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    Summary
    EudraCT Number:2015-003600-23
    Sponsor's Protocol Code Number:APRICOT
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-01-28
    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 ConcernedUK - MHRA
    A.2EudraCT number2015-003600-23
    A.3Full title of the trial
    Treatment of Pustular Psoriasis with the IL-1 receptor antagonist anakinra: a randomised, placebo controlled trial and associated mechanistic studies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparing Anakinra versus placebo in the treatment of pustular psoriasis
    A.4.1Sponsor's protocol code numberAPRICOT
    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 SponsorGuy's and St Thomas NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    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 supportMRC NIHR EME programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGuy's and St Thomas Foundation Trust
    B.5.2Functional name of contact pointProf. Catherine Smith
    B.5.3 Address:
    B.5.3.1Street AddressGuy's Hospital, Great Maze Pond
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSE1 9RT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number40207185 5375
    B.5.5Fax number40207188 8050
    B.5.6E-mailcatherine.smith@kcl.ac.uk
    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 Anakinra
    D.2.1.1.2Name of the Marketing Authorisation holderSwedish Orphan Biovitrum AB
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 nameAnakinra
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNANAKINRA
    D.3.9.1CAS number 143090-92-0
    D.3.9.4EV Substance CodeSUB05500MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acral Pustular Psoriasis, specifically but not limited to Palmo-Plantar Pustulosis will be the target population for therapeutic intervention with Anakinra in this study.
    E.1.1.1Medical condition in easily understood language
    Acral Pustular Psoriasis (APP) is a rare, chronic inflammatory skin disease characterised by sore, red skin covered in pustules involving the hands and feet.
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10037575
    E.1.2Term Pustular psoriasis
    E.1.2System Organ Class 10040785 - Skin and subcutaneous tissue disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of anakinra in treatment of adults with PPP compared to placebo. The primary endpoint is change in disease activity over 8 weeks, adjusted for baseline (visit 1), measured using fresh pustule count, the default primary outcome, unless PPPASI is more discriminating (to be reviewed at the end of stage one).

    The Stage 1 review occurred on 22nd January 2018. As a result of this review the DMC recommended the primary outcome to be PPPASI and this was passed by the TSC. Fresh pustule count will be a secondary outcome.
    E.2.2Secondary objectives of the trial
    - describe any treatment effect of anakinra, indicated by change in disease activity over 8 weeks using the Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI)
    - determine the following:
    - time to response of PPP and relapse rate with anakinra
    - proportion of randomised patients achieving clearance of PPP with anakinra by 8 weeks
    - any treatment effect of anakinra in pustular psoriasis at non acral sites as measured by change in percentage area of involvement at 8 weeks
    - any treatment effect of anakinra in plaque type psoriasis (using Psoriasis Area and Severity Index (PASI) at 8 weeks)
    - collect data on the adverse event profile and adverse reactions induced by anakinra to evaluate the safety and tolerability of anakinra
    - the impact of anakinra on patients' symptoms and quality of life
    - the proportion of randomised patients who find the treatment acceptable or worthwhile
    - the proportion of randomised patients adhering to treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria for the for the double-blind treatment stage, placebo controlled study.
    i. Adults (18 years and over) with diagnosis of Palmo-Plantar Pustulosis (PPP) made by a trained dermatologist with disease of sufficient impact and severity to require systemic therapy
    ii. Disease duration of >6 months, not responding to an adequate trial of topical therapy including very potent corticosteroids
    iii. Evidence of active pustulation on palms and /or soles to ensure sufficient baseline disease activity to detect efficacy
    iv. At least moderate disease on the PPP Investigator’s Global Assessment (PPP-IGA)
    v. Women of child bearing potential who are on adequate contraception (see Appendix A , contraception guidelines), who are not pregnant or not breast feeding
    vi. Who have given written, informed consent to participate

    Inclusion Criteria for the Open Label Extension
    i. Participation in the double-blind placebo controlled study.
    ii. Completion past Visit 4 (Week 8) of the double-blind placebo controlled study.
