| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or Metastatic hepatocellular carcinoma (HCC) |
| CARCINOMA EPATOCELLULARE LOCALMENTE AVANZATO |
|
| E.1.1.1 | Medical condition in easily understood language |
| HCC is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis |
| L'HCC è una malignità primaria del fegato e si verifica prevalentemente in pazienti con patologie epatiche croniche e cirrosi |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077737 |
| E.1.2 | Term | Hepatocellular carcinoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077736 |
| E.1.2 | Term | Hepatocellular carcinoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077738 |
| E.1.2 | Term | Hepatocellular carcinoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of atezolizumab + bevacizumab compared with sorafenib based on overall survival (OS) and progression-free survival (PFS) as determined by the independent review facility (IRF) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
| Valutare l’efficacia di atezolizumab + bevacizumab rispetto a sorafenib, sulla base di sopravvivenza globale (OS) e PFS, intesa come prima occorrenza di progressione di malattia, secondo quanto stabilito dall’IRF in base ai criteri RECIST v1.1 |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate :
• efficacy of atezolizumab + bevacizumab compared with sorafenib based on objective response (OR)
• time to progression (TTP), duration of response (DOR) determined by investigator ; IRF according to RECIST v 1.1 and OR, PFS, TTP, DOR by IRF according to HCC modified (m) RESIST v 1.1
• the association of prespecified biomarkers with efficacy of atezolizumab+ bevacizumab compared with sorafenib based on PFS as determined by the investigator and by an IRF according to RECIST v1.1 and OS
• patient-reported outcome of disease/treatment-related symptoms, health-related quality of life / global health status, function experienced by patients on atezolizumab + bevacizumab versus sorafenib based on TTP |
Valutare:
- l’efficacia di atezolizumab + bevacizumab rispetto a sorafenib sulla base della risposta obiettiva (OR)
- TTP, inteso come il tempo intercorso tra la randomizzazione e la prima comparsa di progressione della malattia, secondo quanto stabilito dallo sperimentatore in base ai criteri RECIST v1.1
- la correlazione tra biomarcatori predefiniti e l’efficacia di atezolizumab + bevacizumab rispetto a sorafenib, sulla base di PFS secondo quanto stabilito dall osperimentatore e dall’IRF in base ai criteri RECIST v1.1 e OS
- Valutare i PRO (in termini di sintomi della malattia/correlati al trattamento, HRQoL/GHS/QoL e funzionalità) manifestati dai pazienti trattati con atezolizumab + bevacizumab rispetto a sorafenib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >= 18 years
- Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/ cytology or clinically by American Association for the Study of Liver Diseases criteria in cirrhotic patients
- Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies
- No prior systemic therapy (including systemic investigational agents) for HCC
- At least one measurable (per RECIST 1.1) untreated lesion
- Patients who received prior local therapy are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST v1.1
- Pre-treatment tumor tissue sample (if available)
- ECOG Performance Status of 0 or 1 within 7 days prior to randomization
- Child-Pugh class A within 7 days prior to randomization
- Adequate hematologic and end-organ function
- Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade <= 1 prior to study entry, with the exception of alopecia
- Negative HIV test at screening
- Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test
- For patients with active hepatitis B virus, HBV DNA 500 IU/mL obtained within 28 days prior to initiation of study treatment and anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study
- For women of childbearing potential: agreement to remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last dose of sorafenib. Women must refrain from donating eggs during this same period
- For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 6 months after the last dose of bevacizumab or 3 months after the last dose of sorafenib |
- Età >= 18 anni
- HCC localmente avanzato o metastatico e/o non resecabile con diagnosi confermata dall’esame istologico/citologico o in termini clinici nei pazienti cirrotici secondo i criteri dell’American Association for the Study of Liver Diseases (AASLD).
- Malattia non candidabile a terapie curative chirurgiche e/o locoregionali o progressione della malattia dopo terapie chirurgiche e/o locoregionali
- Nessuna precedente terapia sistemica (inclusi agenti sistemici sperimentali) per l’HCC
- Almeno una lesione misurabile (secondo i criteri RECIST 1.1) non trattata.
- I pazienti precedentemente sottoposti a terapia locale saranno ritenuti idonei a condizione che la o le lesioni bersaglio non siano state precedentemente trattate con terapia locale o che la o le lesioni bersaglio nel campo della terapia locale siano andate successivamente incontro a progressione secondo i criteri RECIST, versione 1.1.
