| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Renal Cell Carcinoma |
| Advanced Renal Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Kidney cancer that has spread to other parts of the body |
| Kidney cancer that has spread to other parts of the body |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| 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 |
The primary objective of the study is to demonstrate that lenvatinib in
combination with everolimus (Arm A) or pembrolizumab (Arm B) is
superior compared to sunitinib alone (Arm C) in improving progressionfree
survival (PFS) (by independent imaging review [IIR] using
Response Evaluation Criteria In Solid Tumors [RECIST 1.1]) as first-line
treatment in subjects with advanced renal cell carcinoma (RCC). |
| L¿obiettivo primario dello studio ¿ dimostrare che lenvatinib in combinazione con everolimus (Braccio A) o pembrolizumab (Braccio B) ¿ superiore rispetto a sunitinib in monoterapia (Braccio C) nel migliorare la sopravvivenza libera da progressione (PFS) (tramite analisi di diagnostica per immagini indipendente [IIR] utilizzando i criteri di valutazione della risposta nei tumori solidi [RECIST 1.1]) come trattamento di prima linea nei soggetti affetti da carcinoma a cellule renali (RCC) avanzato. |
|
| E.2.2 | Secondary objectives of the trial |
¿To compare objective response rate (ORR) of subjects treated with
lenvatinib in combination with everolimus or pembrolizumab versus
sunitinib.
¿To compare overall survival (OS) of subjects treated with lenvatinib in
combination with everolimus or pembrolizumab versus sunitinib.
¿To compare safety and tolerability of treatment with lenvatinib in
combination with everolimus or pembrolizumab versus sunitinib.
¿To compare the impact of treatment on Health-Related Quality of Life
¿To assess PFS on next-line of therapy (PFS2)
¿ To assess PFS based on investigator assessment per RECIST v.1.1
¿ To characterize the population pharmacokinetics (PK) of lenvatinib
when co-administered with everolimus or pembrolizumab.
¿ To characterize the population PK of everolimus and pembrolizumab
when co-administered with lenvatinib.
¿ To assess the PK/pharmacodynamic relationship between exposure
and efficacy/biomarkers/safety. |
To compare objective response rate (ORR) of subjects treated with
lenvatinib in combination with everolimus or pembrolizumab versus
sunitinib.
¿To compare overall survival (OS) of subjects treated with lenvatinib in
combination with everolimus or pembrolizumab versus sunitinib.
¿To compare safety and tolerability of treatment with lenvatinib in
combination with everolimus or pembrolizumab versus sunitinib.
¿To compare the impact of treatment on Health-Related Quality of Life
¿To assess PFS on next-line of therapy (PFS2)
¿ To assess PFS based on investigator assessment per RECIST v.1.1
¿ To characterize the population pharmacokinetics (PK) of lenvatinib
when co-administered with everolimus or pembrolizumab.
¿ To characterize the population PK of everolimus and pembrolizumab
when co-administered with lenvatinib.
¿ To assess the PK/pharmacodynamic relationship between exposure
and efficacy/biomarkers/safety. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological or cytological confirmation of RCC with a clear-cell
component (original tissue diagnosis of RCC is acceptable).
2. Documented evidence of advanced RCC.
3. At least 1 measurable target lesion according to RECIST 1.1 meeting
the following criteria:
• Lymph node (LN) lesion that measures at least 1 dimension as =1.5 cm
in the short axis
• Non-nodal lesion that measures =1.0 cm in the longest diameter
•The lesion is suitable for repeat measurement using computerized
tomography/magnetic resonance imaging (CT/MRI). Lesions that have
had external beam radiotherapy (EBRT) or locoregional therapy must
show radiographic evidence of disease progression based on RECIST 1.1
to be deemed a target lesion.
4. Male or female subjects age =18 years (or any age greater than 18
years of age if that age is considered to be an adult per the local
jurisdiction) at the time of informed consent
5. Karnofsky Performance Status (KPS) of =70.
6. Adequately controlled blood pressure (BP) with or without
antihypertensive medications, defined as BP =150/90 mmHg at
Screening and no change in antihypertensive medications within 1 week
before the Cycle 1/Day 1.
7. Adequate renal function defined as calculated creatinine clearance =
30 mL/min per the Cockcroft and Gault formula.
8. Adequate bone marrow function defined by:
• Absolute neutrophil count (ANC) =1500/mm3
• Platelets =100,000/mm3
• Hemoglobin =9 g/dL.
