| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Malignant Cutaneous Melanoma |
| Melanoma cutaneo maligno avanzato |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced skin cancer |
| Cancro della cute avanzato |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| 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 | 10025671 |
| E.1.2 | Term | Malignant melanoma 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025670 |
| E.1.2 | Term | Malignant melanoma 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025655 |
| E.1.2 | Term | Malignant melanoma of skin |
| 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 |
Phase Ib: To characterize the safety and tolerability, and subsequently identify the MTD or RP2D, of the combination of durvalumab or tremelimumab with IMCgp100 (Arms 1 and 2) and tremelimumab +
durvalumab with IMCgp100 (Arm 3). To describe the safety of singleagent IMCgp100 at doses higher than 68 mcg on a weekly basis (Arm 4a); identify the MTD or RP2D of single-agent IMCgp100 administered at doses higher than 68 mcg on a weekly basis (Arm 4a) using a slower intra-patient dose escalation. To describe the safety of administering single-agent IMCgp100 at a dose of 68 mcg three times per week (Arm 4b).
Phase II: To evaluate the ORR of IMCgp100 using RECIST v.1.1 criteria as a single agent (Arm 4) and in combination with checkpoint inhibition with durvalumab (Arm 1), tremelimumab (Arm 2), or the combination of durvalumab and tremelimumab (Arm 3). |
Fase Ib: identificare la dose massima tollerata (maximum tolerated dose, MTD) o la dose raccomandata per la fase II (recommended Phase II dose, RP2D) della combinazione di durvalumab o tremelimumab con IMCgp100 (Bracci 1 e 2) e tremelimumab + durvalumab con IMCgp100 (Braccio 3). Descrivere la sicurezza di IMCgp100 come singolo agente a dosi superiori a 68 mcg somministrato una volta alla settimana (Braccio 4a); identificare la MTD o RP2D di IMCgp100 come singolo agente a dosi superiori a 68 mcg somministrato una volta alla settimana (Braccio 4a) mediante un aumento progressivo della dose intra-paziente più lento. Descrivere la sicurezza di IMCgp100 come singolo agente somministrato a una dose di 68 mcg tre volte alla settimana (Braccio 4b).
Fase II: usando i criteri di valutazione della risposta nei tumori solidi (Response Evaluation Criteria in in Solid Tumors, RECIST) v1.1, valutare il tasso di risposta obiettiva (objective response rate, ORR) di IMCgp100 come singolo agente (Braccio |
|
| E.2.2 | Secondary objectives of the trial |
To characterize the safety and tolerability of single agent IMCgp100 (given alone in Arm 4) and in combination with durvalumab and/or tremelimumab.
To characterize the PK profile of single agent IMCgp100 (given alone in Arm 4) and in combination with durvalumab and/or tremelimumab in Arms 1, 2, and 3.
To assess potential predictors of efficacy of gp100 and/or PDL1 expression or baseline lactate dehydrogenase (LDH) level with IMCgp100 in combination with durvalumab and/or tremelimumab in Arms 1, 2, and 3 and IMCgp100 alone in Arm 4.
To assess the preliminary anti tumor efficacy of IMCgp100 alone and in combination with durvalumab and/or tremelimumab.
