)

    Azathioprine specific
    - Patients with low or absent thiopurine methyltransferase (TPMT) activity (defined in our center as <52 nmol/gHb/hour, combined with genotyping showing homozygous of compound heterozygous mutations) and a subsequent risk for life-threatening myelotoxicity
    Algemene criteria voorafgaand aan randomisatie
    - Hyperkeratotisch palmair eczeem zoals gedefinieerd door de Danisch Contact Dermatitis Group
    - Patienten met voornamelijk atopisch eczeem, waarbij de handen ook aangedaan zijn. Patienten met mild atopisch eczeem, waarbij de handen voornamelijk zijn aangedaan zijn wel geschikt voor inclusie
    - Psoriasis
    - Actieve bacteriele, mycotische of virale infectie van de handen
    - Zwangerschap, lactatie of zwangerschapswens tijdens de studieperiode
    - Behandeling met systemische medicatie of UV radiatie in de afgelopen 4 weken
    - Gebruik van topical corticosteroiden > klasse II binnen 1 week voorafgaand aan inclusie
    - Wilsonbekwaamheid
    - Momenteel actieve depressie
    - Immuungecomprommiteerde status
    - Bekende of vermoede allergie voor ingrediënten van studiemedicatie
    - Inclusie in een geneesmiddelenstudie tijdens de afgelopen 60 dagen
    - Huidige maligniteit (afgezien van succesvol behandeld niet-gemetastaseerd plaveiselcel- of basaalcelcarcinoom en/of gelokaliseerd carcinoom in situ van de cervix)
    - Huidige actieve pancreatitis
    - Toediening van een levend vaccin (inclusief BCG, varicella, mazelen, bof, rubella, gele koorts, orale polio en oraal typhoid) tijdens de afgelopen 2 weken
    - Bewijs van alcohol- of middelenmisbruik
    - Chronische of recidiverende infecties
    - Contact sensitisatie met klinische relevantie voor de handen, waarbij het vermijden van blootstelling aan het allergeen niet duidelijk is
    - Hypervitaminose A door het gebruik van vitamine A preparaten met >2000 IU
    - Gebruik van geneesmiddelen met de potentie om de effectieve dosis van de studiemedicatie te beïnvloeden, tijdens de afgelopen 2 weken

    Laboratorium exclusie criteria post randomisatie
    - Alanine aminotransferase (ALAT) en/of aspartaat aminotransferase (ASAT) >200% van de normale bovengrens
    - Afgenomen nierfunctie, geduid als een klinisch relevant abnormaal creatinine (te bepalen door onderzoeker of behandelend arts)
    - Anemie, geduid als een klinisch relevant verlaagd hemoglobine (te bepalen door onderzoeker of behandelend arts)

    Alitretinoïne specifiek
    - Triglyceriden >200% van de normale bovengrens
    - Cholesterol of low density lipoprotein (LDL) cholesterol >200% van de normale bovengrens
    - Ongecontroleerde hypothyreoidie (te bepalen door onderzoeker of behandelend arts)

    Azathioprine specifiek
    - Patienten met een lage of afwezige thiopurine methyltransferase (TPMT) activiteit (gedefinieerd in ons centrum als <52 nmol/gHb/uur, gecombineerd met genotypering waaruit een homozygote of compound heterozygote mutatie blijkt) en het hiermee samenhangende risico op levensbedreigende myelotoxiciteit
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for efficacy is response to treatment, defined as an improvement of ≥ 2 steps on the Physician Global Assessment (PGA), developed by Ruzicka et al, after 24 weeks of treatment.
    De primaire uitkomstmaat voor effectiviteit is respons op de behandeling, gedefinieerd als een verbetering van ≥ 2 stappen op de Physician Global Assessment (PGA), ontwikkeld door Ruzicka et al., na 24 weken behandeling.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 weken
    E.5.2Secondary end point(s)
    Secondary endpoints are improvement in: mean PGA after 12 and 24 weeks, the Hand Eczema Severity Index (HECSI) score, the Health related QoL questionnaire for hand eczema (QOLHEQ), and a Patient Global Assessement (PaGA) of improvement. Adverse events will be registered, as well as time to response.
    Secundaire uitkomstmaten zijn verbetering in: gemiddelde PGA na 12 en 24 weken, de Hand Eczema Severity Index (HECSI) score, de Health related QoL questionnaire for hand eczema (QOLHEQ) en een Patient Global Assessement (PaGA) van verbetering. Adverse events en tijd tot respons zullen eveneens worden geregistreerd.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Improvement in:
    Mean PGA: 12 and 24 weeks.
    HECSI: 4, 8, 12 and 24 weeks.
    QOLHEQ: 12 and 24 weeks.
    PaGA: 12 and 24 weeks.
    Adverse events and time to response at every visit.
    Verbetering in:
    Gemiddelde PGA: 12 en 24 weken.
    HECSI: 4, 8, 12 en 24 weken.
    QOLHEQ: 12 en 24 weken.
    PaGA: 12 en 24 weken.
    Adverse events en time tot respons bij elke visite.
    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 Yes
    E.8.1.7.1Other trial design description
    geblindeerde efficacy beoordelaars, ongeblindeerde behandelend artsen
    blinded efficacy assessors, unblinded treating physicians
    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 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state116
    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)
    Consistent with normal treatment of hand eczema. Alitretinoin will be stopped, azathioprine might be continued, possibly in a lower dose, if required.
    Overeenkomstig normale behandeling voor handeczeem. Alitretinoïne zal worden gestopt, azathioprine zou kunnen worden gecontinueerd, eventueel in een lagere dosering, indien nodig.
    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 Decision2015-06-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-09
    P. End of Trial
    P.End of Trial StatusOngoing
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