9. Adequate blood coagulation function defined by International
Normalized ratio (INR) =1.5 (except for subjects on warfarin therapy
where INR must be =3.0 prior to randomization).
10. Adequate liver function defined by:
• Total bilirubin =1.5 times the upper limit of normal (ULN) except for
unconjugated hyperbilirubinemia of Gilbert's syndrome.
• Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and
aspartate aminotransferase (AST) =3×ULN (in the case of liver
metastases =5×ULN), unless there are bone metastases. Subjects with
ALP values >3 times the ULN and known to have bone metastases can be
included.
11. Provide written informed consent.
12. Willing and able to comply with all aspects of the protocol.
|
1. Conferma istologica o citologica di RCC con un componente a cellule chiare (la diagnosi di RCC sul tessuto originale è accettabile).
2. Evidenza documentata di RCC avanzato.
3. Almeno 1 lesione target misurabile secondo RECIST 1.1 che soddisfa i seguenti criteri:
• Lesione del linfonodo (LN) che possiede almeno una dimensione pari a =1,5 cm nell’asse breve.
• Lesione non nodale che misura =1,0 cm nel diametro più lungo.
• La lesione è adatta per una ripetizione della misura tramite tomografia computerizzata/risonanza magnetica per immagini (TAC/RMI). Per essere considerate lesioni target, le lesioni che sono state sottoposte a radioterapia a fasci esterni (EBRT) o a terapie loco-regionali, devono mostrare evidenza di progressione della malattia secondo RECIST 1.1.
4. Soggetti di sesso maschile o femminile di età =18 anni (o qualsiasi età superiore a 18 anni se questa età è considerata età adulta in base alla giurisdizione locale) al momento del consenso informato.
5. Stato prestazionale di Karnofsky (KPS) =70.
6. Pressione sanguigna (BP) adeguatamente controllata con o senza farmaci antipertensivi, definita come BP =150/90 mmHg allo screening e nessuna variazione nei farmaci antipertensivi entro 1 settimana prima del Ciclo 1/Giorno 1.
7. Funzione renale adeguata definita da una clearance della creatinina calcolata =30 ml/min secondo la formula di Cockcroft-Gault.
8. Adeguata funzionalità del midollo osseo, definita come segue:
• Conta assoluta dei neutrofili (ANC) =1500/mm3.
• Piastrine =100.000/mm3.
• Emoglobina =9 g/dl.
9. Adeguata funzione di coagulazione del sangue definita dal rapporto internazionale normalizzato (INR) =1,5 (ad eccezione dei soggetti che seguono una terapia con warfarin, dove l’INR deve essere =3,0 prima della randomizzazione).
10. Adeguata funzionalità epatica, definita come segue:
• Bilirubina totale =1,5 volte il limite superiore della norma (ULN), ad eccezione dell’iperbilirubinemia non coniugata della sindrome di Gilbert.
• Fosfatasi alcalina (ALP), alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) =3 volte l’ULN (=5 volte l’ULN in caso di metastasi epatiche), a meno che non ci siano metastasi ossee. Possono essere inclusi soggetti con valori ALP >3 volte l’ULN e noti per avere metastasi ossee.
11. Consegna del consenso informato scritto.
12. Paziente disposto/a e in grado di agire in conformità a tutti gli aspetti del protocollo.
|
|
| E.4 | Principal exclusion criteria |
1. Subjects who have received any systemic anticancer therapy for RCC,
including anti-VEGF therapy, or any systemic investigational anticancer
agent. Prior adjuvant treatment with an investigational anticancer agent
is not allowed unless the investigator can provide evidence of subject's
randomization to placebo arm.
2. Subjects with CNS metastases are not eligible, unless they have
completed local therapy (eg, whole brain radiation therapy [WBRT],
surgery or radiosurgery) and have discontinued the use of
corticosteroids for this indication for at least 4 weeks before starting
treatment in this study. Any signs (eg, radiologic) or symptoms of brain
metastases must be stable for at least 4 weeks before starting study
treatment.
3. Active malignancy (except for RCC, definitively treated basal or
squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix
or bladder) within the past 24 months. Subjects with history of localized
& low risk prostate cancer are allowed in the study if they were treated
with curative intent and there is no PSA recurrence within the past 5
years.
4. Prior radiation therapy within 21 days prior to start of study treatment
with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start.
