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    Summary
    EudraCT Number:2016-004354-15
    Sponsor's Protocol Code Number:DANPAPP
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-10-20
    Trial results View 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 ConcernedDenmark - DHMA
    A.2EudraCT number2016-004354-15
    A.3Full title of the trial
    Prevalence, pattern and disease course of arthritis and enthesitis in patients with psoriasis, and the effect of apremilast in subclinical US-defined psoriatic arthritis - A population-based study applying clinical, ultrasonic, MRI and patient-reported outcomes

    Prævalens, sygdomsmønster og -forløb af artrit og entesit hos patienter med psoriasis, samt effekten af apremilast behandling ved subklinisk, ultralydsdefineret psoriasisartrit – et populationsbaseret studie med kliniske, ultrasoniske og patient-rapporterede effektmål.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prevalence, disease pattern and -course of arthritis and enthesitis in patients with psoriasis, as well as the effect of apremilast treatment on inflammatory changes found by ultrasound examination
    Forekomst, sygdomsmønster og -forløb af gigt og senefæstebetændelse hos patienter med psoriasis, samt effekten af apremilast behandling ved gigtsygdom fundet ved hjælp af ultralydsundersøgelse
    A.3.2Name or abbreviated title of the trial where available
    Danish Population-based Assessment of Psoriasis and Psoriatic arthritis (DANPAPP)
    A.4.1Sponsor's protocol code numberDANPAPP
    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 Sponsor Rigshospitalet
    B.1.3.4CountryDenmark
    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 supportCelgene
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportThe Danish Rheumatism Association
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCopenhagen Center for Arthritis Research (COPECARE) Center for Rheumatology and Spine Diseases, Rigshospitalet
    B.5.2Functional name of contact pointCOPECARE
    B.5.3 Address:
    B.5.3.1Street AddressValdemar Hansens Vej 17, Opgang 5, st.
    B.5.3.2Town/ cityGlostrup
    B.5.3.3Post code2600
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4538632982
    B.5.5Fax number+4538634192
    D. IMP Identification
    D.IMP: 1
    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 Otezla
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNapremilast
    D.3.9.1CAS number 608141-41-9
    D.3.9.3Other descriptive nameAPREMILAST
    D.3.9.4EV Substance CodeSUB130837
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 30
    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
    Psoriasis and psoriatic arthritis
    Psoriasis og psoriasisartrit
    E.1.1.1Medical condition in easily understood language
    Psoriasis and psoriatic arthritis
    Psoriasis og psoriasisgigt
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10037160
    E.1.2Term Psoriatic arthritis
    E.1.2System Organ Class 100000004859
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10050576
    E.1.2Term Psoriasis vulgaris
    E.1.2System Organ Class 100000004858
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The study has three parts, described under sub-studies.

    Main objective for the cross-sectional parts (part 1 and 2):
    To quantify and describe a psoriasis (Pso )patient population with regards to musculoskeletal pain, the prevalence and pattern of clinical and US signs of inflammation in joints and entheses, and their impact on patient’s lives.

    Main objective for the interventional part (part 3a):
    To determine the effect of treating psoriatic arthritis (PsA) patients identified in part 2 of the study with apremilast, with respect to decreases in US detected inflammation scores, clinical signs and symptoms and impact on patient’s lives, and the relation between these.
    E.2.2Secondary objectives of the trial
    Part 1 and 2
    -To identify patients within this Pso population, who have PsA by clinical and/or US criteria, which were undiagnosed prior to the study, and to describe the burden of disease and its impact on patient’s lives by clinical, US and patient-reported outcomes.

    Part 3
    -To determine the effect of treating the subgroup of PsA patients identified in part 2, which have dactylitis and/or ankle region enthesitis, with apremilast, with respect to decreases in MRI detected inflammation scores, and clinical signs and symptoms and impact on patient’s lives, and the relation between these.
    -To investigate if induction therapy with apremilast for 6 months will, also after discontinuation, cause sustained improvements in clinical, US and patient/reported outcomes, or if symptoms and clinical and US findings will reappear, documenting a need for continuous treatment in such patients.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The study has 3 parts:

    Part 1:
    A population-based survey of Danish inhabitants, performed by the company YouGov, will by screening of approximately 10.000 Danes identify approximately 425 persons who report to have Pso with or without PsA. These will receive an e-mail invitation to an internet based questionnaire regarding demographics, skin and joint complaints, diagnosed diseases, contact to health care providers, and different aspect of psychological and physical function and wellbeing (incl. function, health-related quality of life, depression, anxiety, social participation, and sleep disturbances). In the questionnaire the participant will be asked if he/she would be interested in participating in a clinical study. Patients will also be recruited from an out-patient clinic at a dermatological department. These patients will fill out a paper-version of the questionnaire.

