| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Adult unresectable metastatic melanoma patients either non pretreated or pretreated with B-Raf inhibitors or their combination
with MEK inhibitors |
Pazienti affetti da melanoma metastatico non resecabile sia in prima linea che dopo trattamento con B-Raf inibitori se il loro
tumore metastatico rivela la mutazione di B-Raf V600 |
|
| E.1.1.1 | Medical condition in easily understood language |
Adult unresectable metastatic melanoma patients either non pretreated or pretreated with B-Raf
inhibitors or their combination with MEK inhibitors, if their tumor harbour B-Raf V600 mutation |
Pazienti adulti affetti da melanoma metastatico non
resecabile sia in prima linea che dopo trattamento con farmaci B-Raf inibitori se il loro tumore metastatico rivela la mutazione di
B-Raf V600. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 assess overall response rate (ORR), duration
of overall response (DOOR), time to progression (TTP) of nivolumab combined with of ipilimumab, both administered at the
reduced dose of 1 mg/Kg, in subjects with stage III unresectable or metastatic melanoma independently of B-Raf status of their
disease if previously untreated or, previously treated with MAPK inhibitors, either alone or in combination, if their melanoma
presented B-Raf V600 mutation.
•To assess toxicity of the treatment. |
•Valutare il tasso di risposta obiettiva (ORR), durata della risposta [ il periodo di tempo dal primo
riscontro di risposta fino a ricaduta o progressione] e il tempo a progressione [ il periodo di tempo dal primo riscontro di stabilità
di malattia fino a ricaduta o progressione] di Nivolumab in combinazione con Ipilimumab somministrati entrambi alla dose ridotta
di 1 mg/Kg in soggetti con melanoma in stadio III non resecabile o metastatico, indipendentemente dallo stato mutazionale di
BRAF, se non precedentemente trattati o, se affetti da melanoma con BRAF mutato, dopo trattamento con farmaci inibitori di
BRAF da soli o in combinazione con MEK inibitori.
•Valutare la tossicità del trattamento sopra illustrato. |
|
| E.2.2 | Secondary objectives of the trial |
•To assess Progression Free Survival (PFS) and Time to progression (TTP) of nivolumab combined with ipilimumab at reduced
doses (1 mg/Kg) in subjects with stage III unresectable or metastatic melanoma independently of B-Raf status.
•To assess Overall Survival (OS) of nivolumab combined with ipilimumab at reduced doses (1 mg/Kg) in subjects with stage III
unresectable or metastatic melanoma independently of B-Raf status.
•To evaluate whether B-Raf mutational status is a predictive biomarker for response.
•To evaluate treatment derived Patient wellbeing as assessed by a simple questionnaire (PWQ) only once at the end of treatment
(appendix 1).
•To evaluate costs of the treatment and compare them with costs sustained in 2015 by using ipilimumab alone and relate them
with tumor ORR and PFS. |
•Valutare la sopravvivenza libera da progressione (PFS) e il tempo di progressione (TTP) di Nivolumab
in combinazione con Ipilimumab in dosi ridotte (1 mg/Kg) in soggetti con melanoma in stadio III non resecabile, o metastatico
indipendentemente dallo stato mutazionale di BRAF;
•Valutare la sopravvivenza complessiva (OS) di Nivolumab in combinazione con Ipilimumab in dosi ridotte (1 mg/Kg) in soggetti
con melanoma in stadio III non resecabile, o metastatico indipendentemente dallo stato mutazionale di BRAF;
•Valutare se la stato mutazionale di BRAF sia un biomarcatore predittivo di risposta;
•Valutare lo stato di benessere derivato al paziente dal trattamento [beneficio clinico sui sintomi e sulle condizioni generali di vita]
attraverso un semplice questionario, somministrato solo una volta, alla fine del trattamento;
•Valutare i costi del trattamento e confrontarli con quelli sostenuti nel 2015, quando ipilimumab è stato usato in monoterapia e
correlarli con ORR e PFS. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 .Subjects capable of giving informed consent must have signed and dated an IRB/IEC approved written informed consent form
in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related
procedures that are not part of normal subject care.
2. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other
requirements of the study.
3. Histologically confirmed unresectable Stage III or Stage IV melanoma, as per AJCC staging system.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Refer to Appendix 4)
5. Treatment naïve subjects (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma). Note that prior
adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to randomization, and all
related adverse events have either returned to baseline or stabilized.
