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    Summary
    EudraCT Number:2018-002261-19
    Sponsor's Protocol Code Number:PRN1008-012
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-10-11
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2018-002261-19
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Efficacy and Safety of Oral BTK Inhibitor PRN1008 in Moderate to Severe Pemphigus
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the efficacy and safety of PRN1008 in patients with pemphigus
    A.4.1Sponsor's protocol code numberPRN1008-012
    A.5.4Other Identifiers
    Name:IND # Number:134595
    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
    B.1.3.4CountryUnited States
    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
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPrincipia Biopharma, Inc.
    B.5.2Functional name of contact pointChief Medical Officer
    B.5.3 Address:
    B.5.3.1Street Address220 East Grand Ave
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+ 1 650 416 7700
    B.5.5Fax number+ 1 650 443-3001
    B.5.6E-mailclinicaltrials@principiabio.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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/157/17
    D.3 Description of the IMP
    D.3.1Product namePRN1008 (Rilzabrutinib)
    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
    D.3.9.2Current sponsor codePRN1008
    D.3.9.3Other descriptive namePRN1008
    D.3.9.4EV Substance CodeSUB182379
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    pemphigus vulgaris [PV] or pemphigus foliaceus [PF]
    E.1.1.1Medical condition in easily understood language
    pemphigus
    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 LLT
    E.1.2Classification code 10052802
    E.1.2Term Pemphigus vulgaris
    E.1.2System Organ Class 100000004858
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10057054
    E.1.2Term Pemphigus foliaceous
    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
    Efficacy objectives
    • To evaluate the efficacy of PRN1008 in achieving durable CR on low to zero doses of oral corticosteroid (CS) and on the timecourse of quantitative disease activity scores
    • To assess the ability of PRN1008 to reduce CS exposure and the adverse effects of CS
    • To evaluate the time to specified clinical endpoints
    • To assesss the longer term durability of CR

    Safety Objectives
    • To evaluate the safety of PRN1008
    • To evaluate differences in potentially CS-related adverse events
    E.2.2Secondary objectives of the trial
    PK/PD Objectives
    • To evaluate the population pharmacokinetics (PK) of PRN1008
    • To evaluate pharmacodynamic (PD) effects of PRN1008 on anti-desmoglein (anti-dsg) autoantibody titers (anti-dsg1 and anti-dsg3)

