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    Summary
    EudraCT Number:2015-003564-37
    Sponsor's Protocol Code Number:PRN1008-005
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-07-06
    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 ConcernedCroatia - MIZ
    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
    Druga faza otvorenog pilot-ispitivanja sigurnosti, kliničkog djelovanja, farmakokinetike i farmakodinamike oralnog inhibitora Bruton-tirozin-kinaze PRN1008 u ispitanika oboljelih od novodijagnosticiranog ili relapsnog vulgarnog pemfigusa
    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
    Pilot-ispitivanje sigurnosti, kliničkog djelovanja, doze lijekova i učinaka PRN1008 u ispitanika oboljelih od novodijagnosticiranog ili relapsnog vulgarnog pemfigusa
    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 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 pointChief Medical Officer
    B.5.3 Address:
    B.5.3.1Street Address220 East Grand Avenue
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16504167700
    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/3/17/1951
    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
    Vulgarni pemfigus
    E.1.1.1Medical condition in easily understood language
    Pemphigus: Pemphigus Vulgaris
    Vulgarni pemfigus
    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 20.0
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical safety of PRN1008 in patients with PV over a 12-week (Part A) or 24-week (Part B) treatment period
    To evaluate the clinical activity of PRN1008 in patients with PV, per criteria in the European Academy of Dermatology and Venereology (EADV) 2014 Pemphigus S2 Guideline
    • Procijeniti kliničku aktivnost i sigurnost inhibitora PRN1008 u ispitanika oboljelih od vulgarnog pemfigusa u razdoblju liječenja od 12 (dio A) ili 24 (dio B) tjedna.
    • Procijeniti kliničku aktivnost lijeka PRN1008 u ispitanika oboljelih od vulgarnog pemfigusa prema kriterijima navedenim u Smjernicama S2 za pemfigus iz 2014. (Hertl i sur. 2015) Europske akademije za dermatologiju i venerologiju (EADV).
    E.2.2Secondary objectives of the trial
    To evaluate the pharmacodynamics (PD) and pharmacokinetics (PK) of multiple doses of PRN1008 in patients with PV
    • Procijeniti farmakodinamiku i farmakokinetiku inhibitora PRN1008 u ispitanika oboljelih od vulgarnog pemfigusa
    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 (positive direct immunofluorescence and appearance on H&E microscopy), mild-moderate PV in Part A (PDAI 8 to 45) and mild-severe PV in Part B (PDAI 8 to 60)
    2.Newly diagnosed or relapsing patients for whom an initial period of PRN1008 monotherapy or combination therapy with low-dose corticosteroids (≤0.5 mg/kg of prednis[ol]one or equivalent), is judged clinically acceptable, provided tapering of the corticosteroid treatment regimen is anticipated with good clinical response to PRN1008
    3.BMI > 17.5 and < 40 kg/m2 Part A only
    4.Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, Hgb > 9 g/dL, platelet count ≥ 100 X 109/L, AST/ALT ≤ 1.5 x ULN, albumin ≥ 3 g/dL, creatinine ≤ ULN (Part A) and creatinine ≤ 1.5 x ULN (Part B)
    5.Female patients who are of reproductive potential must agree for the duration of active treatment in the study to use an effective means of contraception (hormonal contraception methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, condoms, or sexual abstinence). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing.
    6.Able to provide written informed consent and agreeable to the schedule of assessments
    1. Muškarci ili žene stari između 18 i 80 godina s na biopsiji potvrđenim (pozitivnom direktnom imunofluorescencijom i mikroskopijom s bojenjem prema Harrisu) blagim do umjerenim vulgarnim pemfigusom u dijelu A (indeks PDAI 8 do 45) i blagim do teškim vulgarnim pemfigusom u dijelu B (indeks PDAI 8 do 60).
    2. Bolesnici s novopostavljenom dijagnozom ili bolesnici s relapsom bolesti za koje se početno razdoblje monoterapije inhibitorom PRN1008 ili kombinirane terapije s bilo kojom niskom dozom kortikosteroida (≤ 0,5 mg/kg predniz(ol)ona ili ekvivalenta) procijeni klinički prihvatljivim, pod uvjetom da se predviđa postupno smanjivanje doze kortikosteroida uz dobar klinički odgovor na lijek PRN1008.
