| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
- locally advanced or metastatic adrenocortical carcinoma (ACC)
- malignant pheochromocytoma/paraganglioma (MPP) |
- carcinoma adrenocorticale localizzato avanzato o metastatico (ACC)
- feocromocitoma/paraganglioma maligno (MPP) |
|
| E.1.1.1 | Medical condition in easily understood language |
- locally advanced or metastatic adrenocortical carcinoma (ACC)
- malignant pheochromocytoma/paraganglioma (MPP) |
- carcinoma adrenocorticale localizzato avanzato o metastatico (ACC)
- feocromocitoma/paraganglioma maligno (MPP) |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001388 |
| E.1.2 | Term | Adrenocortical 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034876 |
| E.1.2 | Term | Pheochromocytoma |
| 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 | LLT |
| E.1.2 | Classification code | 10075444 |
| E.1.2 | Term | Malignant paraganglioma |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this trial is to evaluate safety and tolerability of EO2401 in combination with nivolumab in patients with unresectable, previously treated, and previously untreated, locally advanced or metastatic ACC, and progressive MPP. |
| L’obiettivo primario dello studio è la valutazione della sicurezza e della tollerabilità di EO2401 in associazione con nivolumab in pazienti con ACC non resecabile, trattato in precedenza e non trattato in precedenza, localmente avanzato o metastatico e MPP in progressione. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives include assessment of:
- immunogenicity in relation to T cells of EO2316, EO2317, EO2318, and UCP2 that compose EO2401; T cell cross-reactivity with the human TAAs IL13Ra2, FOXM1, and BIRC5/surviving will also be evaluated,
- objective response rate (ORR) and duration of response (DOR), and
- progression-free survival (PFS) and overall survival (OS). |
Gli obiettivi secondari comprendono la valutazione di:
• immunogenicità in relazione ai linfociti T di EO2316, EO2317, EO2318 e UCP2, che costituiscono EO2401; sarà inoltre valutata la reattività crociata dei linfociti T con i TAA umani IL13Ra2, FOXM1 e BIRC5/survivina
• tasso di risposta obiettiva (ORR, objective response rate) e durata della risposta (DOR, duration of response) e
• sopravvivenza libera da progressione (PFS, progression-free survival) e sopravvivenza complessiva (OS, overall survival). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. For inclusion in Cohort 1 patients should have adrenocortical carcinoma, or malignant pheochromocytoma/paraganglioma, as defined below for Cohorts 2A and 3A.
2. For inclusion in Cohorts 2A and 2B patients should have histologically confirmed (at primary diagnosis) unresectable locally advanced or metastatic (ENSAT/AJCC] stage 3 = tumor has spread into nearby tissues or lymph nodes, or stage 4 = metastatic disease) adrenocortical carcinoma.
a. In addition, for inclusion in Cohort 2 A patients should also have received treatment with at least one line, but not more than two prior lines, of systemic therapy including mitotane and/or chemotherapy (other groups of systemic therapies utilized in e.g. clinical trials will also be assessed and counted if appropriate).
b. In addition, for inclusion in Cohort 2B patients should not have received prior systemic therapy for their adrenocortical carcinoma.
Note, adjuvant therapy for patients with complete resections should not be counted in the definitions above.
3. For inclusion in Cohorts 3A and 3B patients should have histologically confirmed (at primary diagnosis) unresectable malignant (defined as metastatic disease, i.e. presence of chromaffin tissue in non-chromaffin organs pheochromocytoma/paraganglioma, and RECIST defined progression should have been documented during a maximum of an 18months period.
a. In addition, for inclusion in Cohort 3A patients should also have received treatment with at least two prior lines of systemic therapy including radionuclide therapy and/or chemotherapy (other groups of systemic therapies utilized in e.g. clinical trials will also be assessed and counted if appropriate).
b. In addition, for inclusion in Cohort 3B patients should not have received prior systemic therapy for their malignant pheochromocytoma/paraganglioma.
4. Patients with an age = 18 years old.
5. Patients who are human leukocyte antigen (HLA)-A2 positive.
6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status = 2 (see Section 12.2 [39]).