5. Subjects who are using other investigational agents or who had
received investigational drugs =4 weeks prior to study treatment start.
6. Received a live vaccine within 30 days of planned start of study
treatment (Cycle 1/Day 1). Note: The killed virus vaccines used for
seasonal influenza vaccines for injection are allowed; however intranasal
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are
not allowed within 30 days of C1D1.
7. Subjects with proteinuria >1+ on urine dipstick testing will undergo
24-h urine collection for quantitative assessment of proteinuria.
Subjects with urine protein =1 g/24 h will be ineligible
8. Fasting total cholesterol >300 mg/dL (or >7.75 mmol/L) and/or
fasting triglycerides level >2.5 x ULN. NOTE: these subjects can be
included after initiation or adjustment of lipid-lowering medication.
9. Uncontrolled diabetes as defined by fasting glucose >1.5 times the
ULN. Note: these subjects can be included after initiation or adjustment
of glucose-lowering medication.
10. Prolongation of QTc interval to >480 ms.
11. Subjects who have not recovered adequately from any toxicity
and/or complications from major surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any
other condition that might affect the absorption of lenvatinib,
everolimus, and/or sunitinib.
13. Bleeding or thrombotic disorders or subjects at risk for severe
hemorrhage. The degree of tumor invasion/infiltration of major blood
vessels (eg, carotid artery) should be considered because of the
potential risk of severe hemorrhage associated with tumor
shrinkage/necrosis following lenvatinib therapy.
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks
prior to the first dose of study drug.
15. Significant cardiovascular impairment within 6 months of the first
dose of study drug: history of congestive heart failure greater than New
York Heart Association (NYHA) Class II, unstable angina, myocardial
infarction or stroke, cardiac arrhythmia associated with significant
cardiovascular impairment, or a left ventricular ejection fraction (LVEF)
below the institutional normal range as determined by MUGA or
echocardiogram.
16. Active infection (any infection requiring systemic treatment).
17. Subjects known to be positive for Human Immunodeficiency Virus
(HIV).
18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg,
HCV RNA [qualitative] is detected).
19. Known history of, or any evidence of, interstitial lung disease.
20.Has a history of (non-infectious) pneumonitis that required steroids,
or current pneumonitis
21. Any medical or other condition that in the opinion of the
investigator(s) would preclude the subject's participation in a clinical
study.
22. Subjects with a diagnosis of immunodeficiency or who are receiving
systemic steroid therapy or any other form of immunosuppressive
therapy within 7 days prior to the first dose of study treatment.
23. Active autoimmune disease (with the exception of psoriasis) that has
required systemic treatment in the past 2 years.
24. Females who are breastfeeding or pregnant at Screening or Baseline.
25. Females of childbearing potential who do not agree to use a highly
effective method of contraception for the entire study period and for 120
days after study discontinuation.
26. Males who have not had a successful vasectomy and do not agree to
use condom + spermicide OR have a female partner who does not meet
the criteria above.
27. Known intolerance to any of the study drugs (or any of the excipients).
|
1. Subjects who have received any systemic anticancer therapy for RCC,
including anti-VEGF therapy, or any systemic investigational anticancer
agent. Prior adjuvant treatment with an investigational anticancer agent
is not allowed unless the investigator can provide evidence of subject's
randomization to placebo arm.
2. Subjects with CNS metastases are not eligible, unless they have
completed local therapy (eg, whole brain radiation therapy [WBRT],
surgery or radiosurgery) and have discontinued the use of
corticosteroids for this indication for at least 4 weeks before starting
treatment in this study. Any signs (eg, radiologic) or symptoms of brain
metastases must be stable for at least 4 weeks before starting study
treatment.
3. Active malignancy (except for RCC, definitively treated basal or
squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix
or bladder) within the past 24 months. Subjects with history of localized
& low risk prostate cancer are allowed in the study if they were treated
with curative intent and there is no PSA recurrence within the past 5
years.
4. Prior radiation therapy within 21 days prior to start of study treatment
with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start.
5. Subjects who are using other investigational agents or who had
received investigational drugs =4 weeks prior to study treatment start.
6. Received a live vaccine within 30 days of planned start of study
treatment (Cycle 1/Day 1). Note: The killed virus vaccines used for
seasonal influenza vaccines for injection are allowed; however intranasal
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are
not allowed within 30 days of C1D1.
