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    Summary
    EudraCT Number:2020-002063-60
    Sponsor's Protocol Code Number:PRN1008-018
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-01
    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 ConcernedGermany - BfArM
    A.2EudraCT number2020-002063-60
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-Controlled, Parallel-Group Study with an Open-Label Extension to Evaluate the Efficacy and Safety of Oral Rilzabrutinib (PRN1008) in Adults and Adolescents with Persistent or Chronic Immune Thrombocytopenia (ITP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Trial to Test the Safety, Effect, and Activity of Rilzabrutinib (PRN1008) in Adult and Adolescent Patients with Persistent or Chronic Immune Thrombocytopenia (ITP)
    A.4.1Sponsor's protocol code numberPRN1008-018
    A.5.4Other Identifiers
    Name:IND Number:132668
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/306/2020
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPrincipia Biopharma, Inc.
    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, Inc.
    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 pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street Address220 East Grand Avenue
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18334776700
    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 numberEU/3/20/2278
    D.3 Description of the IMP
    D.3.1Product nameRilzabrutinib
    D.3.2Product code PRN1008
    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 INNRilzabrutinib
    D.3.9.1CAS number 1575591-66-0
    D.3.9.2Current sponsor codePRN1008
    D.3.9.4EV Substance CodeSUB192772
    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 placeboFilm-coated tablet
    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
    Immune Thrombocytopenia (ITP)
    E.1.1.1Medical condition in easily understood language
    Immune Thrombocytopenia (ITP) is a chronic, autoimmune disease that is associated with bleeding risk due to low platelet levels in the blood.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10074667
    E.1.2Term Immune thrombocytopenic purpura
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To demonstrate the efficacy of rilzabrutinib vs placebo in patients with refractory/relapsed ITP, based on the proportion of adult patients able to achieve platelet counts at or above 50,000/μL for at least 8 out of the last 12 weeks of the 24-week blinded treatment period
    E.2.2Secondary objectives of the trial
    •Evaluate effect of rilzabrutinib vs PBO on number of wks with PLT count ≥50,000/μL OR between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline, over the 24-wk blinded treatment period in absence of rescue therapy
    •Evaluate effect of rilzabrutinib vs PBO on number of wks with PLT counts between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline over the 24-wk blinded treatment period in absence of rescue therapy
    •Evaluate effect of rilzabrutinib vs PBO on time to first PLT count of ≥50,000/μL OR between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline
    •Evaluate effect of rilzabrutinib vs PBO on proportion of patients requiring rescue therapy
    •Evaluate effect of rilzabrutinib vs PBO on change from baseline in ITP-BAT assessment.
    •Evaluate safety and tolerability of rilzabrutinib in patients aged 12 to <18 yrs and in adult patients (≥18 yrs) with refractory/relapsed ITP
    •Characterize PK of rilzabrutinib
    •Evaluate effect of rilzabrutinib on QoL
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients will be men and women with primary ITP with duration of > 6 months in ages 12 to < 18 years and duration of > 3 months in ages 18 years and above
    2. Patients who had a response (achievement of platelet count ≥ 50,000/µL) to IVIg/anti-D or CSs that was not sustained and who have documented intolerance or insufficient response to any appropriate courses of standard of care ITP therapy
    3. An average of 2 platelet counts at least 5 days apart of < 30,000µL (and no single platelet count >35,000µL) within 14 days prior to the first dose of study drug
    4. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, AST/ALT ≤ 1.5 x ULN, albumin ≥ 3 g/dL, total bilirubin ≤ 1.5 x ULN, estimated GFR > 50 (Cockcroft and Gault method)
    5. Hemoglobin (Hgb) > 9 g/dL prior to dosing on Study Day 1
    6. Female patients who are of reproductive potential (or are likely to reach reproductive potential during the study) 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) or practice true abstinence (when this is in line with the usual and preferred lifestyle). For females considered not to have reproductive potential: Any woman of age ≥ 55 years with amenorrhea for >1 year, will be considered as having confirmed menopause and follicle-stimulating hormone (FSH) or pregnancy testing will not be needed. Postmenopausal females <55 years of age (defined as amenorrhea > 1 year) must have menopause confirmed by elevated FSH levels at Screening. Surgically sterile females do not require any further confirmation of menopause and will not be considered to have reproductive potential.