- Campione di tessuto tumorale pre-trattamento (se disponibile)
- Performance status secondo l’Eastern Cooperative Oncology Group (ECOG) pari a 0 o 1, entro i 7 giorni precedenti la randomizzazione
- Classe Child-Pugh A entro i 7 giorni precedenti la randomizzazione
- Adeguata funzionalità ematologica, epatica e renale
- Risoluzione di eventuali tossicità acute clinicamente significative correlate al trattamento derivanti dalla precedente terapia a un grado <= 1 prima dell’ingresso nello studio, fatta eccezione per l’alopecia.
- Test di screening negativo per il virus dell’immunodeficienza umana (HIV).
- Stato virologico documentato di epatite confermato dal test sierologico di screening per il virus dell’epatite B (HBV) e C (HCV).
- Nei pazienti con HBV attivo: HBV-DNA 500 UI/ml nei 28 giorni precedenti l’inizio del trattamento in studio e Trattamento anti-HBV (secondo la terapia standard locale, per es. entecavir) per almeno 14 giorni prima dell’ingresso nello studio e volontà di proseguire la terapia per l’intera durata della sperimentazione.
- Nelle donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o ad adottare metodi contraccettivi con un tasso di insuccesso inferiore all'1% all’anno durante il periodo di trattamento e per almeno 5 mesi dopo l’ultima dose di atezolizumab, 6 mesi dopo l’ultima dose di bevacizumab o 1 mese dopo l’ultima dose di sorafenib. Le donne devono astenersi dal donare ovociti durante lo stesso periodo
- Per gli uomini: consenso a praticare l’astinenza o ad adottare metodi contraccettivi, nonché consenso ad astenersi dalla donazione del seme periodo di trattamento e per almeno 6 mesi dopo l’ultima dose di bevacizumab o 3 mesi dopo l’ultima dose di sorafenib |
|
| E.4 | Principal exclusion criteria |
-H.of leptomeningeal disease, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest TC scan
-Active/h.of autoimmune disease or immune deficiency, known active tuberculosis, moderate/severe ascites
-Sign. cardiovascular disease within 3 m prior initiation study treat, unstable arrhythmia or unstable angina
-H.of congenital long QT syndrome or corrected QT interval>500 ms at screening and uncorrectable electrolyte disorder affecting serum level of K, Ca, or Mg
-Major surgical procedure within 4w prior initiation of study treat or anticipation of need for a major surgical procedure during the study
-H.of malignancy other than HCC within 5y prior screening with the exception of malignancies with a negligible risk of metastasis or death and hepatic encephalopathy
-Treat with therapeutic oral or IV antibiotics within 2w prior initiation study treat, a live attenuated vaccine within 4w prior initiation study treat or anticipation of need for such a vaccine during atezo treat or within 5m after last dose of atezo
-Prior allogeneic stem cell or solid organ transp, Prior treat with CD137agonists or immune checkpoint blockade therapies, including antiCTLA4, antiPD1 and antiPDL1 therapeutic antibodies
-Any other disease, metabolic dysfunction, physical examination finding or clinical lab finding that contraindicates the use of an investing drug, may affect the interpretation of the results or may render the patient at high risk from treat complications
-Known hypers. to CHO cell products or to any component of the atezo or bevacizumab formulation
-Fibrolamellar and sarcomatoid HCC or mixed cholangiocarcinoma and HCC
-Pregnancy/breastfeeding/intention of becoming pregnant during study treat or within at least 5m after last dose atezo, 6m after last dose bevacizumab or 1m after last dose sorafenib
-P. with untreated/incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding
-A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
-Coinfection of hepatitis B/C virus
-Symptomatic, untreated or actively progressing SNC metastases
-Uncontrolled: tumor-related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
-Uncontrolled/symptomatic hypercalcemia
-Treat with: investing.therapy within 28 d prior study treat, strong CYP3A4 inducers within 14d prior study treat, systemic immunostimulatory agents and immunosuppressive medication within 4w or 5 half-lives of the drug and 2w prior initiation of study treat or anticipation of need for systemic immunosupp. medication during study treat
-Inadequately controlled arterial hypert.
-Sign. vascular disease within 6m prior initiation of study treat
-Metastatic disease that involves major airways or blood vessels or centrally located mediastinal tumor masses of large volume
-Evidence of bleeding diathesis or sign. coagulopathy
-Current/recent use of aspirin or treat with dipyramidole, ticlopidine, clopidogrel, and cilostazol and current/recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic p.