7. Patients with a life expectancy > 4 months as judged by their treating physician.
8. Patients with at least one measurable lesion according to RECIST 1.1 (see Section 12.1).
9. Males or non-pregnant, non-lactating, females who are:
e) female, post-menopausal (serum follicle-stimulating hormone (FSH) level > 40 mIU/mL >),
f) female and male, surgically sterile (e.g. bilaterally blocked or removed fallopian tubes, vas deferens),
g) female of childbearing potential with a negative highly sensitive serum pregnancy test within 72 hours prior to first administration of study treatment and use of a highly effective contraception from signing the Informed Consent Form (ICF) through 5 months after the last study treatment dose administered; note, the male partner should in addition to the use of highly effective contraception by the female patient also use condoms,
h) male patient with female partners of childbearing potential must use condoms from signing the ICF through 5 months after the last study treatment dose administered; in addition, male patients must ensure that their partners of childbearing potential also use highly effective contraception.
Highly effective barrier and non-barrier contraception include:
i) combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal,
ii) progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable, intrauterine device, and
iii) sexual abstinence when in line with the preferred and usual lifestyle of the patient (e.g. periodic abstinence is not considered a highly effective method).
10. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.
11. see Protocol |
1. Per essere inclusi nella coorte 1, i pazienti devono essere affetti da carcinoma adrenocorticale o feocromocitoma/paraganglioma maligno, come definito di seguito per le coorti 2A e 3A.
2. Per essere inclusi nelle coorti 2A e 2B, i pazienti devono essere affetti da carcinoma adrenocorticale istologicamente confermato (alla diagnosi primaria), non resecabile, localmente avanzato o metastatico (stadio 3 ENSAT/AJCC = tumore diffuso ai tessuti adiacenti o ai linfonodi oppure stadio 4 = malattia metastatica).
a. Inoltre, per essere inclusi nella coorte 2A, i pazienti devono anche essere stati trattati con almeno una linea, ma non più di due linee precedenti, di terapia sistemica contenente mitotano e/o chemioterapia (se opportuno, saranno valutati e calcolati anche altri gruppi di terapie sistemiche utilizzate per esempio negli studi clinici).
b. Inoltre, per essere inclusi nella coorte 2B, i pazienti non devono essere stati sottoposti in precedenza a terapia sistemica per il carcinoma adrenocorticale.
La terapia adiuvante per i pazienti con resezioni complete non va calcolata nelle definizioni riportate sopra.
3. Per essere inclusi nelle coorti 3A e 3B, i pazienti devono essere affetti da feocromocitoma/paraganglioma maligno, istologicamente confermato (alla diagnosi primaria), non resecabile (definito come malattia metastatica, ovvero presenza di tessuto cromaffine in organi non cromaffini) e deve essere stata documentata progressione secondo i criteri RECIST in un periodo massimo di 18 mesi.
a. Inoltre, per essere inclusi nella coorte 3A, i pazienti devono anche essere stati trattati con almeno due linee precedenti di terapia sistemica contenente radionuclidi e/o chemioterapia (se opportuno, saranno valutati e calcolati anche altri gruppi di terapie sistemiche utilizzate per esempio negli studi clinici).
b. Inoltre, per essere inclusi nella coorte 3B, i pazienti non devono essere stati sottoposti in precedenza a terapia sistemica per il feocromocitoma/paraganglioma maligno.
4. Pazienti di età = 18 anni.
5. Pazienti positivi all’antigene leucocitario umano (HLA, human leukocyte antigen)-A2.
6. Pazienti con performance status secondo l’Eastern Cooperative Oncology Group (ECOG) = 2.
7. Pazienti con aspettativa di vita > 4 mesi secondo il giudizio del medico curante.
8. Pazienti con almeno una lesione misurabile secondo i criteri RECIST 1.1.
9. vedi Protocollo
10. vedi Protocollo
11. vedi Protocollo |
|
| E.4 | Principal exclusion criteria |
1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e. 13 mg/day of prednisone, or 53 mg/day of hydrocortisone) within 14 days before the first EO2401 administration, unless required to treat an adverse event. Note, inhaled steroids and adrenal replacement steroid doses > 13 mg daily prednisone equivalents are permitted. Thus, patients needing hydrocortisone replacement therapy due to prior or
ongoing mitotane therapy can receive hydrocortisone doses > 53 mg/day, i.e. also in the normally used range of 60-80 mg/day, and still be included in the trial.