    3. Indeks tjelesne mase > 17,5 i < 40 kg/m2 samo u dijelu A.
    4. Odgovarajuće hematološke, jetrene i bubrežne funkcije (apsolutni broj neutrofila ≥ 1,5 X 109/l, Hgb > 9 g/dl, trombociti ≥ 100 X 109/l, AST/ALT ≤ 1,5 x ULN, albumin ≥3 g/dl i kreatinin ≤ ULN (dio A) i kreatinin ≤ 1,5 x ULN (dio B).
    5. Bolesnice koje mogu zatrudnjeti moraju pristati na korištenje učinkovitih metoda kontracepcije (hormonalne kontracepcijske metode koje sprječavaju ovulaciju, unutarmaternični uložak, unutarmaternični sustav otpuštanja hormona, obostrano podvezivanje jajovoda, vazektomija partnera, kondomi ili seksualna apstinencija) tijekom aktivnog liječenja u ispitivanju. Ako nisu kirurški sterilizirane, ženama u postmenopauzi se menopauza mora potvrditi testiranjem folikostimulirajućih hormona.
    6. Bolesnici moraju biti sposobni dati informirani pristanak te na zakazane procjene moraju dolaziti u skladu s rasporedom.
    E.4Principal exclusion criteria
    1.Previous use of a BTK inhibitor. Patients enrolled in a previous version of this protocol who are still in their 12-week active treatment period with PRN1008 are eligible to continue treatment, initially with their current dose level, under this amended protocol for an additional 12 weeks, i.e. 24 weeks total, following review and signature of the EC approved patient’s consent.Patients who completed Part A and did not discontinue the study due to a medical condition that might compromise safety assessments or for a PRN1008 related adverse event may be screened for entry under Part B.
    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: as concomitant therapy, other immunologic response modifiers not detailed in this exclusion apart from corticosteroids; 1 week: cyclophosphamide; 4 weeks: IVIG, Kinaret (anakinra) and Enbrel (etanercept); 12 weeks: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), plasmapheresis; 6 months: Rituxan/MabThera (rituximab), ofatumumab, any other anti-CD20 antibody, other long-acting biologics
    6.More than 0.5 mg/kg of prednis(ol)one per day (“low-dose corticosteroids”) within the two weeks prior to Day 1
    7.Use of proton pump inhibitor drugs such as omeprazole and 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 (Appendix 2) within 3 days or 5 half-lives (whichever is longer) of study drug dosing
    9.Use of CYP3A-sensitive substrate drugs (Appendix 3) with a narrow therapeutic index within 3 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 approximately 3 standard drinks per day
    13.Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate study drug absorption
    14.History of anorexia nervosa or periods of three months or more of low body weight (BMI < 17.5) in the past 5 years
    15.Donation of a unit or more of blood or blood products within 4 weeks prior to Day 1
    16.History of solid organ transplant
    17.History of epilepsy or other forms of seizure in the last 5 years
    18.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)
    19.Positive interferon-gamma release assay (IGRA) (e.g.,T-SpotTB test, QuantiFERON®-TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) 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 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
    oriii. Isoniazid and Rifapentine weekly for 3 months (3HP)
    On a case by case basis, after discussion and approval by the ponsor, 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 a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) is positive and a local blood test or T-Spot TB test is negative, the patient may be enrolled using the local result upon approval of the Sponsor.
    20.History of serious infections requiring intravenous therapy with the potential for recurrence
    21.Live vaccine within 28 days prior to baseline or plan to receive one during the study
    1. Prethodno korištenje inhibitora Bruton-tirozin-kinaze.
    2. Trudnice i dojilje.
    3. Snimka EKG-a s intervalom QTc > 450 msec (za muškarce) ili > 470 msec (za žene), slabo kontrolirana atrijalna fibrilacija (odnosno simptomatski bolesnici s brzinom ventrikularne kontrakcije većom od 100 otkucaja u minuti na EKG-u) ili druge klinički značajne abnormalnosti.
    4. Povijest malignih bolesti bilo koje vrste, osim kirurški odstranjenih nemelanomskih karcinoma kože ili karcinoma vrata maternice in situ u 5 godina prije davanja prve doze.