6. Measurable disease by CT or MRI per RECIST 1.1 criteria [89]
7. Tumor tissue from an unresectable or metastatic site of disease must be provided for disease diagnsis.
8. Subjects must have known BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional
standards during the Screening Period.
9. Prior radiotherapy must have been completed at least 2 weeks prior to study drug
administration.
10. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to study entry:
i) WBC ≥ 2000/μL
ii) Neutrophils ≥ 1500/μL
iii) Platelets ≥100 x103/μL
iv) Hemoglobin ≥ 9.0 g/dL
v) Serum creatinine ≥ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (using the
Cockcroft-Gault formula):
Female CrCl = (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
vi) AST/ALT ≤ 3 x ULN
vii) Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
viii) normal ACTH level, and thyroid function tests, negative pregnancy test within 24 hours prior to the start of investigational
product.
11. Men and women, >18 years of age
12. Women of childbearing potential (WOCBP as defined below) and Men who are sexually active with WOCBP must use any
contraceptive method with a failure rate of less than 1% per year as indicated in Appendix 5 for at least 6 and 7,5 months,
respectively, after the last dose of investigational drug (see also 2014_09_HMA_CTFG_Contraception.pdf).
13. Subject must consent to undergo a biopsy of their metastasis for confirmation of the diagnosis and/or BRAF V600 mutational
testing |
1.Sottoscrizione del consenso informato da parte del paziente
2.Volontà e capacità di aderire alle visite e agli accertamenti programmati e ai trattamenti
3.Conferma istologica della diagnosi di metastasi da melanoma in stadio III (non resecabile) o stadio IV, secondo la stadiazione
AJCC
4.ECOG PS 0 o 1
5.Pazienti con melanoma BRAF V600 non mutato, naive, (non precedentemente trattati con terapia sistemica antineoplastica per
melanoma non resecabile o metastatico) o pazienti con melanoma BRAF V600 mutato pretrattati e non con farmaci inibitori della
via delle MAP Kinasi dopo almeno 6 settimane da una eventuale precedente terapia e solo nel caso in cui tutti gli eventi avversi
riferiti siano ritornati al basale o stabilizzati
6.Malattia misurabile da CT o MRI per criteri RECIST 1.1
7.La diagnosi di melanoma metastatico deve essere confermata istologicamente
8.Lo stato mutazionale di BRAF deve essere noto al momento dell’ingresso in studio oppure il paziente deve dare il suo consenso
ad effettuare il test per la valutazione dello stato mutazionale di BRAF V600 secondo gli standards di valutazione locale prima
dell’ingresso in studio
9.Una precedente Radioterapia deve essere stata completata almeno 2 settimane prima dell’ingresso in studio
10.Esami ematologici, effettuati entro 14 giorni dall’ingresso in studio, devono essere nella norma e comunque entro i parametri
stabiliti dal protocollo
11.Età > 18 anni
12.Le donne in età riproduttiva e gli uomini in età fertile devono seguire metodi contraccettivi di elevata efficacia, a tale proposito
si rimanda alle linee guida: 2014_09_HMA_CTFG_Contraception.pdf
13.Sottoscrizione del consenso al prelievo di campione tissutale con biopsia, routinario per confermare la diagnosi di metastasi e/o
effettuare il test di mutazione di BRAF V600 |
|
| E.4 | Principal exclusion criteria |
1.Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated
and there is no magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks after treatment is complete and
within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of
systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
2.Ocular melanoma
3.Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study
participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the
interpretation of study results.
4.Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as
basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
5.Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual
hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
6.Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or
other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal
replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
7.Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically
targeting T-cell costimulation or immune checkpoint pathways, are permitted only under exceptional circumstances and always
after PI approval.
8.Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute
or chronic infection, as determined in subjects where the condition is unknown at time of study entry.
9.Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
(AIDS).
10.History of allergy to study drug components.
11.History of severe hypersensitivity reaction to any monoclonal antibody.
12.WOCBP who are pregnant or breastfeeding
13.Women with a positive pregnancy test at enrollment or prior to administration of study medication.
14.Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone
surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12
months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes.In additional, women
under the age of 62 must have a documented serum follicle stimulating hormone, (FSH) level > 40mIU/mL.
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:
• Immunosuppressive agents (except to treat a drug-related adverse event)
• Systemic corticosteroids > 10 mg daily prednisone equivalent (except as stated in section 5.6 or to treat a drug-related adverse
event).
• Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, radiation therapy except for
palliative radiation therapy described in Palliative radiation therapy, or standard or investigational agents for treatment of cancer).
