| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| giant cell arteritis |
| Arteritis divovskih stanica |
|
| E.1.1.1 | Medical condition in easily understood language |
| an inflammatory disease of blood vessels |
| Upalna bolest krvnih žila |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| 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 | 10018250 |
| E.1.2 | Term | Giant cell arteritis |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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 |
| The primary objective of the study is to evaluate the efficacy of KPL-301 versus placebo, coadministered with a 26-week steroid taper, for maintaining sustained remission for 26 weeks in subjects with newonset or relapsing/refractory giant cell arteritis (GCA). |
| Primarni cilj ispitivanja jeste procijeniti učinkovitost lijeka KPL-301 u usporedbi s placebom, kada se primjenjuje zajedno s 26-tjednim smanjenjem terapije kortikosteroidima, za održavanje remisije tijekom 26 tjedana u ispitanika s novim ili relapsnim/refraktornim gigantocelularnim arteritisom (GCA). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study, in subjects with new-onset and relapsing/refractory GCA, are:
a) To evaluate the effect of KPL-301 vs placebo on cumulative corticosteroid dose.
b) To evaluate the effect of KPL-301 vs placebo on health-related quality of life (HRQoL).
c) To evaluate the safety and tolerability of KPL-301.
d) To evaluate the pharmacokinetics (PK) of KPL-301. |
Sekundarni ciljevi ispitivanja, u ispitanika s novim i relapsnim/refraktornim GCA-om, su:
a) Procijeniti učinak lijeka KPL-301 u usporedbi s placebom na kumulativnu dozu kortikosteroida.
b) Procijeniti učinak lijeka KPL-301 u usporedbi s placebom na kvalitetu života povezanu sa zdravljem (HRQoL).
c) Procijeniti sigurnost i podnošljivost lijeka KPL-301.
d) Procijeniti farmakokinetiku (FK) lijeka KPL-301.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able and willing to provide written informed consent and to comply with the study protocol
2. Age of ≥ 50 to 85 inclusive
3. Diagnosis of new-onset or relapsing GCA classified according to the following criteria:
New-onset: Initial diagnosis of GCA within 6 weeks of Day 0, defined as:
a) Westergren ESR > 30 mm/hour or CRP ≥ 1 mg/dL
b) AND at least one of the following:
i. Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp or temporal artery pain or tenderness, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication)
ii. Unequivocal extracranial symptoms of GCA such as claudication of the extremities
iii. Symptoms of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory morning stiffness
c) AND at least one of the following:
i. TAB or ultrasound revealing features of GCA
ii. Evidence of large-vessel vasculitis by angiography or cross-sectional imaging study such as MRI, CT/CTA, or PET-CT of the aorta or other great vessels
Relapsing: Diagnosis of GCA > 6 weeks before Day 0 AND:
Active GCA within 6 weeks of Day 0 defined as clinical sign/symptom(s) as per above and Westergren ESR> 30 mm/hour or CRP ≥ 1 mg/ dL
Refractory nonremitting: Diagnosis of GCA > 6 weeks before Day 0 AND
No remission since the diagnosis of disease as per clinical expectations. i.e. Presence of sign/symptoms as per above and Westergren ESR>30mm/hour or CRP ≥ 1 mg/ dL within 6 weeks of Day 0
4. Remission of GCA at or before Day 0 (resolution of GCA symptom(s) and CRP < 1.0 mg/dL or ESR < 20 mm in the first hour), such that the subject can safely participate in the study and follow the protocol defined rocedures, including initiation of the prednisone taper at the protocol-specified starting dose (i.e., ≤60 mg/day)
5. At Day 0, receiving or able to receive oral prednisone up to 60 mg/day for the treatment of GCA
6. If using methotrexate (MTX), oral or parenteral up to 25mg/week is permitted in screening if started more than 6 weeks prior to Day 0 and should be tapered to zero by Day 0.