    5. Korištenje modifikatora imunološkog odgovora u sljedećim razdobljima prije 1. dana kao popratna terapija, ostali modifikatori imunološkog odgovora koji nisu navedeni u ovom kriteriju za isključivanje osim kortikosteroida: 1 tjedan za ciklofosmamid, 4 tjedna za intravenozne imunoglobuline, Kinaret (anakinra) i Enbrel (etanercept), 12 tjedana za lijekove Remicade (infliksimab), Humira (adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (sekukinumab) i plazmaferezu, 6 mjeseci za lijekove Rituxan i MabThera (rituksimab), ofatumumab ili bilo koje drugo antitijelo anti-CD20, ostali dugodjelujući biološki lijekovi.
    6. Više od 0,5 mg/kg predniz(ol)ona na dan („niska doza kortikosteroida“) u dva tjedna prije 1. dana.
    7. Korištenje inhibitora protonske pumpe poput omeprazola i ezomeprazola (prihvatljivo je bolesnika prije prve doze inhibitora PRN1008 prebaciti na lijekove za blokiranje receptora H2).
    8. Popratno korištenje poznatih umjerenih do snažnih induktora ili inhibitora izoenzima CYP3A (prilog 2) u 3 dana ili 5 poluživota (ovisno o tome što je dulje) od primjene ispitivanog lijeka.
    9. Korištenje supstrata osjetljivih na izoenzim CYP3A (prilog 3) s uskim terapijskim indeksom u 3 dana ili 5 poluživota (ovisno o tome što je dulje) od primjene ispitivanog lijeka uključujući, ali se ne ograničavajući samo na alfentanil, astemizol, cisaprid, ciklosporin, dihidroergotamin, ergotamin, fentanil, pimozid, kinidin, sirolimus, takrolimus, ili terfenadin.
    10. Primanje bilo kojeg eksperimentalnog lijeka (ili trenutno korištenje eksperimentalnog medicinskog sredstva) u 30 dana prije primanja prve doze ispitivanog lijeka ili najmanje u 5 puta duljem vremenu od poluvremena eliminacije (ovisno o tome što je dulje).
    11. Povijest zloporabe droga u prethodnih 12 mjeseci.
    12. Alkoholizam ili pretjerana konzumacija alkohola, definirana kao redovna konzumacija više od oko 3 standardna pića na dan.
    13. Refraktorna mučnina i povraćanje, eksterni bilijarni stent ili značajna resekcija crijeva koja bi spriječila odgovarajuću apsorpciju ispitivanog lijeka.
    14. Povijest anoreksije nervoze ili razdoblja niske tjelesne težine (indeks tjelesne mase < 17,5) od tri mjeseca ili dulje u zadnjih 5 godina.
    15. Doniranje jedne jedinice ili više krvi ili krvnih derivata u 4 tjedna prije 1. dana.
    16. Povijest presađivanja čvrstih organa.
    17. Povijest epilepsije ili drugih oblika napadaja u zadnjih 5 godina.
    18. Pozitivnost na HIV i hepatitis B (antitijela HBsAb i HBcAb nepovezana s cijepljenjem) ili C (antitijela anti-HCV potvrđena testiranjem RNK na hepatitis C).
    19. Pozitivan test oslobađanja interferona gama (IGRA) (npr. T-spot TB test, QuantiFERON®-TB Gold ili QuantiFERON®-TB Gold Plus (QFT Plus), na probiru. Osim ako bolesnik ima latentni TBC i sva su 3 sljedeća stanja točna:
    a. Rendgenski snimak prsnog koša ne pokazuje dokaz koji ukazuje na aktivnu tuberkulozu (TBC)
    b. Nema kliničkih znakova i simptoma TBC-a u plućima i/ili izvan pluća
    c. Dokumentirano primanje jednog od sljedećih režima profilaktičkog liječenja:
    i. Izoniazid svakodnevno, oralno, tokom 6 mjeseci
    ii. Rifampin (RIF) svakodnevno, oralno, tokom 4 mjeseca
    ili
    iii. Izoniazid i Rifapentin tjedno, tokom 3 mjeseca (3HP)
    Na temelju pojedinačnih slučajeva, nakon rasprave i odobrenja od strane naručitelja ispitivanja, lokalni test na TBC koji je negativan, a smatra se ekvivalentom za 1 od gore navedenih testova, može se koristiti za određivanje podobnosti. Primjerice, ako je QuantiFERON®-TB Gold ili QuantiFERON-TB Gold Plus (QFT Plus) pozitivan, a lokalna pretraga krvi ili T-Spot TB test negativan, bolesnik može biti upisan primjenom lokalnog rezultata nakon odobrenja naručitelja ispitivanja.
    20. Povijest ozbiljnih infekcija koje zahtijevaju intravensku terapiju s potencijalom za povratak bolesti.
    21. Živa cjepiva u 28 dana prije utvrđivanja početnih vrijednosti ili planirano primanje živog cjepiva tijekom ispitivanja.
    22. Bilo koja druga klinički značajna bolest, stanje ili zdravstvena povijest koja bi prema mišljenju ispitivača utjecala na sigurnost ispitanika, procjene i/ili postupke iz ispitivanja.
    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.