To evaluate the incidence of anti IMCgp100, anti durvalumab and anti tremelimumab antibody formation following multiple infusions of IMCgp100 alone and in combination with durvalumab and/or tremelimumab. |
Caratterizzare la sicurezza e la tollerabilit¿ di IMCgp100 come singolo agente (somministrato in monoterapia nel Braccio 4) e in combinazione con durvalumab e/o tremelimumab
¿ Caratterizzare il profilo PK di IMCgp100 come singolo agente (somministrato in monoterapia nel Braccio 4) e in combinazione con durvalumab e/o tremelimumab nei Bracci 1, 2 e 3
¿ Valutare i potenziali fattori predittivi dell¿efficacia di gp100 e/o dell¿espressione di PD-L1 o del livello di lattato deidrogenasi (lactate dehydrogenase, LDH) al basale con IMCgp100 in combinazione con durvalumab e/o tremelimumab nei Bracci 1, 2 e 3 e IMCgp100 in monoterapia nel Braccio 4
¿ Valutare l¿efficacia antitumorale preliminare di IMCgp100 in monoterapia e in combinazione con durvalumab e/o tremelimumab
¿ Valutare l¿incidenza della formazione di anticorpi anti-IMCgp100, anti-durvalumab e anti-tremelimumab in seguito a infusioni multiple di IMCgp100 in monoterapia e in combinazione con durvalumab e/o tremelimumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age = 18 years
2. Written informed consent must be obtained from all patients prior to any study procedures.
3. Patients with advanced non-uveal melanoma defined as unresectable Stage III or metastatic Stage IV disease. Patients with acral or mucosal melanoma are acceptable. Patients with melanoma of unknown primary source are acceptable for Phase Ib cohorts (Arms 1 to 4), but are excluded in Phase II cohorts. Patients with the diagnosis of uveal melanoma are excluded from all cohorts
4. Phase Ib Arm 4 and Phase II: Patients with disease progression following initiation of treatment with an approved PD-1 inhibitor. No prior cytotoxic therapy in the advanced setting is permitted. Patients
with BRAF mutations must be refractory to approved BRAF-based therapy. CTLA-4-inhibition therapy is acceptable as a prior line of therapy or in combination with anti-PD-1 therapy
5. Note: intentionally left blank by Sponsor in order to align with Protocol revision.
6. Phase Ib Arms 1, 2 and 3: no restriction on prior therapy
7. Human leukocyte antigen-A*0201 (HLA- A*0201) positive
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
9. Life expectancy of at least 3 months
10. Phase II cohorts only: patients must have measurable disease according to RECIST v.1.1 criteria. Patients enrolled in Phase Ib cohorts must have evaluable disease
11. Phase Ib Arm 4 and Phase II cohorts only: Patients must have a site of disease amenable to biopsy that is not an index lesion, and be a candidate for tumor biopsy according to the treating institution's guidelines. Phase Ib Arms 1-3 patients need not have disease accessible to biopsy
12. Those receiving prior immunotherapy must meet all of the following conditions:
-Must not have experienced an immune-related adverse event(irAE) which was the reason for permanent discontinuation of prior immunotherapy in the most recent prior treatment regimen.
- All irAEs while receiving prior immunotherapy must have resolved to = grade 1 or Baseline prior to Screening for this study. Must not have experienced a = grade 3 immune-related AE within the past 16 weeks or any grade 4 life-threatening AE (regardless of duration) or neurologic or ocular AE of any grade while receiving prior immunotherapy. (NOTE:
Patients with endocrine AE of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy, but must have no history of adrenal crisis and be asymptomatic)
- Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged
- Patients currently receiving chronic corticosteroid treatment (longer than 8 weeks duration) for management of pre-existing adverse events, or patients with a history of chronic corticosteroid treatment longer than 8 weeks’ duration for adverse events within 6 months of Screening are excluded |
1. Età = 18 anni
2. Prima di eseguire qualsiasi procedura correlata allo studio si dovrà ottenere il consenso informato scritto di tutti i pazienti
3. Pazienti con melanoma non uveale avanzato, definito come malattia non resecabile allo stadio III o metastatica allo stadio IV. I pazienti con melanoma acrale o mucosale sono accettabili. I pazienti con melanoma con sito primario sconosciuto sono accettabili per le coorti della fase Ib (Bracci 1-4), ma sono esclusi nelle coorti della fase II. I pazienti con diagnosi di melanoma uveale sono esclusi da tutte le coorti
4. Braccio 4 di fase Ib e fase II: pazienti con progressione della malattia dopo l’inizio del trattamento con un inibitore di PD-1 approvato. Non è consentita alcuna pregressa terapia citotossica nel contesto avanzato. I pazienti con mutazioni di BRAF devono essere refrattari alla terapia a base di BRAF approvata. La terapia di inibizione di CTLA-4 è consentita come linea di terapia pregressa o in combinazione con la terapia anti-PD-1.