7. Willing to receive antiplatelet therapy depending on the Investigator’s decision
8. Willing to receive treatment for prevention of corticosteroid-induced osteopenia/osteoporosis depending on the Investigator’s decision
9. Female subjects must be:
a) postmenopausal, defined as at least 12 months post cessation of menses (without an alternative medical cause), or
b) permanently sterile following documented hysterectomy, bilateral salpingectomy, bilateral ophorectomy, or tubal ligation or having a male partner with vasectomy as affirmed by the subject, or
c) nonpregnant, nonlactating, and if sexually active having agreed to use a highly effective method of contraception (i.e., hormonal contraceptives associated with inhibition of ovulation or intrauterine device [IUD], or intrauterine hormone-releasing system [IUS], or sexual abstinence) from Screening visit until the final Washout Safety Follow-up visit 84 ± 3 days from EOT Visit.
10. Male subjects must have documented vasectomy or if sexually active must agree to use a highly effective method of contraception with their partners of childbearing potential (i.e., hormonal contraceptives associated with the inhibition of ovulation or intrauterine device [IUD], or intrauterine hormone-releasing system [IUS], or sexual abstinence) from Day 0 until the final Washout Safety Follow-up visit 84± 3 days from EOT Visit. Male subjects must agree to refrain from donating sperm during this time period. |
Kriteriji podobnosti:
Kriteriji uključenja
1. Sposobnost i spremnost davanja pisanog informiranog pristanka i pridržavanje plana ispitivanja
2. Starost d ≥ 50 d 85 godina
3. Dijagnoza novog ili relapsnog GCA klasificiranog prema sljedećim kriterijima:
Novi: Početna dijagnoza GCA unutar 6 tjedana prije 0. dana definirana kao
a) Westergrenov ESR > 30 mm/sat ili CRP ≥ 1 mg/dl
b) I najmanje jedan od sljedećih kriterija:
i. Nedvosmisleni kranijalni simptomi GCA (nova lokalizirana glavobolja, bol ili osjetljivost glave ili temporalne arterije, gubitak viza povezan s ishemijom ili inače neobjašnjeni bolovi u ustima ili vilici prilikom žvakanja)
ii. Nedvosmisleni ekstrakranijalni simptomi GCA, kao što je klaudikacija ekstremiteta
iii. Simptomi PMR-a, koja se definira kao bolovi u ramenu i/ili zdjelici povezani s jutarnjom upalnom ukočenošću
c) I najmanje jedan od sljedećih kriterija:
i. TAB ili ultrazvuk koji pokazuje znakove GCA
ii. Dokazi o postojanju vaskulitisa velikih krvnih žila pomoću angiografije ili snimanja poprečnog presjeka kao što je MR, CT/CTA ili PET-CT aorte ili drugih velikih krvnih žila
Relapsni: Dijagnoza GCA > 6 tjedana prije 0. dana:
Aktivni GCA unutar 6 tjedana prije 0. dana što se definira kao gore navedeni klinički znak/simptom(i) i Westergrenov ESR > 30 mm/sat ili CRP ≥ 1 mg/dl
Refraktorno nesmanjujuće: Dijagnoza GCA > 6 tjedana prije 0. dana i bez remisije od postavljanja dijagnoze bolesti prema kliničkim očekivanjima, odnosno prisutnost znakova i simptoma kako je gore navedeno i Westergrenov ESR > 30 mm/sat ili CRP ≥ 1 mg/dl unutar 6 tjedana prije 0. dana.
4. Remisija GCA 0. dana ili prije (povlačenje GCA simptoma i CRP < 1,0 mg/dl ili ESR < 20 mm unutar prvog sata), tako da ispitanik može sigurno sudjelovati u ispitivanju i pridržavati se postupaka definiranih planom ispitivanja, uključujući početak smanjenja terapije prednizonom u početnoj dozi definiranoj planom ispitivanja (tj. ≤60 mg/dan)
5. Primanje ili mogućnost primanja oralnog prednizona 0. dana u dozi od najviše 60 mg/dan za liječenje GCA
6. Ako se koristi metotreksat (MTX), oralna ili parenteralna doza od najviše 25 mg/tjedan dozvoljena je prilikom probira ako se primjena započne više od 6 tjedana prije 0. dana te treba biti smanjena na 0 mg do 0. dana.