    Efficacy:
     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)
    Primarne mjere ishoda

    Sigurnost:
    • učestalost štetnih događaja proizašlih iz liječenja, uključujući klinički značajne promjene na fizikalnom pregledu te u vrijednostima sigurnosnih laboratorijskih pretraga i rezultata mjerenja vitalnih znakova.

    Učinkovitost:
    • udio ispitanika sposobnih ostvariti kontrolu aktivnosti bolesti* u 4 tjedna od početka primjene lijeka PRN1008 bez potrebe za dozama predniz(ol)ona > 0,5 mg/kg.
    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.
    ispitanici će se probirati u 28 dana prije primjene lijeka, a na procjenu za kraj ispitivanja doći će u ispitivački centar 84 dana nakon primanja zadnje doze ispitivanog lijeka. Ispitanici će se tijekom ispitivanja liječiti kao izvanbolnički pacijenti te će u zakazana vremena dolaziti u posjete radi mjerenja vitalnih znakova, procjene štetnih događaja, provjere korištenja popratnih lijekova, procjene kliničke korisnosti i davanja uzoraka krvi za farmakokinetičke i farmakodinamičke analize te radi drugih kliničkih laboratorijskih pretraga.
    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 (and 24 weeks in Part B)
     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 (and 24 weeks in Part B)
     Time to CDA
     Time to CR
     Time to end of consolidation phase
     Time to relapse after PRN1008 treatment discontinuation
     Cumulative corticosteroid usage over the first 12 weeks (and 24 weeks in Part B)
     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) with the exception that CR is defined as CR at a single point in time rather than present for ≥2 months
    • udio ispitanika sposobnih ostvariti kontrolu aktivnosti bolesti u 4 tjedna liječenja bez primanja kortikosteroida
    • udio ispitanika sposobnih ostvariti potpuni odgovor bez kortikosteroida u 12 tjedana liječenja (kao i u 24 tjedna za dio B)
    • udio ispitanika sposobnih ostvariti potpuni odgovor bez potrebe za dozama predniz(ol)ona većim od 0,5 mg/kg u 12 tjedana liječenja (kao i u 24 tjedna za dio B)
    • vrijeme do kontrole aktivnosti bolesti
    • vrijeme do potpunog odgovora
    • vrijeme do kraja faze konsolidacije
    • vrijeme do relapsa nakon prekida liječenja inhibitorom PRN1008
    • kumulativna potrošnja kortikosteroida u prvih 12 tjedana liječenja (kao i u 24 tjedna za dio B)
    • primjene u odnosu na početne vrijednosti upitnika Indeksa površine zahvaćene pemfigusom (PDAI) i Ocjene intenziteta autoimunog buloznog poremećaja kože (ABSIS) na svakom posjetu za praćenje
    • primjene u odnosu na početne vrijednosti upitnika Kvalitete života s autoimunom buloznom bolešću (ABQOL) i Kvalitete života s liječenjem autoimune bulozne bolesti (TABQOL) na svakom posjetu za praćenje
    • promjene u odnosu na početne vrijednosti Kratkog upitnika za nutricionističku procjenu (SNAQ) na svakom posjetu za praćenje.

    * Krajnje točke kliničke aktivnosti definirane prema Smjernicama S2 za pemfigus Europske akademije za dermatologiju i venerologiju iz 2014. godine (Hertl i sur. 2015.).

    Farmakokinetičke mjere ishoda:

    • koncentracija inhibitora PRN1008 u plazmi otprilike u trenutku maksimalne koncentracije 1. dana i u različitim sljedećim trenucima tijekom vanbolničke primjene lijeka.

    Farmakodinamičke mjere ishoda:

    • postotak okupacije Bruton-tirozin-kinaze u mononuklearnim stanicama periferne krvi 2 i 24 sata nakon prve doze lijeka PRN1008 i u različitim sljedećim trenucima tijekom vanbolničke primjene lijeka
    • promjena razina autoantitijela anti-dsg-1 i -3 u odnosu na početne vrijednosti utvrđena enzimski vezanim imunosorbentnim testom (ELISA) u raznim vremenskim točkama.

    Istraživačke mjere ishoda:

    • istraživačke farmakokinetičke/farmakodinamičke analize ispitivat će učinke, ako ih bude, kovarijata na farmakokinetiku i/ili farmakodinamiku i odnos između farmakokinetike, farmakodinamike i učinkovitosti u toj populaciji
    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 (and 24 weeks in Part B)
     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 (and 24 weeks in Part B)
     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 (and 24 weeks in Part B)
     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
    Kvaliteta života
    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 EEA7
    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 final safety follow-up after the LPLV.
    Završetak ispitivanja definira se kao datum konačnog posjeta sigurnosnog praćenja nakon zadnjeg posjeta ispitanika koji je bio zadnji uključen u ispitivanje.
    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 months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 50
    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)
    Ispitanici će biti liječeni na temelju odluke liječnika po završetku ispitivanja.
    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 Decision2016-04-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-01-10
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