5. Non più applicabile – (coorti di fase II naïve all’IMT: i pazienti non hanno ricevuto una terapia citotossica sistemica o immunoterapia per melanoma avanzato. Se il tumore del paziente presenta una mutazione di BRAF, una terapia con inibitori di BRAF e/o MEK è accettabile prima dell’immunoterapia ove clinicamente indicato. In questa sottopopolazione non sono consentite altre terapie citotossiche sistemiche o mirate).
6. Fase Ib, Bracci 1, 2 e 3: nessuna restrizione sulla terapia pregressa
7. Positivo all’antigene leucocitario umano A*0201 (human leukocyte antigen A*0201, HLA-A*0201)
8. Stato di validità secondo il Gruppo cooperativo orientale sull’oncologia (Eastern Cooperative Oncology Group) pari a 0 oppure a 1 |
|
| E.4 | Principal exclusion criteria |
1. Presence of untreated or symptomatic central nervous system metastases, or central nervous system metastases that currently require local therapy (such as radiotherapy or surgery), or require doses of corticosteroids within the prior 4 weeks.
2. History of severe hypersensitivity reactions to other monoclonal antibodies (mAb)s.
3. History of treatment-related interstitial lung disease/pneumonitis.
4. Patient with any out of range laboratory values.
• Serum creatinine > 1.5 x ULN and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
• Total bilirubin > 1.5 x upper limit of normal (ULN), except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
• Alanine aminotransferase (ALT) > 3 x ULN
• Aspartate aminotransferase (AST) > 3 x ULN
• Absolute neutrophil count (ANC) < 1.0 x 109/L
• Absolute lymphocyte count < 0.5 x 109/L
• Platelet count < 75 x 109/L
• Hemoglobin (Hgb) < 8 g/dL
• Potassium, magnesium, corrected calcium or phosphate abnormality of National Cancer Institute Common Terminology Criteria for Adverse Events, (CTCAE) > grade 1
5. Clinically significant cardiac disease or impaired cardiac function.
• Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association NYHA grade = 2), uncontrolled hypertension or clinically significant arrhythmia currently requiring medical treatment
• QTcF >470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome
• Acute myocardial infarction or unstable angina pectoris < 6 months prior to Screening
6. Active autoimmune disease or a documented history of autoimmune disease within 3 years before Screening (or as indicated below), including the following:
• A documented history of inflammatory bowel disease (ulcerative colitis or Crohn’s disease, within 3 years)
• Patients with vitiligo, alopecia, managed hypothyroidism (on stable replacement doses), psoriasis, resolved childhood asthma/atopy, well-controlled asthma and type I diabetes mellitus are NOT excluded
7. Recent (< 12 months) active diverticulitis (PhIb combination arms and PhII only)
8. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy before Screening is initiated.
9. Known history of human immunodeficiency virus (HIV) infection.
10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, currently requiring medical intervention, per institutional protocol.
11. Malignant disease, other than that being treated in this study.
12. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.
13. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity and any prior immunotherapy approach, 4 weeks is indicated as washout period.
14. Presence of NCI CTCAE = grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if = NCI CTCAE grade 3) due to prior cancer therapy.
15. Chronic, systemic corticosteroid use
16. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
17. Major surgery as defined by the investigator within 2 weeks of the first dose of study treatment (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery).
18. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. |
1. Presenza di metastasi non trattate o sintomatiche a carico del sistema nervoso centrale, oppure metastasi a carico del sistema nervoso centrale che attualmente richiedono una terapia locale (come radioterapia o chirurgia) oppure hanno richiesto dosi di corticosteroidi nelle 4 settimane precedenti
2. Anamnesi di reazioni di ipersensibilità grave ad altri anticorpimonoclonali
3. Anamnesi di malattia polmonare/polmonite interstiziale correlata al trattamento
4. Paziente con qualsiasi valore di laboratorio fuori dall’intervallo normale, definito come:
¿ Creatinina sierica > 1,5 x limite superiore dell’intervallo normale (upper limit of normal, ULN) e/o clearance della creatinina (calcolata usando la formula di Cockcroft-Gault o misurata) < 50 ml/min
¿ Bilirubina totale = 1,5 x ULN, eccetto nel caso di pazienti con sindrome di Gilbert, che saranno esclusi se la bilirubina totale è > 3,0 x ULN o la bilirubina diretta è > 1,5 x ULN
¿ Alanina aminotransferasi (ALT) > 3 x ULN
¿ Aspartato aminotransferasi (AST) > 3 x ULN
¿ Conta assoluta dei neutrofili (absolute neutrophil count, ANC) < 1,0 x 109/l
¿ Conta assoluta dei linfociti < 0,5 x 109/l
¿ Conta piastrinica < 75 x 109/l
¿ Emoglobina (Hemoglobin, Hgb) < 8 g/dl
¿ Anomalia nel potassio, magnesio, fosfato o calcio corretti secondo i criteri terminologici comuni per gli eventi avversi (Common Terminology Criteria for Adverse Events, CTCAE) del National Cancer Institute > grado 1
5. Cardiopatia clinicamente significativa o disfunzione della funzionalità cardiaca, incluso uno qualsiasi dei seguenti eventi:
¿ Cardiopatia clinicamente significativa e/o non controllata, come insufficienza cardiaca congestizia (New York Heart Association, NYHA grado = 2), ipertensione non controllata o aritmia clinicamente significativa, che necessita attualmente di trattamento medico
¿ QTcF >470 msec all’elettrocardiogramma (ECG) dello screening o sindrome congenita del QT lungo
¿ Infarto miocardico acuto o angina pectoris instabile < 6 mesi prima dello screening
6. Malattia autoimmune attiva o anamnesi documentata di malattia autoimmune nei 3 anni precedenti lo screening (o come indicato di seguito), incluso quanto segue:¿ Anamnesi documentata di malattia intestinale infiammatoria (colite ulcerosa o morbo di Crohn, negli ultimi 3 anni)¿ Pazienti con vitiligine, alopecia, ipotiroidismo sotto controllo (con dosi sostitutive stabili), psoriasi, asma/atopia infantile risolta, asma e diabete mellito di tipo I ben controllati NON sono esclusi
7. Diverticolite attiva recente (<12 mesi) (solo bracci combinati PhIb e PhII) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib: Number of Dose limiting toxicity(ies) (DLTs)
Phase II: Objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 |
Fase Ib: numero di tossicità limitanti alla dose (DLT)
Fase II: tasso di risposta obiettiva (ORR) per risposta Criteri di valutazione in tumori solidi (RECIST) v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLTs observed in the first 2 cycles of combination treatment (C1D15 through C2D28) for patients enrolled in the 3 Phase Ib cohorts.
The primary endpoint of the study will be assessed as ORR per RECIST v.1.1; however, patients experiencing Progressive disease (PD) per RECIST v.1.1 criteria may continue to be treated until meeting the criteria for unequivocal, confirmed PD by Immune related response criteria modified (irRC). |
DLT osservati nei primi 2 cicli di trattamento combinato (da C1D15 a C2D28) per pazienti arruolati nelle 3 coorti di fase Ib.