2. Patients with prior treatment with compounds targeting PD-1, PD-L1, CTLA-4, or similar compounds where general resistance against therapeutic vaccination approaches might have developed (e.g. defects to the cellular antigen processing/presentation machinery, including mutations in Janus kinas [JAK] 1, JAK2, and ß-2-microglobulin [B2M]) allowing tumor cells to avoid recognition and attack by immune cells.
3. Patients with prior exposure to EO2401, e.g. patients treated in Cohorts 2B or 3B of the current trial cannot be re-enrolled for treatment also in Cohorts 2A or 3A.
4. Patients treated with immunotherapy (meaning immunostimulatory or immunosuppressive therapy; beside excluded, or allowed, compounds per other inclusion/exclusion criteria specifications), radionuclide therapy, radiotherapy, cytoreductive therapy, or received treatment with any other investigational agent within 28 days before the first EO2401 administration. Note, for patients with ACC continued treatment with mitotane during this trail is allowed provided tumor progression on this therapy has been demonstrated under therapeutic plasma level or at maximum individual tolerated dose and mitotane plasma level monitoring is maintained during the trial (mitotane might have been given in the adjuvant and/or established disease settings as long as progression on this therapy before trial inclusion has been documented). For patients with MPP, concurrent therapy with octreotide is allowed provided tumor progression on this therapy has been demonstrated; concurrent therapy with bisphosphonates (e.g. zoledronic acid) or denosumab is also allowed.
5. Patients with ACC with more than three organs involved by disease, combined with high ki-67 expression in tumor (= 20%), and unresectable primary tumor.
6. Patients with ACC and uncontrolled cortisol secretion (according to the judgement of the treating physician).
7. Patients with MPP and uncontrolled blood pressure (according to the judgement of the treating physician).
8. Patients with abnormal laboratory values according to the following list (note, lab ranges according to the performing laboratory's reference ranges):
a. hemoglobin < 10 g/dL (6.2 mmol/L) (transfusion to correct the value is acceptable),
b. white blood cell count decrease (< 3.0 × 109/L),
c. absolute neutrophil count decrease (< 1.5 × 109/L),
d. platelet count decrease (< 75 × 109/L),
e. bilirubin > 1.5 x upper limit of normal (ULN) (note, benign hereditary hyperbilirubinemia, e.g. Gilbert's syndrome is permitted),
f. alanine aminotransferase (ALT) > 3 x ULN; if disease metastatic to the liver > 5 x ULN,
g. aspartate aminotransferase (AST) > 3 x ULN; if disease metastatic to the liver > 5 x ULN,
h. serum creatinine increase (> 1.5 x ULN); however, if creatinine clearance (measured, or calculated according to the Cockcroft/Gault [40] formula; CCr={((l40–age) x weight)/(72xSCr)} x 0.85 (if female); CCr (creatinine clearance) = mL/minute, age = years, weight = kg, SCr (serum creatinine) = mg/dL) is > 40 mL/minute the patient can be enrolled, and
i. abnormal thyroid function per local laboratory levels (note, patients with hypothyroidism only requiring hormone replacement therapy are permitted to enroll).
9. see Protocol
10. see Protocol
11. see Protocol |
1. Pazienti trattati con desametasone > 2 mg/giorno o equivalente (13 mg/giorno di prednisone o 53 mg/giorno di idrocortisone) nei 14 giorni precedenti alla prima somministrazione di EO2401, a meno che non sia necessario per trattare un evento avverso. Sono ammessi steroidi per inalazione e dosi di terapia steroidea di sostituzione surrenalica > 13 mg al giorno di equivalenti del prednisone. Quindi, i pazienti che hanno necessità di una terapia di sostituzione dell’idrocortisone a causa della terapia con mitano precedente o in corso possono ricevere dosi di idrocortisone > 53 mg/giorno, anche nell’intervallo usato normalmente di 60-80 mg/giorno, ed essere comunque inclusi nello studio.