    Part 2:
    Participants who accept the above mentioned invitation (estimated 273) will be seen in a Department of Rheumatology, for the following examination programme: Clinical examination with a focus on skin, joints and entheses, US examination of joints and entheses, patient-reported outcomes and blood sampling for both stratification and identification of biochemical signs of inflammation.
    Patients with musculoskeletal pain and joint and/or entheseal inflammation documented by US (definition and criteria, see ‘definition of patient populations’ section of protocol), will be invited to participate in a 12 months’ interventional study (part 3a, below), whereas patients without musculoskeletal pain but with US findings (as above) will be invited to participate in a 12 months non-interventional follow-up study (part 3b, below). Patients with pre-diagnosed PsA that by US have active inflammation (same definition and criteria as above, see ‘definitions of patient population’ section), will also be invited to participate in the interventional study if they fit the criteria, especially those described under concomitant medication, otherwise they will be offered to participate in the non-interventional study.

    Part 3a:
    Patients with musculoskeletal pain in relation to joints and/or entheses (that is not explained by alternative diagnosis, as assessed by including rheumatologist) and “US-defined PsA”, i.e. with certain joint and/or entheseal inflammation as documented by US (see paragraph on ‘definitions of patient populations’), will be offered inclusion in a 12 months’ interventional study, in which 6 month induction therapy with apremilast (in addition to their usual therapy) will be followed by cessation of apremilast and 6 months of observation. Patients will be followed with clinical examination, PRO’s, blood sampling and US at months 3, 6, 9 and 12. In case of early discontinuation from the study, an early discontinuation visit will be performed including PRO’s, clinical, US and biochemical examination
    MRI will be performed at inclusion and at 6 months follow-up in selected patients (patients with dactylitis or with enthesitis in the ankle region (Achilles enthesitis or plantar fasciitis)).

    Part 3b:
    Patients without musculoskeletal pain but with certain joint or enthesal inflammation verified by US will be offered inclusion in a 12 months’ non-interventional study. Patients will continue their current therapy and be followed with clinical examination, patient-reported outcomes, blood sampling and US at months 3, 6, 9 and 12.

    For objectives, please see section E 2.1. and E.2.2.
    E.3Principal inclusion criteria
    In general (all parts of the study):
    • Age >18 years
    • Being able and willing to comply with the requirements of this protocol
    • Having signed informed consent
    Part 2:
    • Psoriasis, diagnosed by a physician according to patient
    Part 3a:
    • Musculoskeletal pain in relation to joints or entheses (that is not explained by alternative diagnosis, as assessed by including rheumatologist) and“US-defined PsA” (ie. with certain joint and/or entheseal inflammation as documented by US (see ‘Definitions of patient populations’ for definition))
    • MRI substudy:
    o Clinical dactylitis or enthesitis in the ankle region (Achilles enthesitis or plantar fasciitis)
    o No contraindications for MRI
    Part 3b:
    • Not having musculoskeletal pain but still “US-defined PsA” (i.e. with certain joint and/or entheseal inflammation as documented by US (see ‘Definitions of patient populations’ in protocol for definition))
    Patients that fulfill the inclusion criteria for part 3, but also fulfill some exclusion criteria for part 3a, but not for 3b, may be included in part 3b.
    E.4Principal exclusion criteria
    In general (all parts of study):
    • Incapability of complying with the examination program of this protocol for physical, mental or practical reasons.
    Part 2:
    • Incapability of understanding spoken or written Danish.
    Part 3a:
    • Pregnancy, pregnancy wish or breast-feeding.
    • Hypersensitivity to the active substance (apremilast) or any of the excipients.
    • Hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose
    • malabsorption
    • Severe renal failure (glomerular filtration rate (GFR) <30ml/min)
    • Current treatment with potent CYP3A4 enzyme inhibitors (rifampicin, phenobarbital, carbamazepin, phenytoin, perikon (“grønne lykkepiller” , Neurokan, Modigen, Calmigen, Velzina))
    • Current or planned (during the study period) treatment that might cause psychiatric symptoms
    • Known active tuberculosis (TB) or history of incompletely treated TB.
    • Clinical history of serious liver disease.
    • Hepatitis B antigen positivity or Hepatitis C antibodies positivity at screening.
    • Bacterial infections requirering antibiotics (oral or intravenously) or serious viral or fungal infections within the last four weeks before screening. Treatment of such infections should be completed 4 weeks prior to screening.
    • Clinical history of serious immunological disease (including HIV or other congenital or aqiured immune disease) or other serious uncontrolled disease.
    • Current depression, previous depression, previous suicidal thoughts/tendencies or psychiatric symptoms
    • Conditions, including abnormal laboratory measurements, which might put the patient at an unnecessary risk by participation in the study or make data difficult to interpret.
    • Known inflammatory rheumatic disease other than PsA.
    • MRI substudy: Contraindications for MRI
    Part 3b:
    • Known inflammatory rheumatic disease other than PsA.

