| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pemphigus: Pemphigus Vulgaris |
| Vulgarni pemfigus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pemphigus: Pemphigus Vulgaris |
| Vulgarni pemfigus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052802 |
| E.1.2 | Term | Pemphigus vulgaris |
| E.1.2 | System Organ Class | 100000004858 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main 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). |
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| E.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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| E.4 | Principal 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
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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.
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| E.5 End points |
| E.5.1 | Primary 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.
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| E.5.1.1 | Timepoint(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. |
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| E.5.2 | Secondary 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
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| E.5.2.1 | Timepoint(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 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life |
| Kvaliteta života |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If 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.8.7 | Trial 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. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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