2. Pazienti trattati in precedenza con composti mirati a PD-1, PD-L1, CTLA-4 o composti simili che possono aver indotto lo sviluppo di resistenza generale verso gli approcci terapeutici di vaccinazione (per es. difetti cellulari di processazione/
presentazione dell’antigene, comprese mutazioni di Janus chinasi [JAK] 1, JAK2 e ß-2-microglobulina [B2M]), che permettano alle cellule tumorali di evitare il riconoscimento e l’attacco da parte delle cellule immunitarie.
3. Pazienti esposti in precedenza a EO2401, per es. i pazienti trattati nelle coorti 2B o 3B del presente studio non possono essere nuovamente arruolati per il trattamento anche nelle coorti 2A o 3A.
4. Pazienti trattati con immunoterapia (ovvero terapia immunostimolatoria o immunosoppressiva; oltre i composti esclusi, o ammessi, in base ad altri criteri di inclusione/esclusione), terapia con radionuclidi, radioterapia, terapia di citoriduzione o trattamento con qualsiasi altro farmaco sperimentale nei 28 giorni precedenti alla prima somministrazione di EO2401. Per i pazienti con ACC è ammessa la continuazione del trattamento con mitotano durante il presente studio, purché sia stata dimostrata progressione del tumore durante questa terapia a livello plasmatico terapeutico o alla dose massima tollerata individuale e il monitoraggio del livello plasmatico di mitotano sia continuato durante lo studio (il mitotano può essere stato somministrato nel contesto adiuvante e/o di malattia conclamata purché sia stata documentata la progressione durante questa terapia prima dell’inclusione nello studio). Per i pazienti con MPP è ammessa la terapia concomitante con octreotide purché sia stata dimostrata progressione del tumore con questa terapia; è ammessa anche la terapia concomitante con bifosfonati (per es. acido zoledronico) o denosumab.
5. Pazienti con ACC con più di tre organi interessati dalla malattia, in combinazione con espressione elevata di ki-67 nel tumore (= 20%) e tumore primitivo non resecabile.
6. Pazienti con ACC e secrezione non controllata di cortisolo (secondo il giudizio del medico curante).
7. Pazienti con MPP e pressione arteriosa non controllata (secondo il giudizio del medico curante).
8-23. vedi Protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint regarding safety and tolerability of EO2401 in combination with nivolumab is a descriptive medical assessment of the combined profile of incidences of adverse events (AEs), treatmentemergent AEs (TEAEs), serious AEs (SAEs), deaths, reasons for treatment discontinuation/delays, and laboratory abnormalities using the NCICTCAE v5.0 grading system. |
| L’endpoint primario relativo alla sicurezza e alla tollerabilità di EO2401 in associazione con nivolumab è una valutazione medica descrittiva del profilo combinato delle incidenze di eventi avversi (AE, adverse event), AE emergenti dal trattamento (TEAE, treatment-emergent AE), AE gravi (SAE, serious AE), decessi, motivi di interruzione/ritardo del trattamento e anomalie di laboratorio utilizzando il sistema di classificazione NCI-CTCAE v5.0. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| AEs will be monitored throughout the study. AEs are collected from the date of the patient's signing the ICF until 30 days after the final administration of study drug. SAEs with a plausible causal relationship to study drug will be reported from the date of the patient's signing the ICF until indefinitely (regardless of time elapse from the final study drug administration). An AE causally not related to study drug will be monitored (followed-up) until resolution, stabilization, or end of the clinical trial. Clinically relevant laboratory abnormalities will be followed up until they return to normal or become stabilized (permanent condition). Any AE with a plausible causal relationship to study drug as well as all SAEs will be followed up until the event has resolved or stabilized. |
| AEs will be monitored throughout the study. AEs are collected from the date of the patient's signing the ICF until 30 days after the final administration of study drug. SAEs with a plausible causal relationship to study drug will be reported from the date of the patient's signing the ICF until indefinitely (regardless of time elapse from the final study drug administration). An AE causally not related to study drug will be monitored (followed-up) until resolution, stabilization, or end of the clinical trial. Clinically relevant laboratory abnormalities will be followed up until they return to normal or become stabilized (permanent condition). Any AE with a plausible causal relationship to study drug as well as all SAEs will be followed up until the event has resolved or stabilized. |
|
| E.5.2 | Secondary end point(s) |
• Percentage of patients with shown immunogenicity (expansion of specific T cells comparing samples taken at baseline versus on treatment n an individual patient determining if the patient has a positive response to the immunization, or not) in relation to EO2316, EO2317, EO2318, and UCP2 that compose EO2401 by interferon-gamma (IFN-¿) enzyme-linked immunospot (ELISpot), and if needed by intracellular cytokines staining, or multimers staining assays. Cross reactivities with the human TAAs IL13Ra2, FOXM1, and BIRC5/survivin will also be evaluated by the same methods.