    For allowed and disallaowed medications, please see protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1: YouGov Questionnaire (cross-sectional study)
    Primary outcome
    The prevalence of musculoskeletal pain in patients with Pso.

    Part 2: Clinical and US assessments (cross sectional study)
    Primary outcome
    The prevalence of synovitis and enthesitis, as defined by US, in patients with Pso with and without musculoskeletal pain.

    Part 3: 12 month’s follow-up study
    Primary outcome
    Change in OMERACT-EULAR Global US score of synovitis, from baseline to 6 months, in patients treated with apremilast (intervention group).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1: After all patients completed the questionnaire (cross-sectional study)
    Part 2: After last patient has been assessed in this part (cross-sectional study)
    Part 3: At months 6
    E.5.2Secondary end point(s)
    Part 1: YouGov Questionnaire
    Secondary outcomes
    The correlations between presence of musculoskeletal pain and patient reported outcomes of function, health related quality of life, and impact on patient’s lives (including EQ5D, HAQ and PsAID)

    Part 2: Clinical and US assessments
    Secondary outcomes
    The prevalence of synovitis and enthesitis, as defined by US, at the individual 48 joints and 12 entheseal sites in patients with Pso with and without musculoskeletal pain.
    The correlation between clinical and US scores of synovitis and enthesitis with patient reported outcomes of pain, function and impact on patient’s lives (including pain, HAQ and PsAID).
    Sensitivity and specificity of screening questionnaires, with fulfillment of CASPAR criteria as gold standard, and “US defined PsA” as alternative.

    Part 3: 12 month’s follow-up study
    Secondary and tertiary outcomes
    Change in “US total count of inflamed joints and entheses” from baseline to 3, 6 and 12 months, and from 6 to 12 months, in intervention and non-intervention groups.
    Change in patient pain on a VAS, from baseline to 6 months and from 6 to 12 months in intervention group.
    Change in OMERACT-EULAR Global US score of synovitis from baseline to 3 and 6 months, and from 6 to 12 months, in intervention and non-intervention groups.
    Change in US enthesitis activity score from baseline to 3, 6 and 12 months, and from 6 to 12 months, in intervention and non-intervention groups.
    Change in PRO’s (including PsAID, HAQ) from baseline to 3, 6, 9 and 12 months.
    The correlation between changes in clinical and US scores of synovitis and enthesitis and changes in patient reported outcomes of pain, function and impact on patient’s lives (pain, HAQ and PsAID and others), overall and in intervention and non-intervention groups.
    Change in various composite indices for disease activity and treatment response used in PsA (DAS28-CRP (Disease Activity Score, 28 joints, CRP)(40), PASDAS (Psoriatic Arthritis Disease Activity Score)(41), DAPSA (Disease Activity Index for Psoriatic Arthritis)(42), mCPDAI (modified Composite Psoriatic Disease Activity Index)(43), EULAR response criteria(44), ACR(American College of Rheumatology) response criteria(45) and PsARC (Psoriatic Arthritis Response Criteria)(46)) from baseline to month 3 and 6, and from month 6 to month 12.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1: After all patients completed the questionnaire (cross-sectional)
    Part 2: After last patient has been assessed in this part (cross-sectional)
    Part 3: At month 3, 6 and 12 (see details above)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.4.1Number of sites anticipated in Member State concerned7
    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
    LVLS
    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 months18
    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: 325
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state425
    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)
    None
    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 Decision2017-12-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-12-05
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