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    Summary
    EudraCT Number:2015-003564-37
    Sponsor's Protocol Code Number:PRN1008-005
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-01-13
    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 ConcernedGreece - EOF
    A.2EudraCT number2015-003564-37
    A.3Full title of the trial
    An Open-Label, Phase 2, Pilot Study Investigating the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Oral Treatment with the BTK Inhibitor PRN1008 in Patients with Newly Diagnosed or Relapsing Pemphigus Vulgaris
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Pilot Study Investigating the Safety, Clinical Activity, Drug Levels, and Effects on PRN 1008 in Patients with Newly Diagnosed or Relapsing Pemphigus Vulgaris
    A.4.1Sponsor's protocol code numberPRN1008-005
    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 SponsorPrincipia Biopharma Australia Pty Ltd
    B.1.3.4CountryAustralia
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPrincipia Biopharma Australia Pty Ltd
    B.4.2CountryAustralia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD Global Limited
    B.5.2Functional name of contact pointProject management
    B.5.3 Address:
    B.5.3.1Street Address3900 Perimeter Park Drive
    B.5.3.2Town/ cityMorrisville
    B.5.3.3Post codeNC 27560-7200
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 919 5309116
    B.5.6E-mailpamela.grillini@ppdi.com
    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 No
    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.3.2Product code PRN1008
    D.3.4Pharmaceutical form 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 INNNot available
    D.3.9.1CAS number 1575596-29-0
    D.3.9.2Current sponsor codePRN1008
    D.3.9.3Other descriptive namePRN1008 Freebase
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 1575596-29-0
    D.3.9.2Current sponsor codePRN1008
    D.3.9.3Other descriptive namePRN1008 Freebase
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 1575596-30-3
    D.3.9.2Current sponsor codePRN1008
    D.3.9.3Other descriptive namePRN1008 Freebase
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 1575596-30-3
    D.3.9.2Current sponsor codePRN1008
    D.3.9.3Other descriptive namePRN1008 Freebase
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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
    Pemphigus: Pemphigus Vulgaris
    E.1.1.1Medical condition in easily understood language
    Pemphigus: Pemphigus Vulgaris
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10052802
    E.1.2Term Pemphigus 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
    To evaluate the clinical activity and safety of PRN1008 in patients with PV over a 12 week treatment period
    E.2.2Secondary objectives of the trial
    To evaluate the pharmacodynamics (PD) and pharmacokinetics (PK) of multiple doses of PRN1008 in patients with PV and the relationship of PK and PD to each other, and to efficacy and safety
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1 Male or female patients, aged 18 to 80 years old, with biopsy-proven, mild-moderate PV (PDAI 15 to 45) that are either newly diagnosed patients (i.e. naïve to an effective induction treatment regimen) for whom an initial period of PRN1008 monotherapy is judged clinically acceptable, or relapsing patients, for whom an initial period of PRN1008 monotherapy or combination therapy with any of low dose corticosteroid (≤ 10 mg/day), azathioprine, mycophenylate mofetil, sulfasalazine and dapsone, is judged clinically acceptable, provided cessation of azathioprine, mycophenylate mofetil, sulfasalazine, and dapsone within two to four weeks is anticipated
    2. BMI >17.5 and <40 kg/m2
    3. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5 X 10^9/L, Hgb > 9 g/dL, platelet count ≥100 X 10^9/L, AST/ALT ≤ 1.5 x ULN, albumin ≥3 g/dL, creatinine ≤ ULN
    4. Female patients or female partners of a male patient who are of reproductive potential must agree for the duration of the study to use an effective means of contraception (e.g., diaphragm plus spermicide, condoms, or oral contraceptive). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing.
    5. Male patients must agree to use a condom during sexual intercourse with female partners who are of reproductive potential for the duration of PRN1008 treatment and for 12 weeks thereafter (i.e. during the entire period of follow up)
    6. Able to provide written informed consent and agreeable to the schedule of assessments
    E.4Principal exclusion criteria
    1. Previous use of a BTK inhibitor
    2. Pregnant or lactating women
    3. ECG findings of QTc >450 msec (males) or >470 msec (females), poorly controlled atrial fibrillation (i.e. symptomatic patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant abnormalities
    4. A history of malignancy of any type, other than surgically excised non-melanoma skin cancers or in situ cervical cancer within 5 years before the day of dosing
    5. Use of immunologic response modifiers with the following periods prior to Day 1: 1 week: cyclophosphamide; 4 weeks: Kinaret (anakinra) and Enbrel (etanercept); 12 weeks: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), IVIG, plasmapheresis; 6 months: Rituxan/MabThera (rituximab), ofatumumab, any other anti-CD20 antibody
    6. Use of >10 mg per day of oral prednisolone for more than 1 week within 4 weeks prior to Day 1 (inhaled and mucosal [for symptomatic treatment of oral lesions] corticosteroids are allowed)
    7. Use of proton pump inhibitor drugs such as omeprazole, esomeprazole (it is acceptable to change patient to H2 receptor blocking drugs prior to the first dose of PRN1008)
    8. Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A within 7 days or 5 half-lives (whichever is longer) of study drug dosing
    9. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 7 days or 5 half-lives (whichever is longer) of study drug dosing including, but not limited to, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine
    10. Has received any investigational drug (or is currently using an investigational device) within the 30 days before receiving the first dose of study medication, or at least 5 times the respective elimination half-life time (whichever is longer)
    11. History of drug abuse within the previous 12 months
    12. Alcoholism or excessive alcohol use, defined as regular consumption of more than 14 standard drinks per week
    13. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate study drug absorption
    14. Donation of a unit or more of blood or blood products within 4 weeks prior to Day 1
    15. History of solid organ transplant
    16. Positive for screening for HIV, hepatitis B (surface and core antibodies unrelated to vaccination), or hepatitis C (anti-HCV antibody confirmed with Hep C RNA)
    17. History of active or latent tuberculosis (TB) infection (subjects must also test negative using the QuantiFERON® test to be eligible for the study)
    18. Any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator, would interfere with subject safety, study evaluations, and/or study procedures
    E.5 End points
    E.5.1Primary end point(s)
    Safety:
     The incidence of treatment-emergent adverse events (AEs) including clinically significant changes in physical examination, laboratory safety tests, and vital signs.