7. Subjects with proteinuria >1+ on urine dipstick testing will undergo
24-h urine collection for quantitative assessment of proteinuria.
Subjects with urine protein =1 g/24 h will be ineligible
8. Fasting total cholesterol >300 mg/dL (or >7.75 mmol/L) and/or
fasting triglycerides level >2.5 x ULN. NOTE: these subjects can be
included after initiation or adjustment of lipid-lowering medication.
9. Uncontrolled diabetes as defined by fasting glucose >1.5 times the
ULN. Note: these subjects can be included after initiation or adjustment
of glucose-lowering medication.
10. Prolongation of QTc interval to >480 ms.
11. Subjects who have not recovered adequately from any toxicity
and/or complications from major surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any
other condition that might affect the absorption of lenvatinib,
everolimus, and/or sunitinib.
13. Bleeding or thrombotic disorders or subjects at risk for severe
hemorrhage. The degree of tumor invasion/infiltration of major blood
vessels (eg, carotid artery) should be considered because of the
potential risk of severe hemorrhage associated with tumor
shrinkage/necrosis following lenvatinib therapy.
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks
prior to the first dose of study drug.
15. Significant cardiovascular impairment within 6 months of the first
dose of study drug: history of congestive heart failure greater than New
York Heart Association (NYHA) Class II, unstable angina, myocardial
infarction or stroke, cardiac arrhythmia associated with significant
cardiovascular impairment, or a left ventricular ejection fraction (LVEF)
below the institutional normal range as determined by MUGA or
echocardiogram.
16. Active infection (any infection requiring systemic treatment).
17. Subjects known to be positive for Human Immunodeficiency Virus
(HIV).
18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg,
HCV RNA [qualitative] is detected).
19. Known history of, or any evidence of, interstitial lung disease.
20.Has a history of (non-infectious) pneumonitis that required steroids,
or current pneumonitis
21. Any medical or other condition that in the opinion of the
investigator(s) would preclude the subject's participation in a clinical
study.
22. Subjects with a diagnosis of immunodeficiency or who are receiving
systemic steroid therapy or any other form of immunosuppressive
therapy within 7 days prior to the first dose of study treatment.
23. Active autoimmune disease (with the exception of psoriasis) that has
required systemic treatment in the past 2 years.
24. Females who are breastfeeding or pregnant at Screening or Baseline.
25. Females of childbearing potential who do not agree to use a highly
effective method of contraception for the entire study period and for 120
days after study discontinuation.
26. Males who have not had a successful vasectomy and do not agree to
use condom + spermicide OR have a female partner who does not meet
the criteria above.
27. Known intolerance to any of the study drugs (or any of the excipients). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) by independent review is defined as
the time from the date of randomization to the date of the first
documentation of disease progression or death (whichever occurs first)
as determined by IIR using RECIST 1.1. PFS censoring rules will follow
the FDA guidance of 2007; specifics of this will be detailed in the
Statistical Analysis Plan. |
| • La sopravvivenza libera da progressione (PFS) stabilita da una revisione indipendente è definita come l’intervallo di tempo dalla data di randomizzazione alla data di prima documentazione di progressione della malattia o di decesso (a seconda di quale evento si verifichi per primo) determinati dall’IIR tramite RECIST 1.1. Le regole di eliminazione per la PFS seguiranno le linee guida della FDA del 2007; informazioni più dettagliate a riguardo sono fornite nel Piano di analisi statistica. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary PFS analysis will be performed when a total of at least 551
PFS events (as determined by IIR) are observed among the 3 treatment
arms. Assuming an enrolment rate of 30 subjects per month, a final
analysis of PFS will occur approximately 37 months (25 months
enrolment period and 12 months follow up period) after first subject is
randomized. |
The primary PFS analysis will be performed when a total of at least 551
PFS events (as determined by IIR) are observed among the 3 treatment
arms. Assuming an enrolment rate of 30 subjects per month, a final
analysis of PFS will occur approximately 37 months (25 months
enrolment period and 12 months follow up period) after first subject is
randomized. |
|
| E.5.2 | Secondary end point(s) |
Objective response rate (ORR) is defined as the proportion of subjects
who have best overall response of CR or PR as determined by IIR using
RECIST 1.1.
¿ Overall survival (OS) is defined as the time from the date of
randomization to the date of death from any cause. Subjects who are
lost to follow-up and those who are alive at the date of data cut-off will
be censored at the date the subject was last known alive, or date of data
cut-off, whichever occurs first.