    7. Patients must be able to provide written informed consent or informed assent with corresponding informed consent obtained from the patient’s guardian and agree to the schedule of assessments.
    E.4Principal exclusion criteria
    1. Patients with secondary ITP
    2. Pregnant or lactating women
    3. Electrocardiogram (ECG) findings for patients:
    • aged ≥ 12 and < 16: QTc > 449 msec (males) or > 457 msec (females)
    • aged ≥ 16 and < 18: QTc >450 msec (males) or > 460 msec (females)
    • aged ≥ 18, of QTcF > 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. History (within 5 years of Study Day 1) or current, active malignancy requiring or likely to require chemotherapeutic or surgical treatment during the study, with the exception of non-melanoma skin cancer
    5. Transfusion with blood, blood products, plasmapheresis, or use of any other rescue medications with intent to increase platelet count within 14 days before Study Day 1
    6. Change in CS and/or TPO-RA dose within 14 days prior to Study Day 1 (more than 10% variation from current doses)
    7. Immunosuppressant drugs other than CSs within 14 days of Study Day 1
    8. Treatment with rituximab or splenectomy within the 3 months prior to Study Day 1
    • Patients treated with rituximab will have normal B-cell counts prior to enrollment
    9. Ongoing need for the use of proton pump inhibitor drugs such as omeprazole and esomeprazole (it is acceptable to change patient to H2 receptor blocking drugs prior to Study Day 1)
    10. Use of known strong-to-moderate inducers or inhibitors of CYP3A within 3 days or 5 half-lives (whichever is longer) of Study Day 1 and until the end of the active treatment period
    11. Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting drugs such as aspirin (except for low dose aspirin up to 100 mg per day), nonsteroidal anti-inflammatory drugs (NSAIDs), thienopyridines within 14 days of Study Day 1 and until the end of the active treatment period
    12. Has received any investigational drug within the 30 days before receiving the first dose of study medication, or at least 5 times elimination half-life of the drug (whichever is longer); patient should not be using an investigational device at the time of dosing
    • Patients who previously received treatment with BTK inhibitors (except rilzabrutinib) within 30 days before the first dose of study drug are not eligible
    • Patients who previously received rilzabrutinib (PRN1008) at any time are not eligible
    13. Current drug or alcohol abuse
    14. Refractory nausea and vomiting, malabsorption, external biliary shunt, significant bowel resection, or any other condition that would preclude adequate study drug absorption
    15. History of solid organ transplant
    16. Positive at Screening for human immunodeficiency virus (HIV), hepatitis B virus (HBV) (surface and core antibodies unrelated to vaccination), or hepatitis C virus (anti-HCV antibody confirmed with Hep C RNA)
    • Patients who are hepatitis B virus surface antigen (HBsAg) positive will not be eligible
    • Patients who are HBsAg negative and hepatitis B core antigen antibody (HBcAb) positive will be tested for HBV surface antibody (HBsAb) and HBV DNA. If HBsAb titer is >100 IU/ml, patients may be enrolled. Monthly HBV DNA monitoring will be required while on treatment and for 6 months after the last dose of the study drug. Positive HBV DNA results will be managed appropriately as per local standard of care
    • Patients who are HBcAb positive and HBsAg negative with HBsAb titer <100 IU/ml or negative, are not eligible
    17. Positive QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus) at Screening unless 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 extra-pulmonary TB disease
    c) Documented receipt of one of the following prophylactic treatment regimens:
    i. Oral daily Isoniazid for 6 months or
    ii. Oral daily Rifampin (RIF) for 4 months or
    iii. 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.