    Clinical activity*:
     Proportion of subjects who are able to achieve control of disease activity (CDA)* within 4 weeks of treatment, without the need for doses of prednis(ol)one >0.5mg/kg.

    *Clinical activity endpoints as defined by the EADV 2014 pemphigus S2 guideline (Hertl et al. 2015;29:405-414)

    Pharmacokinetics:
     Plasma concentrations of PRN1008
     Population PK analysis (data pooled with that from other studies)
     Exploratory PK/PD analysis

    Pharmacodynamics:
     BTK occupancy in PBMCs
     Change in anti-dsg1-3 autoantibody levels by enzyme-linked immunosorbent assay (ELISA)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients will be screened within 28 days of dosing and will return for an end-of-study assessment 84 days after receiving their final dose of study drug. Patients will return at specified times on an outpatient basis for assessment of vital signs, physical examination,
    assessment of adverse events, assessment of concomitant medication use, assessment of clinical benefit, and provision of blood samples for PK and PD, and other clinical laboratory tests.
    E.5.2Secondary end point(s)
    Secondary*:
     Proportion of subjects able to achieve CDA without corticosteroids within 4 weeks
     Proportion of subjects able to achieve a complete response (CR) without corticosteroids within 12 weeks
     Proportion of subjects able to achieve CR without the need for doses of prednis(ol)one of greater than 0.5mg/kg within 12 weeks
     Time to CDA
     Time to CR
     Time to end of consolidation phase
     Time to relapse after PRN1008 treatment discontinuation
     Cumulative corticosteroid usage over 12 weeks
     Change from baseline in Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) scores at each follow up visit
     Change from baseline in Autoimmune Bullous Diseases Quality of Life (ABQOL) and Treatment of Autoimmune Bullous Diseases Quality of Life (TABQOL) scores at each follow up visit

    *Clinical activity endpoints as defined by the EADV 2014 pemphigus S2 guideline (Hertl et al. 2015;29:405-414)
    E.5.2.1Timepoint(s) of evaluation of this end point
     Proportion of subjects able to achieve CDA without corticosteroids within 4 weeks
     Proportion of subjects able to achieve a complete response (CR) without corticosteroids within 12 weeks
     Proportion of subjects able to achieve CR without the need for doses of prednis(ol)one of greater than 0.5mg/kg within 12 weeks
     Time to CDA
     Time to CR
     Time to end of consolidation phase
     Time to relapse after PRN1008 treatment discontinuation
     Cumulative corticosteroid usage over 12 weeks
     Change from baseline in Pemphigus Disease Area Index (PDAI) and ABSIS scores at each follow up visit
     Change from baseline in ABQOL and Treatment of TABQOL scores at each follow up 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Croatia
    France
    Greece
    Israel
    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
    The end of the study is defined as the date of the last participant's last visit (LPLV) to the study center for study-related assessments.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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.1.3Elderly (>=65 years) Yes
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 25
    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 (Subjects will be treated as determined by their treating physician based upon their clinical presentation after protocol treatment is completed)
    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 Decision2016-02-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-01-10
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