    iii. Women of child bearing potential who are on adequate contraception (see Appendix A), contraception guidelines), who are not pregnant or not breast feeding
    iv. Who have given written, informed consent to participate
    E.4Principal exclusion criteria
    Double-blind stage
    i. Previous treatment with anakinra or other IL-1 antagonists
    ii. A history of recurrent bacterial, fungal or viral infections which, in the opinion of the principal investigator, present a risk to the patient
    iii. Evidence of active infection or latent TB or who are HIV, Hepatitis B or C sero-positive
    iv. A history of malignancy of any organ system (other than treated, localised non melanoma skin cancer), treated or untreated, within the past 5 years
    v. Use of therapies with potential or known efficacy in psoriasis during or within the following specified timeframe before treatment initiation (week 0, visit 2):
    a. very potent topical corticosteroids within 2 weeks b. topical treatment that is likely to impact signs and symptoms of psoriasis (e.g. corticosteroids, vitamin D analogues, calcineurin inhibitors, retinoids, keratolytics, tar, urea) within 2 weeks c. methotrexate, ciclosporin, acitretin, alitretinoin within 4 weeks d. phototherapy or PUVA within 4 weeks e. etanercept or adalimumab within 4 weeks f. infliximab or ustekinumab or secukinumab within 3 months g. other TNF antagonists within 3 months h. other immunosuppressive or immunomodulatory therapy within 30 days or 5 half lives prior to treatment initiation, whichever is longer
    i. any other investigational drugs within 30 days(or 3 months for investigational monoclonal antibodies)or 5 half-lives prior to treatment initiation, whichever is longer
    vi. With moderate renal impairment[CrCl<50ml/min]
    vii. With neutropenia(<1.5x109/L)
    viii. With thrombocytopenia(<150x109/L)
    ix. With known moderate hepatic disease &/or raised hepatic transaminases (ALT/AST) >2xULN at baseline. Patients who fail this criterion may still be considered following review by a hepatologist&confirmed expert opinion that study entry is clinically appropriate.
    x. Live vaccinations within 3 months prior to the start of study medication, during the trial, & up to 3 months following the last dose
    xi. Women who are pregnant, breastfeeding or of child bearing age not on adequate contraception or men planning conception
    xii. Poorly controlled diabetes mellitus, cardiovascular disease, asthma, concomitant therapy that may interact with anakinra(eg phenytoin or warfarin)or any condition where, in the opinion of the investigator, anakinra would present risk to the patient.
    xiii. Unable to given written, informed consent.
    xiv. Unable to comply with the study visit schedule
    xv.Diagnosis(or historic diagnosis)of either childhood or adult onset Still’s disease.
    Open Label Extension
    i. A history of recurrent bacterial, fungal or viral infections which, in the opinion of the principal investigator, present a risk to the patient
    ii.Evidence of active infection or latent TB or who are HIV, Hepatitis B or C sero-positive(only required for patients who are beyond Visit 5 the double-blind treatment stage, placebo controlled study).
    iii.A history of malignancy of any organ system(other than treated, localised non-melanoma skin cancer),treated or untreated, within the past 5 years
    iv.Use of therapies with potential or known efficacy in psoriasis during or within the following specified timeframe before treatment initiation (Visit OLE 1):
    a. methotrexate, ciclosporin, acitretin, alitretinoin within 4 weeks b. phototherapy or PUVA within 4 weeks c. etanercept or adalimumab within 4 weeks d. infliximab or ustekinumab or secukinumab within 3 months e. other TNF antagonists within 3 months f. other immunosuppressive or immunomodulatory therapy within 30 days or 5 half-lives prior to treatment initiation, whichever is longer g. any investigational drugs within 30 days (or 3 months for investigational monoclonal antibodies) or 5 half-lives prior to treatment initiation, whichever is longer
    v. With moderate renal impairment[CrCl<50ml/min]
    vi. With neutropenia(<1.5x109/L)
    vii. With thrombocytopenia(<150x109/L)
    viii. With known moderate hepatic disease &/or raised hepatic transaminases(ALT/AST)>2 xULN at baseline. Patients who fail this criterion may still be considered following review by a hepatologist & confirmed expert opinion that study entry is clinically appropriate.