    18. History of recurring (2 or more) serious infections requiring intravenous antibiotic therapy within the last 3 months before Study Day 1 or active serious or moderate infection ongoing on the day of randomization
    19. Myelodysplastic syndrome
    20. Live vaccine within 28 days prior to Study Day 1 or plan to receive one during the study
    21. Planned surgery in the time frame of the dosing period
    22. Any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator or Sponsor’s medical monitor, would interfere with patient safety, study evaluations, and/or study procedures
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients able to achieve platelet counts at or above 50,000/μL for at least 8 out of the last 12 weeks of the 24-week blinded treatment period in the absence of rescue therapy
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy (blinded period): At every visit Week 2 through Week 25 including weekly lab visits between clinic visits and early withdrawal/unscheduled visits
    E.5.2Secondary end point(s)
    Efficacy
    • Number of weeks with platelet count ≥50,000/μL OR between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline over the 24-week blinded treatment period in the absence of rescue therapy
    • Number of weeks with platelet counts between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline over the 24-week blinded treatment period in the absence of rescue therapy
    • Time to first platelet count of ≥50,000/μL OR between ≥ 30,000/μL and <50,000/μL and doubled from baseline
    • Proportion of patients requiring rescue therapy
    • Change from baseline in ITP Specific Bleeding Assessment Tool (ITP-BAT) assessment

    Safety
    • Frequency and severity of TEAEs
    • Frequency and severity of bleeding TEAEs
    • Change from baseline in physical examination, ECG, clinical laboratory test results, vital signs. and laboratory tests (serum chemistry, hematology (except for platelet counts included in the primary efficacy endpoint)

    PK
    • Plasma concentrations of rilzabrutinib

    QoL
    • Change from baseline on the Symptoms, Bother and Activity domains of the ITP Patient Assessment Questionnaire (ITP-PAQ) in adult patients (≥18 years)
    • Change from baseline in disease-specific quality of life (QoL) as measured by the Kids’ ITP Tools (ITP-KIT) score in patients ages 12 to <18

    Exploratory
    • Proportion of patients able to achieve platelet counts ≥50,000/μL for 4 out of last 8 weeks of the 24-week treatment period
    • Proportion of patients who have a platelet count that exceeds 250,000/μL or 450,000/µL (for patients on TPO RA’s)
    • Change from baseline on the Fatigue, Psychological, Fear, Social Activity, Women’s Reproductive Health, Work, and Overall QoL domains of the ITP-PAQ in adult patients (≥18 years)
    • Change from baseline in quality of life as measured by the Euro-QoL-5 Dimensions-5 Level (Euro-QoL-5D-5L) in adult patients (≥18 years)
    • Change from baseline in disease-related symptom severity as measured by the Patient Global Impression of Severity (PGIS)
    • Patient perception of disease-related symptom improvement as measured by Patient Global Impression of Change Scale (PGIC)
    • PK parameters as assessed by population pharmacokinetic analysis
    • BTK occupancy
    • Changes from baseline in TPO levels, T/B/NK counts, immunoglobulin (IgG, IgG1, IgG4, IgM, IgE) levels
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy (blinded period): At every visit Week 2 through Week 25 including weekly lab visits between clinic visits and early withdrawal/unscheduled visits
    Efficacy (open-label): Week 26 through Week 53 including end of study 4-weeks post last dose and early withdrawal/unscheduled visits
    Safety (blinded period, open-label): At every visit
    PK (blinded period): Week 1 and Week 13
    PK (open-label): Week 25 and Week 53
    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 No
    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 EEA35
    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
    Austria
    Brazil
    Bulgaria
    Canada
    Chile
    Czechia
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Mexico
    Netherlands
    Norway
    Poland
    Russian Federation
    Singapore
    Spain
    Thailand
    Turkey
    Ukraine
    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
    End of trial is defined as the point at which the last patient has completed final assessments at the last visit of the study (LPLV).
    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 months
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 139
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 194
    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)
    Patients may continue in the 12 month LTE until the patient is:
    a) no longer responding (platelet counts <30,000/µL or less than 20,000/µL above baseline on four consecutive visits)
    b) the drug is no longer being developed by the Sponsor for ITP
    c) the program is stopped for safety reasons or
    d) the drug becomes commercially available in the patient’s country
    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 Medical Research Network Ltd
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-12
    P. End of Trial
    P.End of Trial StatusOngoing
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