L'endpoint primario dello studio sarà valutato come ORR per RECIST v.1.1; tuttavia, i pazienti che presentano una malattia progressiva (PD) secondo i criteri RECIST v.1.1 possono continuare a essere trattati fino a soddisfare i criteri per la PD confermata e inequivocabile dai criteri di risposta correlati all'immunità modificati (irRC). |
|
| E.5.2 | Secondary end point(s) |
Safety incidence and severity of AEs and SAEs including changes in laboratory parameters, vital signs and electrocardiogram (ECG)
Tolerability: Dose interruptions, reductions and dose intensity of all administered study medications
Serum PK parameters (eg, AUC, Cmax, time of maximum concentration [Tmax], and t1/2) of all administered study medications)
Correlation of PD-L1 and gp100 evaluated in biopsies taken in the Screening period with anti-tumor activity
Progression free survival (PFS), duration of response, time to response, and disease control rate (DCR)
Formation of Anti-drug antibody (ADA) |
Incidenza di sicurezza e gravità di eventi avversi (AE) e eventi avversi gravi (SAE), inclusi cambiamenti nei parametri di laboratorio, nei parametri vitali e nell'elettrocardiogramma (ECG)
Tollerabilità: interruzioni della dose, riduzioni e intensità della dose di tutti i farmaci dello studio somministrati
Parametri PK sierici (ad es. AUC, Cmax, tempo di concentrazione massima [Tmax] e t1 / 2) di tutti i farmaci di studio somministrati)
Correlazione di PD-L1 e gp100 valutati in biopsie effettuate nel periodo di Screening con attività antitumorale
Sopravvivenza libera da progressione (PFS), durata della risposta, tempo di risposta e tasso di controllo della malattia (DCR)
Formazione di anticorpi anti-droga (ADA) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AEs and SAEs: From baseline at each study visit.
PK: samples taken at various timepoints during both phase Ib and II.
PFS: time from first dose of IMCgp100 until date of disease progression or death.
Duration of response: time from first documented response until date of documented progression or death in the absence of disease progression.
Time to response: time from initiation of therapy to time that Overall Survival (OR) per RECISTv1.1 is achieved.
DCR: proportion of patients with either a best response of PR or CR or with SD over 24 weeks after first dose in the study.
ADA samples: pre-dose at C1D1, C2D15, C3D15 and all odd numbered cycles through C13 (¿CX¿) and at 30-day End of Treatment visit. ADA samples to coincide with PK samples in Ph II during odd numbered cycles (CX¿). |
AE e SAE: dalla linea di base ad ogni visita di studio.
PK: campioni prelevati a vari tempi durante entrambe le fasi Ib e II.
PFS: tempo dalla prima dose di IMCgp100 fino alla data di progressione della malattia
o morte.
Durata della risposta: tempo dalla prima risposta documentata fino alla data di
progressione documentata o morte in assenza di progressione della malattia.
Tempo di risposta: tempo dall'avvio della terapia al tempo in cui è raggiunta la Sopravvivenza Complessiva (OR) per RECISTv1.1.
DCR: percentuale di pazienti con una migliore risposta di PR o CR o con SD per 24 settimane dopo la prima dose nello studio.
Campioni ADA: pre-dose a C1D1, C2D15, C3D15 e tutti i cicli numerati dispari attraverso |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase Ib and II |
| fase Ib e II |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| La fase II dello studio sar¿ randomizzata |
| The phase II part of the study will be randomized. |
|
| 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 | 7 |
| 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 | 16 |
| 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 |
| United States |
| France |
| Germany |
| Italy |
| United Kingdom |
|
| 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 the study will be when a minimum of 80% of the patients in all treatment arms in the Phase II part have completed the follow up for disease progression or discontinued the study for any reason, and all patients have completed treatment and the 90-day safety follow up period, or if the study is terminated early. |
Il fine dello studio avverr¿ quando almeno l'80% dei pazienti in
tutti i bracci di trattamento nella fase II hanno completato il follow-up
per la progressione della malattia o interrotto lo studio per qualsiasi motivo, e
tutti i pazienti hanno completato il trattamento e il periodo di follow up di sicurezza a 90 giorni , o se lo studio ¿ terminato in anticipo. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 20 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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