7. Spremnost primanja antitrombocitne terapije u zavisnosti od ispitivačeve odluke
8. Spremnost primanja liječenja za sprječavanje osteopenije/osteoporoze izazvane kortikosteroidima u zavisnosti od ispitivačeve odluke
9. Žene ispitanice moraju:
a) biti u postmenopauzi, koja se definira kao najmanje 12 mjeseci bez menstruacije (bez alternativnog medicinskog uzroka), ili
b) biti trajno sterilne nakon dokumentirane histerektomije, obostrane salpingektomije, obostrane ooforektomije ili podvezivanja jajnika ili imati muškog partnera podvrgnutog vazektomiji što može potvrditi ispitanica, ili
c) ne smiju biti trudne, ne smiju dojiti i, ako su seksualno aktivne, moraju pristati na korištenje visokoučinkovite kontracepcijske metode (tj. hormonski kontraceptivi povezani sa sprječavanjem ovulacije ili unutarmaterični umetak (IUD) ili unutarmaternični sustav otpuštanja hormona ili seksualna apstinencija) od posjeta za probir do zadnjeg posjeta iz razdoblja sigurnosnog praćenja i ispiranja lijeka 84±3 dana nakon posjeta za kraj liječenja.
10. Muškarci ispitanici moraju biti podvrgnuti dokumentiranoj vazektomiji ili, ako su seksualno aktivni, moraju pristati na korištenje visokoučinkovite metode kontracepcije (na primjer, hormonski kontraceptivi povezani sa sprječavanjem ovulacije ili unutarmaterični umetak (IUD) ili unutarmaternični sustav otpuštanja hormona ili seksualna apstinencija) s partnericom koja može zatrudnjeti od 0. dana do zadnjeg posjeta iz razdoblja sigurnosnog praćenja i ispiranja lijeka 84±3 dana nakon posjeta za kraj liječenja. Muškarci moraju pristati na izbjegavanje doniranja sperme tijekom tog razdoblja.
|
|
| E.4 | Principal exclusion criteria |
General Exclusion Criteria
1. Major surgery within 8 weeks prior to Screening or planned major surgery within 12 months after randomization
2. Transplanted organs (except corneal transplant performed more than 3 months prior to randomization)
3. Major ischemic event unrelated to GCA within 12 weeks of Screening
Exclusions Related to Prior or Concomitant Therapy
4. Concurrent enrollment in another clinical study, with the exception of observational studies
5. Previous treatment with KPL-301
6. Treatment with any non-biologic investigational drug therapy within 4 weeks or 5 half-lives of the study agent, whichever was longer, prior to Screening
7. Any cell-depleting biological therapies (e.g., anti-CD20) within 12 months prior to Day 0; or previous treatment with noncell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], anakinra, anti-Interleukin [IL]-6 receptor [e.g. tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer) prior to Screening
8. Treatment with alkylating agents within 12 weeks prior to Screening
9. Intramuscular, IV corticosteroids, Intra-articular corticosteroids within 4 weeks prior to Screening
10. Receipt of live (attenuated) vaccine within the 4 weeks before Day 0
11. Treatment with hydroxychloroquine, cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks of Screening Relating to Medical History
12. Female subjects who are pregnant, intending to become pregnant, or are breastfeeding
13. Any condition that, in the opinion of the Investigator, could interfere with evaluation of KPL-301 or interpretation of subject safety or confound the results of the study
14. Known history of allergy or reaction to any component of the KPL-301 or placebo formulation or to any other biologic therapy or prednisone or any of its excipients
15. Positive (or 2 indeterminate) QuantiFERON test results.
16. Clinically significant active infection including signs/symptoms suggestive of infection, any significant recurrent or chronic infection (including positive hepatitis C virus antibody [HCVAb]), or any episode of infection requiring hospitalization or treatment with IV antibiotics within 12 weeks before Screening. Subjects with any opportunistic infection within 6 months before Screening will be excluded from the study.