    ix. Live vaccinations within 3 months prior to the start of study medication, during the trial, & up to 3 months following the last dose
    x. Women who are pregnant, breastfeeding or of child bearing age not on adequate contraception or men planning conception
    xi. Poorly controlled diabetes mellitus, cardiovascular disease, asthma, concomitant therapy that may interact with anakinra (eg phenytoin or warfarin) or any condition where, in the opinion of the investigator, anakinra would present risk to the patient.
    xii. Unable to give written,informed consent.
    xiii. Unable to comply with study visit schedule
    xiv. Has been previously invited to the OLE therapy&the patient declined during that instance.
    xv.Diagnosis(or historic diagnosis)of either childhood or adult onset Still’s disease.
    E.5 End points
    E.5.1Primary end point(s)
    The determination of the efficacy of anakinra in treatment of adults with PPP compared to placebo, measured by an independent blinded assessor using:

    1. Fresh pustule count on palms and soles across 1, 4 and 8 weeks, OR
    2. Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) across 1, 4 and 8 weeks
    The default primary endpoint will be fresh pustule count unless PPPASI is more discriminating (to be reviewed at the end of stage one).
    The Stage 1 review occurred on 22nd January 2018. As a result of this review the DMC recommended the primary outcome to be PPPASI and this was passed by the TSC. Fresh pustule count will be a secondary outcome.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of treatment at 8 weeks and end of follow up at 12 weeks.
    E.5.2Secondary end point(s)
    Investigator Assessed
    1. Total pustule count on palms and soles across 1, 4, 8 weeks adjusted for baseline (visit 1)
    2. Investigator's Global Assessment (PPP-IGA) at 1, 4 and 8 compared to baseline (visit 1)
    3. Time to response of PPP (defined as a 75% reduction in fresh pustule count [default primary outcome] compared to baseline), and relapse rate (defined as return to baseline fresh pustule count)
    4. Achievement of ‘clear ‘ on PPP-IGA by 8 weeks
    5. Development of a disease flare (ie: >50% deterioration in PPPASI compared to baseline, visit 1)
    6. Pustular psoriasis at non acral sites as measured by change in percentage area of involvement at 8 weeks compared to baseline (visit 1)
    7. Plaque type psoriasis (if present) measured using Psoriasis Area and Severity Index (PASI) at 8 weeks compared to baseline (visit 1)
    8. Serious infection as defined by any infection leading to death, hospital admission or requiring IV antibiotics
    9. Neutropenia (ie: neutrophil count of 1.0x10-9/l on at least one occasion)
    Patient Reported Outcomes
    1. Patient's Global Assessment (clear, nearly clear, mild, moderate, severe, very severe) across 1, 4, 8 weeks compared to baseline (visit 1)
    2. Palmoplantar Quality of Life Instrument score in randomised patients at 8 weeks compared to baseline (visit 0)
    3. Dermatology Life Quality Index at 8 weeks compared to baseline (visit 0)
    4. EQ5D-3L score at 8 weeks compared to baseline (visit 0)
    5. Treatment acceptability (ie: whether the treatment is 'worthwhile') evaluated using a brief questionnaire with a response scale of 1-5 at study end
    6. Adherence to treatment measured by responses to daily text message over 8 weeks of treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of treatment at 8 weeks and end of follow up at 12 weeks.
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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
    Double blind, randomised, placebo controlled, 2 stage adaptive design, with an open label extension
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    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 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 concerned25
    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 (and subsequent data analysis)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial 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: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 64
    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 state64
    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)
    Study participants will be made aware that access to anakinra will not be routinely available. However, all patients will be offered ongoing Dermatology review and if on-going anakinra therapy is deemed clinically appropriate (i.e: standard treatment approaches inappropriate or cannot be used, evidence of benefit), consideration will be given to seeking ongoing funding via the NHS on an 'exceptional' basis
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR CRN Dermatology network, UK Dermatology Clinical Trials Network and NIHR BRC at Guy's
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-08-10
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