-H. of abdo. or tracheoesophageal fistula, GI perforation or intra-abdo. abscess and intra-abdo. inflammatory process within 6m prior study treat, intestinal obstruction and/or clinical signs or symptoms of GI obstruction within 6m prior study treat
-Evidence of abdom. free air that is not explained by paracentesis or recent surgical procedure
-Radiotherapy within 28d and abdominal/ pelvic radiotherapy within 60d prior initiation of study treat, except palliative radiot. to bone lesions within 7d prior study treat
- Local therapy to liver within 28 days prior to initiation of study treatment
-Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment |
-Anamnesi + per malattia leptomeningea e per fibrosi polmonare idiopatica, polmonite in organizzazione, polmonite indotta da f. o polmonite idiopatica, oppure evidenza di polmonite attiva alla TC del torace allo screening
-Presenza di o anamnesi positiva per malattia autoimmune o immunodef., Tubercolosi attiva nota, ascite moderata o severa
-Cardiovasculopatia signif. nei 3m precedenti inizio tratt in studio, aritmia instabile o angina instabile
-Anamnesi + per sindrome del QT lungo congenita o dell'intervallo QT corretto>500 ms allo screening e Anamnesi di disordine elettrolitico non correggibile che influenza livelli sierici di K, Ca o Mg
-Procedura chirurgica maggiore, per ragioni diverse dalla diagnosi, nelle 4 sett precedenti inizio tratt in studio o necessità prevista di procedura chirurgica maggiore durante studio
-Anamnesi + per neoplasia maligna diversa dall’HCC nei 5 anni precedenti lo screening, fatta eccezione per quelle soggette a rischio trascurabile di metastasi o decesso e encefalopatia epatica
-Tratt con antibiotici terapeutici orali o e.v. nelle 2 sett precedenti inizio tratt in studio, tratt con vaccino vivo attenuato nelle 4 sett precedenti inizio tratt in studio o necessità prevista di somministrare un tale vaccino durante tratt con atezo o nei 5m successivi ultima dose di atezo
-Tratt precedente con agonisti CD137 o terapie che bloccano i punti di controllo immunitari, tra cui anticorpi terapeutici antiCTLA-4, antiPD-1 e antiPD-L1
-Qualsiasi altra m., disfunzione metabolica, obiettività o referto di lab che rappresenti una controindicazione all’uso di un farmaco sperimentale, che possa interferire con l’interpretazione dei risultati o che esponga il p. ad alto rischio complicanze correlate al tratt
-Ipersens. nota ai prodotti contenenti cellule CHO o a qualsiasi componente della formulazione di atezo o bevacizumab
-HCC fibrolamellare, HCC sarcomatoide o colangiocarcinoma-HCC misto noti
-Gravidanza o allattamento o intenzione di iniziare una gravidanza durante tratt studio o entro almeno 5m dopo ultima dose atezo, 6m dopo ultima dose bevacizumab o 1m dopo ultima dose sorafenib
-Varici esofagee e/o gastriche non tratt o tratt in modo incompleto con sanguinamento o ad alto rischio di sanguinamento
-Precedenti eventi di sanguinamento per varici esofagee e/o gastriche nei 6 mesi precedenti l'inizio del trattamento in studio
-Co-infezione da HBV e HCV
-Metastasi a carico del SNC sintomatiche, non trattate o in progressione attiva
-Dolore non controllato correlato al tumore
-Versamento pleurico non controllato, versamento pericardico o ascite che necessita di ricorrenti procedure di drenaggio
-Ipercalcemia non controllata o sintomatica
-Tratt con: terapia sperimentale nei 28 gg precedenti inizio tratt in studio, potenti induttori di CYP3A4 nei 14 gg precedenti inizio tratt in studio, immunostimolanti sistemici nelle 4 sett o nelle 5 emivite del farmaco precedenti inizio tratt in studio
-Ipert. arteriosa non adeguatamente controllata
-Vasculopatia signif. nei 6 mesi precedenti inizio tratt in studio
-M. metastatica che interessa le principali vie aree o vasi sanguigni o masse tumorali mediastiniche localizzate a livello centrale di grosso volume
-Evidenze di aria libera a livello add. non spiegata da paracentesi o da una recente procedura chirurgica
-Uso concomitante/recente di aspirina o tratt con dipiridamolo, ticlopidina, clopidogrel e cilostazolo e concomitante/recente uso di anticoagulanti o agenti trombolitici orali o parenterali a dose piena per finalità terapeutiche
-Radioterapia nei 28 gg precedenti inizio tratt in studio e radioterapia addominale/pelvica nei 60 gg precedenti inizio tratt in studio, fatta eccezione per radioterapia palliativa delle lesioni ossee nei 7 gg precedenti inizio tratt in studio
-Terapia locale al fegato entro 28 giorni prima dell'inizio del trattamento di studio
-Procedura chirurgica maggiore, biopsia aperta o lesione traumatica significativa nei 28d precedenti l’inizio del |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) OS
2) PFS as determined by the IRF according to RECIST v1.1 |
1) OS