Supportive care for disease-related symptoms may be offered to all subjects on the trial.
|
1.Pazienti con metastasi cerebrali sono elegibili se queste sono state trattate e non c’è evidenza di progressione alla MRI per
almeno 4 settimane dopo il completamento del trattamento ed entro 28 giorni prima della somministrazione della prima dose dei
farmaci in studio. Non ci deve essere l’esigenza di somministrare corticosteroidi sistemici a dosi immunosopressive (> 10 mg/die
di prednisone o equivalenti) per almeno 2 settimane prima della somministrazione dei farmaci in studio
2.soggetti con melanoma oculare
3.Non è ammessa qualunque patologia che, a giudizio dello sperimentatore, possa aumentare il rischi associati allo studio, inficiare
la capacità di ricevere i farmaci in studio o interferire con l’interpretazione dei risultati dello studio
4.Sono escusi soggetti che abbiano avuto diagnosi di neoplasia nei tre anni precedenti eccetto, tumori basocellulari e squamosi
della cute, carcinomi in situ di vescica, prostata, cervice o mammella
5.Possono essere arruolati i pazienti con vitiligine, diabete mellito di tipo I, ipotiroidismo residuo dovuto a condizioni autoimmuni
che richiedono solo terapia ormonale sostitutiva, psoriasi che non richiede trattamento sistemico, o condizioni che non ci si
aspetta possano recidivare in assenza di un fattore scatenante esterno
6.Pazienti con condizioni cliniche che richiedono il trattamento sistemico con corticosteroidi (> 10 mg/die di prednisone o
equivalenti) o altri farmaci immunosopressivi nei 14 giorni precedenti la somministrazione dei farmaci in studio. Steroidi topici o
inalati, e dosi sostitutive della funzione surrenale >10mg/die di prednisone o equivalenti sono permessi in assenza di malattie
autoimmuni attive
7.Precedente trattamento con singoli agenti anti PD-1, anti PD-L1, anti PD-L2, o anticorpi CTLA-4, o altri anticorpi o farmaci che
abbiano come bersaglio specifico la costimolazione delle cellule T o le vie di controllo specifiche della risposta immune sono
permessi solo in situazioni particolari e sempre previa approvazione dello Sperimentatore Responsabile
8.Soggetti HBV e HCV positivi. HBV e HCVsaranno determinati solo nei pazienti in cui questi non fossero ancora noti al momento
dell’ingresso in studio.
9.Storia clinica di positività per HIV o nota sindrome da immunodeficienza acquisita (AIDS) conclamata
10.Soggetti con storia di allergia ai componentidei farmaci in studio
11.Soggetti con severa reazione di ipersensibilità a qualunque anticorpo monoclonale
12.Donne in età fertile in corso di in gravidanza o allattamento
13.Donne con test di gravidanza positivo al momento dell’ingresso in studio o prima della somministrazione dei farmaci in studio
14.Soggetti con malattie psichiatriche o fisiche che impongono l’isolamento
LDH è determinato prima di entrare nello studio tra gli esami ematochimici routinari, utile in quanto dotato di significato
prognostico e utilizzato nella pratica clinica corrente per orientare la scelta terapeutica.
Lo stato mutazionale di BRAF è determinato prima di entrare nello studio in quanto elemento indispensabile per guidare la scelta
terapeutica nella pratica clinica corrente. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
•Primary endpoints of the study will be
measured by the endpoints of ORR, duration of Objective Response and Time to progression. The ORR is defined as the number of
subjects with a BOR of CR or PR divided by the number of subjects included in the study. The BOR is defined as the best response
designation, as determined by the investigator, recorded between the date of study entry and the date of objectively documented
progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first. first. For subjects without
documented progression or subsequent therapy, all available response designations will contribute to the BOR assessment. Tumor
assessments are scheduled to be performed at Week 14, every 8 Weeks up to Week 52 and then every 12 Weeks until disease
progression or for a maximum of 5 years.
Duration of response will be measured by the endpoints duration of objective response (DOOR). DOOR is defined as the time
between the date of first response to the date of first documented tumor progression (per RECIST 1.1) or death due to any cause.
Subjects who neither progress nor die will be censored on the date of their last tumor assessment. DOOR will be evaluated for
responders (CR or PR) only.
•Response is defined by irCriteria and WHO criteria (table 1) [89]. Measurable disease is assessed by means of CT or MRI
according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 [90]
•Safety and tolerability will be measured by the incidence of adverse events, serious adverse events, deaths, and laboratory
abnormalities. Toxicity will be evaluated according to ECOG criteria [91].