¿ Safety will be assessed summarizing the incidence of treatmentemergent
adverse events (TEAEs) and SAEs together with all other
safety parameters.
¿ Proportion of subjects who discontinued treatment due to toxicity is
defined as the proportion of subjects who discontinue study treatment
due to treatment-emergent adverse events (TEAEs).
¿ Time to treatment failure due to toxicity is defined as the time from the
date of randomization to the date that a subject discontinues study
treatment due to TEAEs.
¿ Health-Related Quality of Life (HRQoL) will be assessed using the
Functional Assessment of Cancer Therapy Kidney Syndrome Index-
Disease-Related Symptoms (FKSI-DRS), the European Organization for
the Research and Treatment of Cancer (EORTC) QLQ-C30 and the
European Quality of Life (EuroQOL) EQ-5D-3L instruments.
¿ PFS on next-line of therapy (PFS2) is defined as the time from
randomization to disease progression on next-line of treatment, or death
from any cause, (whichever occurs first).
¿ Progression-free survival (PFS) by investigator assessment is defined
as the time from the date of randomization to the date of first
documentation of disease progression based on the investigator
assessment per RECIST v.1.1 or death (whichever occurs first).
¿ Model-predicted clearance and AUC for lenvatinib in Arms A and B.
¿ Model-predicted clearance and AUC for everolimus in Arm A, and
pembrolizumab in Arm B.; ¿ Il tasso di risposta obiettivo (ORR) ¿ definito come la percentuale di soggetti con la miglior risposta complessiva di CR o PR determinata dall¿IIR tramite RECIST 1.1.
¿ La sopravvivenza complessiva (OS) ¿ definita come il tempo trascorso dalla data della randomizzazione alla data del decesso per qualsiasi causa. I soggetti persi al follow-up e quelli in vita alla data del cutoff dei dati saranno eliminati all¿ultima data nota in cui il soggetto era vivo, oppure alla data del cutoff dei dati, a seconda di quale evento avviene per primo.
¿ La sicurezza verr¿ valutata sintetizzando l¿incidenza degli eventi avversi emergenti dal trattamento (TEAE) e i SAE insieme ad altri parametri di sicurezza.
¿ La percentuale di soggetti che interrompono il trattamento a causa di tossicit¿ ¿ definita come la percentuale di soggetti che interrompono il trattamento dello studio a causa di eventi avversi emergenti dal trattamento (TEAE).
¿ Il tempo al fallimento del trattamento dovuto a tossicit¿ ¿ definito come il tempo dalla data di randomizzazione alla data in cui un soggetto interrompe il trattamento dello studio a causa di TEAE.
¿ La qualit¿ di vita correlata alla salute (HRQoL) sar¿ valutata tramite l¿Indice della valutazione funzionale della terapia tumorale-sintomi renali correlati alla malattia (FKSI-DRS), QLQ-C30 dell¿Organizzazione europea per la ricerca e il trattamento del tumore (EORTC) e il questionario europeo sulla qualit¿ della vita (EuroQOL) EQ-5D-3L.
¿ La PFS sulla linea di terapia successiva (PFS2) ¿ definita come il tempo dalla randomizzazione alla progressione della malattia sulla linea di trattamento successiva, oppure il decesso per qualsiasi causa (a seconda di quale evento avviene per primo).
¿ La sopravvivenza libera da progressione (PFS) secondo la valutazione dello sperimentatore ¿ definita come il tempo dalla data di randomizzazione alla data della prima documentazione di progressione della malattia sulla base della valutazione dello sperimentatore secondo RECIST v1.1 o al decesso (a seconda di quale evento avviene per primo).
¿ La clearance e l¿area sottesa alla curva (AUC) stimate mediante modello per levantinib nei bracci A e B.
¿ La clearance e l¿area sottesa alla curva (AUC) stimate mediante modello per everolimus nel braccio A e per pembrolizumab nel braccio B.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As per primary endpoint. |
| Come per l'end point primario |
|
| 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 | 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 78 |
| 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 |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Switzerland |
| United States |
|
| 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
|
| Date of the data cutoff for the final analysis or last subject/last visit, including discontinuation from the study for any reason, whichever occurs later. |
| Date of the data cutoff for the final analysis or last subject/last visit, including discontinuation from the study for any reason, whichever occurs later. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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