2) PFE secondo quanto stabilito dall'IRF in base ai criteri RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) From randomization to death from any cause
2) From randomization to the occurrence of disease or death from any cause |
1) dalla randomizzazione al decesso per ogni causa
2) intesa come il tempo dalla randomizzazione alla prima occorrenza di progressione di malattia in base ai criteri RECIST v1.1 o, decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo. |
|
| E.5.2 | Secondary end point(s) |
1) ORR, by IRF per RECIST 1.1
2) PFS, by investigator and IRF, per RECIST 1.1
3) TTP, by investigator and IRF, per RECIST 1.1
4) DOR, by investigator and IRF, per RECIST 1.1
5) OR as determined by the investigator and by an IRF according to RECIST v1.1
6) OS by baseline serum a-fetoprotein level
7) Time to deterioration determined by European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for cancer subscales, including HRQoL/GHS, physical and role functioning |
1) ORR, sulla base di IRF e RECIST 1.1
2) PFS, secondo quanto stabilito dallo sperimentatore in base ai criteri RECIST v1.1
3) TTP, secondo quanto stabilito dallo sperimentatore in base ai criteri RECIST v1.1
4) DOR, secondo quanto stabilito dallo sperimentatore in base ai criteri RECIST v1.1
5) OR secondo quanto stabilito dallo sperimentatore e dall'IRF in base ai criteri RECIST v1.1
6) OS, in funzione del livello sierico dell'alfafetoproteina
7) Tempo di peggioramento determinato secondo le seguenti sottoscale del questionario EORTC QLQ-C30: HRQoL/GHS, Funzionalità fisica, Funzionalità nel ruolo |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) At 6 months after the last patient is enrolled which us anticipated to occur Up to 22 months after FPI
2) From randomization to from randomization to the first occurrence of disease progression or death from any cause
3) From the date of randomization to the date of the first documented tumor progression
4) From the first occurrence of a documented objective response to disease progression or death from any cause
5) At 6 months after the last patient is enrolled which us anticipated to occur 22 months after FPI
6) From randomization to death from any cause
7) From time from randomization to first deterioration |
1) effettuata 6 mesi dopo l’arruolamento dell’ultimo paziente, che si prevede avrà luogo circa 22 mesi dopo la randomizzazione del primo paziente
2) tra la randomizzazione e la prima comparsa di progressione della malattia o il decesso per qualsiasi causa
3) tra la randomizzazione e la prima comparsa di progressione della malattia
4) tra la prima comparsa di una risposta obiettiva documentata e la progressione della malattia o il decesso per qualsiasi causa
5) effettuata 6 mesi dopo l’arruolamento dell’ultimo paziente, che si prevede avrà luogo circa 22 mesi dopo la randomizzazione del primo paziente
6) dalla randomizzazione al decesso per ogni causa
7) dalla randomizzazione al primo peggioramento |
|
| 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 | No |
| 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 |
| Immunogenicity, Biomarker and Health status objectives |
| Immunogenicità, Obiettivi in termine di Biomarker e condizioni di salute |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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.8.2.4 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 | Information not present in EudraCT |
| 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 |
| Canada |
| China |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Singapore |
| Taiwan |
| Thailand |
| United States |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
| Czechia |
| Argentina |
|
| E.8.7 | Trial 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
|
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs (i.e., last patient in the global and extended China enrollment phases combined) or safety follow-up is received from the last patient (global and extended China enrollment phases combined), whichever occurs later.
In addition, the Sponsor may decide to terminate the study at any time. |
| La fine dello studio coinciderà con la data in cui avrà luogo l’ultima visita dell’ultimo p. (LPLV; da intendersi come l’ultimo p. della fase di arruolamento globale e della fase di arruolamento esteso cinese combinate) o con la data di ricezione del follow-up di sicurezza dell’ultimo p. (fase di arruolamento globale e fase di arruolam. esteso cinese combinate), a seconda di quale evento si verifichi per ultimo. Lo Sponsor potrà inoltre decidere di interrompere la ricerca in qualsiasi momento |
|
| 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 | 7 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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