• ORR and DOR as described by RECIST 1.1 and iRECIST criteria.
• PFS as described by RECIST 1.1 and iRECIST criteria, defined as the time interval from the date of first study treatment administration to the date of progression (by RECIST 1.1 or iRECIST criteria) or death due to any cause, whichever is earlier. Patients without progression or death are to be censored at the time of the last tumor assessment.
• OS defined as the time interval from the date of first study treatment administration to the date of death due to any cause. Patients alive will be censored at the date of the last documented follow-up. |
• Percentuale di pazienti con evidenza di immunogenicità (espansione di linfociti T specifici mediante il confronto di campioni prelevati al basale rispetto a quelli prelevati durante il trattamento in un singolo paziente, per determinare se il paziente ha o meno una risposta positiva all’immunizzazione) in relazione a EO2316, EO2317, EO2318 e UCP2, che costituiscono EO2401, valutata mediante tecnica immunospot enzimatica (ELISpot, enzyme-linked immunospot) per la rilevazione di interferone-gamma (IFN-¿) e, se necessario, mediante colorazione delle citochine intracellulari o test di colorazione dei multimeri. Anche le reattività crociate con i TAA umani IL13Ra2, FOXM1 e BIRC5/survivina saranno valutate con gli stessi metodi.
• ORR e DOR come descritto dai criteri RECIST 1.1 e iRECIST.
• PFS come descritto dai criteri RECIST 1.1 e iRECIST, definita come il tempo trascorso dalla data della prima somministrazione del trattamento dello studio alla data della progressione (in base ai criteri RECIST 1.1 o iRECIST) o del decesso dovuto a qualsiasi causa, a seconda di quale evento si verifichi per primo. I pazienti senza progressione o ancora in vita saranno censurati alla data dell’ultima valutazione del tumore.
• OS definita come il tempo trascorso dalla data della prima somministrazione del trattamento dello studio alla data del decesso dovuto a qualsiasi causa. I pazienti in vita saranno censurati alla data dell’ultimo follow-up documentato. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Percentage of patients with shown immunogenicity is evaluated on Week 1, 5 , 7 , 11, 15 and 19, then every 4 weeks of treatment onwards. Post treatment is evaluated on Day 30 and every 8 weeks before disease
progression.
• Objective Response Rate (ORR) and Duration of Response (DOR) as described by RECIST 1.1 and iRECIST criteria.
• PFS as described by RECIST 1.1 and iRECIST criteria, defined as the time interval from the date of first study treatment administration to the date of progression (by RECIST 1.1 or iRECIST criteria) or death due to any cause, whichever is earlier. Patients without progression or death are to be censored at the time of the last tumor assessment. |
• Percentage of patients with shown immunogenicity is evaluated on Week 1, 5 , 7 , 11, 15 and 19, then every 4 weeks of treatment onwards. Post treatment is evaluated on Day 30 and every 8 weeks before disease
progression.
• Objective Response Rate (ORR) and Duration of Response (DOR) as described by RECIST 1.1 and iRECIST criteria.
• PFS as described by RECIST 1.1 and iRECIST criteria, defined as the time interval from the date of first study treatment administration to the date of progression (by RECIST 1.1 or iRECIST criteria) or death due to any cause, whichever is earlier. Patients without progression or death are to be censored at the time of the last tumor assessment. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
| Immunogenicità |
|
| 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 |
| A phase Ib/II trial but another trial is the First in Human. |
| Fase Ib/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 sperimentazione è uno studio con 5 coorti. |
| The trial is a 5-cohort study. |
|
| 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 | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 8 |
| 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 |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
|
| 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
|
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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