    Exploratory Objectives
    • To examine the effects of PRN1008, if any, of the baseline covariates on PK and/or PD, and the relationship between PK, PD, and efficacy
    • To examine the effect of PRN1008 on the costs of hospitalizations, outpatient medical visits, adverse events, concomitant medication use and other relevant health economic outcomes
    • To examine the temporal relationship of change from baseline in Pemphigus Disease Area Index (PDAI) total activity score and quality of life and health economic measures
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients, aged 18 to 80 years old with moderate to severe, newly diagnosed or relapsing PV or PF, with a clinical presentation and histopathology consistent with PV or PF.
    2. Positive circulating anti-dsg1 or 3 autoantibody titer
    3. At screening PDAI score of at least 9 points for relapsing patients (> 6 months since diagnosis) or at least 15 points for newly diagnosed patients (diagnosed ≤ 6 months prior to Screening)
    4. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 × 109/L, hemoglobin (Hgb) > 9 g/dL, platelet count ≥ 100 × 109/L, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 1.5 × upper limit of normal (ULN), albumin ≥ 3 g/dL, creatinine ≤ 1.5 × ULN
    5. Female patients who are of reproductive potential must agree for the duration of the study to use an effective means of contraception (e.g., hormonal contraception methods that inhibit ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner or condoms). Unless surgically sterile, postmenopausal females should have menopause confirmed by follicle-stimulating hormone (FSH) testing. For females considered not to have reproductive potential: any woman of age ≥55 years with amenorrhea for > than 1 year, will be considered as having confirmed menopause and FSH or pregnancy testing will not be needed. Postmenopausal females <55 years of age (defined as amenorrhea >1 year) must have menopause confirmed by lelvated FSH levels at screening. Surgically sterile females do not require any further confirmation of menopause and will not be considered to have reproductive potential.
    6. Able to provide written informed consent and agreeable to the schedule of assessments
    E.4Principal exclusion criteria
    1. Suspected paraneoplastic pemphigus and other forms of pemphigus that are not pemphigus vulgaris or pemphigus foliaceus
    2. Previous use of a Bruton’s tyrosine kinase (BTK) inhibitor
    3. Pregnant or lactating women
    4. Electrocardiogram (ECG) findings of QT corrected for heart rate (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
    5. A history of malignancy of any type within 5 years before Day 1, other than surgically excised non-melanoma skin cancers or in situ cervical cancer
    6. Use of immunologic response modifiers as concomitant medication and with the following washout periods:
    A) stop at least 2 weeks prior to Screening: mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, dapsone, intravenous immunoglobulin (IVIG), Kinaret (anakinra), Enbrel (etanercept) or any other immunosuppressant not mentioned in this exclusion criterion;
    B) 12 weeks prior to Screening: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), plasmapheresis;
    C) 6 months prior to Screening (or shorter if there is documented B cell reconstitution for anti-CD20 drugs): antiCD20 drugs such as rituximab, ofatumumab, other long-acting biologics
    7. Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of Day 1(It is acceptable to change patient to H2 receptor blocking drugs prior to Day 1.)
    8. Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A within 3 days or 5 half-lives (whichever is longer) of Day 1 (Appendix 8)
    9. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of Day 1 and for the remainder of the trial including, but not limited to alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus (topical or oral), or terfenadine
    10. Has received any investigational drug (or is currently using an investigational device) within the 30 days before Day 1, 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 approximately 3 standard drinks per day
    13. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate PRN1008/placebo 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 at Screening for human immunodeficiency virus (HIV), hepatitis B (surface and core antibodies unrelated to vaccination, surface antigen), or hepatitis C (anti-HCV antibody confirmed with Hep C RNA)
    17. Positive interferon-gamma release assay (IGRA) (e.g., T-spot TB test, QuantiFERON®-TB Gold or QuantiFERON®-TB Gold Plus (QFTPlus)) at Screening. Unless the patient has latent TB and all of the
    following 3 conditions are true:
    a. Chest X-ray does not show evidence suggestive of active tuberculosis (TB) disease
    b. There are no clinical signs and symptoms of pulmonary and/or extrapulmonary TB disease
    c. Documented receipt of one of the following prophylactic treatment regimens:
    - oral daily Isoniazid for 6 months
    OR
    - oral daily Rifampin (RIF) for 4 months
    OR
    - Isoniazid and Rifapentine weekly for 3 months (3HP) On a case by case basis, after discussion and approval by the Sponsor, a local TB test that is negative and is considered equivalent to 1 of the
    above tests may be used for eligibility. For example, if QuantiFERON®- TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus) is indeterminate for any reason and a local blood tests or T-Spot TB test is negative, the patient may be enrolled using the local result upon approval of the Sponsor.
    18. History of serious infections requiring intravenous therapy with the potential for recurrence or currently active moderate to severe infection at screening (Grade 2 or higher)
    19. Live vaccine within 28 days prior to Day 1 or plan to receive one during the trial
    20. Any other clinically significant disease, condition (including contraindication to CS and/or inability to follow CS dosing as outlined in the protocol (see table 1 for more details in the protocol), or medical history that, in the opinion of the Investigator, would interfere with patient safety, trial evaluations, and/or trial procedures. In areas endemic for Chagas disease, screening is recommended prior to enrollment.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy endpoint: The proportion of patients who are in CR from Week ≤ 29 to Week 37 with a daily prednisone dose of ≤ 5 mg/day

    Safety Endpoints
    • Nature, frequency, and severity of adverse events, including serious adverse events, adverse events leading to discontinuation and possible corticosteroid-related adverse effects
    • Change from baseline in vital signs and clinical laboratory test results (including complete blood count and blood chemistry)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy endpoints: at every visit between week 29 and Week 37
    Safety endpoints: at every visit
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoints
    • Cumulative CS dose over first 36 weeks (to Week 37)
    • Time to the beginning of the CR event used to define success for patients reaching the primary endpoint
    • Proportion of patients with CR from Week ≤ 29 to Week 37 with a daily CS dose of ≤ 10 mg/day

    Other Secondary Endpoints
    • GTI score at Week 37
    • Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) score from baseline to Week 37
    • Change in EQ-5D-5L score from baseline to Weeks 5, 13, 25, and 61
    • Change in Autoimmune Bullous Disease Quality of Life (ABQOL) score from baseline to Weeks 5, 13, 25, 37 and 61
    • Change in PDAI score from baseline to Weeks 5, 13, 25, 37 and 61
    • Change in Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) score from baseline to Weeks 5, 13, 25, 37, and 61
    • Proportion of patients in CR for ≥ 8 weeks on zero CS at Week 61 by original PRN1008/placebo group assignment and overall
    • Proportion of patients in CR at Week 37 to maintain CR continuously to Week 61
    • Proportion of patients not in CR at Week 37 to achieve CR at Week 61
    • Proportion of patients to achieve CR of any duration at any time up to Week 37
    • Duration of CR
    E.5.2.1Timepoint(s) of evaluation of this end point
    at 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 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 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    double-blind for the first 36 weeks, then open label from week 37 to 61, after that LTE for 48 Weeks
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA49
    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
    Argentina
    Australia
    Brazil
    Bulgaria
    Canada
    Croatia
    France
    Germany
    Greece
    Israel
    Italy
    Poland
    Serbia
    Spain
    Taiwan
    Turkey
    Ukraine
    United Arab Emirates
    United Kingdom
    United States
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months3
    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: 20
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 59
    F.4.2.2In the whole clinical trial 120
    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)
    The patients will continue standard of care after completing the study.
    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 Decision2018-11-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-12-17
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