17. Subjects with chronic active hepatitis B infection as defined below will be excluded from the study:
Hepatitis B surface antigen (HbsAg) positive
Hepatitis B anti-core antibody positive but anti-surface antibody negative
18. Subjects at a high risk of infection (e.g., history of hereditary or acquired immune deficiency disorder including a history of known human immunodeficiency virus [HIV] infection), a history of an infected joint prosthesis at any time with that prosthesis still in situ, leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections
19. History of cancer within the last 10 years - except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured
20. Evidence of clinically uncontrolled respiratory disease. The Investigator should review the data from subjects’ respiratory assessments including chest x-ray and pulmonary function tests (PFTs) including DLCO performed during the screening period or within 12 weeks prior to Day 0 if results of prior assessments are available. Available PFT and DLCO assessments must have had values ≥ 60% of predicted for measurements performed and no uncontrolled lung disease. A subject’s medical regimen should not have been significantly intensified to control lung disease within 12 weeks prior to Day 0.
21. History of chronic respiratory tract infections
22. Congestive heart failure of New York Heart Association classification III or IV
23. At screening blood tests, any of the following:
a) Aspartate transaminase (AST) > 2 × upper limit of normal (ULN)
b) Alanine transaminase (ALT) > 2 × ULN
c) Hemoglobin < 75 g/L
d) Neutrophils < 1.5 × 109/L
e) Creatinine clearance (CrCl) <30 mL/min |
Opći kriteriji isključenja
1. Veći kirurški zahvat unutar 8 tjedana prije probira ili planirani veći kirurški zahvat unutar 12 mjeseci nakon randomizacije
2. Presađeni organi (izuzev presađivanja rožnice više od 3 mjeseca prije randomizacije)
3. Veći ishemijski događaj nepovezan s GCA unutar 12 tjedana prije probira
Kriteriji isključenja povezani s prethodnom ili usporednom terapijom
4. Istovremeno sudjelovanje u drugom kliničkom ispitivanju, izuzev opažajnih ispitivanja
5. Ranije liječenje lijekom KPL-301
6. Liječenje bilo kojim nebiološkim ispitivanim lijekom unutar 4 tjedna ili 5 poluvijekova ispitivanog sredstva, ovisno o tome što je duže, prije probira
7. Bilo koje biološke terapije koje izazivaju depleciju stanica (npr. anti-CD20) unutar 12 mjeseci prije 0. dana; ili ranije liječenje biološkim terapijama koje ne izazivaju depleciju stanica (kao što je sredstvo protiv faktora tumorske nekroze [TNF], anakinra, sredstvo protiv interleukinskog [IL]-6 receptora [npr. tocilizumab] ili abatacept) unutar 8 tjedana (ili 5 poluvijekova, ovisno o tome što je duže) prije probira
8. Liječenje alkilacijskim sredstvima unutar 12 tjedan prije probira
9. Intramuskularni, intravenski ili intraartikularni kortikosteroidi unutar 4 tjedna prije probira
10. Primanje živog (atenuiranog) cjepiva unutar 4 tjedan prije 0. dana
11. Liječenje hidroksiklorokinom, ciklosporinom A, azatioprinom, ciklofosfamidom ili mikofenolat mofetilom (MMF) unutar 4 tjedna prije probira
Kriteriji isključenja povezani s poviješću bolesti
12. Žene ispitanice koje su trudne, namjeravaju zatrudnjeti ili doje
13. Svako stanje koje bi, prema mišljenju ispitivača, utjecati na procjenu lijeka KPL-301 ili tumačenje sigurnosti ispitanika ili pomutiti rezultate ispitivanje
14. Poznata povijest alergije ili reakcije na bilo koju komponentu pripravka lijeka KPL-301 ili placeba ili na bilo koju drugu biološku terapiju ili prednizon ili bilo koji od njegovih pomoćnih tvari
15. Pozitivni ili 2 neodrediva rezultata na testu QuantiFERON.
16. Klinički značajna aktivna infekcija uključujući znakove/simptome koji ukazuju na infekciju, bilo koja značajna rekurentna ili kronična infekcija (uključujući pozitivno antitijelo na virus hepatitisa C [HCVAb]) ili bilo koja epizoda infekcije koja zahtijeva hospitalizaciju ili liječenje i.v. antibioticima unutar 12 tjedana prije probira. Ispitanici s oportunističkom infekcijom unutar 6 mjeseci prije probira bit će isključeni iz ispitivanja.
17. Ispitanici s kroničnom aktivnom infekcijom hepatitisom B koji su definirani u nastavku bit će isključeni iz ispitivanja:
• pozitivno na površinski antigen hepatitisa B (HbsAg)
• pozitivno na antitijelo na jezgru virusa hepatitisa B ali negativno na antitijelo na površinski antigen
18. Ispitanici izloženi visokom riziku od infekcije (npr. povijest poremećaja nasljedne ili stečene imunodeficijencije uključujući povijest poznate infekcije virusom humane imunodeficijencije [HIV]), povijest zaražene zglobne proteze u bilo kojem trenutku dok je proteza još uvijek in situ, čirevi na nogama, trajni urinarni kateter ili perzistentne ili rekurentne infekcije prsnog koša
19. Povijest raka u proteklih 10 godina izuzev karcinoma bazalnih stanica ili pločastih stanica kože ili in situ karcinoma cerviksa koji je tretiran i smatra se izliječenim
20. Dokaz o postojanju klinički nekontroliranog respiratornog oboljenja. Ispitivač treba pregledati podatke iz respiratornih procjena ispitanika uključi rendgen prsnog koša i testove funkcije pluća uključujući difuzijski kapacitet za ugljični monoksid (DLCO) obavljene tijekom razdoblja probira ili unutar 12 tjedana prije 0. dana ako su dostupni rezultati prethodnih procjena. Dostupni rezultati procjena testova funkcije pluća i difuzijskog kapaciteta za ugljični monoksid moraju imati vrijednosti ≥ 60 % od predviđenih za obavljena mjerenja i ne smiju imati nekontroliranu plućnu bolest. Ispitanikov režim lijekova ne smije biti značajno pojačan radi kontroliranja plućne bolesti unutar 12 tjedana prije 0. dana.
21. Povijest kroničnih infekcija dišnih puteva
22. Kongestivno zatajenje srca klase III ili IV prema klasifikaciji New York Heart Association (Kardiološkog udruženja New Yorka)
23. Bilo koje od sljedećih vrijednosti na pretragama krvi prilikom probira:
a) aspartat transaminaza (AST) > 2 × gornja granica normale (GGN)
b) alanih transaminaza (ALT) > 2 × GGN
c) hemoglobin < 75 g/l
d) neutrofili < 1,5 × 109/l
e) klirens kreatinina (CrCl) <30 ml/min
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to flare by week 26 defined as time from randomization to the first flare occurring within the first 26-weeks of the double-blind period |
| Vrijeme do ponovne pojave bolesti do 26. tjedna definirano kao vrijeme od randomizacije prve pojave bolesti |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Appro. 32 weeks after the start of the study |
| Približno 32 tjedna nakon početka ispitivanja |
|
| E.5.2 | Secondary end point(s) |
Time to flare by week 26 from randomization to first flare occurring within the first 26 weeks of the double-blind period in the per protocol population
Percentage of subjects who have completed the 26-week corticosteroid taper and who have a normal ESR
Percentage of subjects who have completed the 26-week corticosteroid taper and who have a normal CRP
Percentage of subjects who completed the 26-week corticosteroid taper and who have no signs/symptoms of GCA
Time to corticosteroid dose of zero mg/day
Cumulative steroid dose at Week 26 and at the end of the Washout Safety Follow-up Period
Change in clinical GCA assessments (including NRS and FACIT) over time
Change in quality-of-life over time
|
• postotak ispitanika u 26. tjednu s normalnim ESR-om
• postotak ispitanika na kraju randomiziranog liječenja s normalnim
ESR-om
• postotak ispitanika u 26. tjednu s normalnim CRP-om
• postotak ispitanika na kraju randomiziranog liječenja s normalnim
CRP-om
• vrijeme do nulte doze kortikosteroida
• kumulativna doza kortikosteroida u 26. tjednu i na kraju razdoblja
dvostruko slijepog liječenja
• promjena u kliničkim procjenama GCA (uključujući NRS i FACIT)
tijekom vremena
• promjena kvalitete života tijekom vremena |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Appro. 44 weeks after the start of the study |
| Približno 44 tjedna nakon početka ispitivanja |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| Belgium |
| Croatia |
| Estonia |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| Serbia |
| Slovenia |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| LVLS |
| Posljednji posjet posljednjeg uključenog ispitanika |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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