•Any patient who received at least one dose of study drug will be included in the assessment of safety. The severity of adverse
events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0
[90]. Safety assessments will be made continuously during the treatment phase and up to 100 days after the last dose of study
drug. |
•Percentuale di risposte obiettive (ORR), [definita come il numero di soggetti con la risposta migliore (BOR) ottenuta – CR o PR - sul
numero di soggetti inclusi nello studio. BOR è la migliore risposta, determinata dallo sperimentatore, registrata tra la data di
ingresso in studio e la data di documentata progressione secondo i criteri RECIST 1.1 (Eisenhauer EA, Therasse P, Bogaerts J, et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47) o la data
della successiva terapia, qualunque si verifichi per prima. In soggetti senza documentata progressione o successiva terapia, tutte
le risposte designate contribuiranno alla BOR] La valutazione della risposta inizia a 14 settimane (+/-1 settimana) dopo il primo
ciclo di trattamento e continua ogni 8 settimane (+/- 1 settimana) fino alla settimana 52 e poi ogni 12 settimane (+/- 1 settimana)
fino a progressione o per massimo 5 anni;
•La risposta al trattamento è definita da Criteri immunocorrelati (irCriteria) e criteri WHO (Wolchok JD, Hoos A, O'Day S, et al.
Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res
2009;15:7412-20). La malattia misurabile è valutata mediante CT o MRI secondo i criteri RECIST versione 1.1
•Durata della risposta obiettiva (DOOR) [definita come il periodo di tempo dalla data della prima risposta fino alla data del primo
riscontro di progressione di malattia (secondo RECIST 1.1) o morte dovuta a qualunque causa]. DOOR verrà valutata solo per i
pazienti in CR o PR.
•Tossicità al trattamento: misurata dall’incidenza di eventi avversi, eventi avversi seri, decessi e anomalie dei test di laboratorio.
La tossicità verrà valutata secondo i criteri ECOG (Eastern Cooperative Oncology Group) (Common Terminology Criteria for
Adverse Events (CTCAE) v.4 (http://evs .nci .nih .gov/ ftp1/ CTCAE/ About .html). La tossicità verrà valutata nei soggetti che
abbiano ricevuto almeno un ciclo di trattamento e per 100 giorni dopo la somministrazione dell’ultimo ciclo e graduata secondo i
criteri ECOG. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR will be recorded at week 14 and confirmed at week 22. Toxicity will be recorded continuously during treatment and up to 22
weeks from the last treatment |
ORR rilevato a 14 settimane e confermato a 22 settimane tossicità
continuativamente fino a 22 settimane dall'ultima somministrazione |
|
| E.5.2 | Secondary end point(s) |
The first secondary objective will be
measured by the endpoint of PFS. PFS is defined as the time between the date of study entry and the first date of documented
progression, as determined by the investigator, or death due to any cause, whichever occurs first. Subjects who die without a
reported progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be
censored on the date of their last evaluable tumor assessment. Subjects who did not have any on study tumor assessments and
did not die will be censored on their date of study entry. Subjects who started anti-cancer therapy without a prior reported
progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer
therapy. Tumor assessments are scheduled to be performed at Week 14, every 8 Weeks up to Week 52 and then every 12 Weeks
until disease progression for a maximum of 5 years.
The second secondary objective will be measured by the endpoint of OS in all subjects entering the study. OS is defined as the
time between the date of study entry and the date of death due to any cause. OS will be censored on the last date a subject was
known to be alive. OS data will be collected continuously while subjects are on study medication and every 2 months up to 1 year
and then every 3 months up to 5 years.
• Time to progression (TTP) will be measured between the date of study entry and the date of first documented tumor progression
(per RECIST 1.1) or death due to any cause. TTP will be evaluated for stable disease (SD).
•B-Raf status will be determined prior to study entry to evaluate which treatment would be more appropriate for the patient and
his/her clinical situation, in paraffin embedded tissue samples, stored for 10 years, per local institutional standards . B-Raf status
will be correlated with ORR, PFS and OS.
•Detection of wellbeing questionnaire will be administered only once within 2 weeks from the last treatment cycle (appendix 1)
•An analysis of costs of the study will be conducted in collaboration with the Pharmacy Unit of Azienda Ospedalira Pisana. Costs of
study drugs, diagnostic procedures and hospital admissions will be compared with the same costs sustained in 2015 by using
ipilimumab alone and related with tumor ORR, PFS and OS |
•sopravvivenza libera da progressione (PFS): definita come il tempo dall’ingresso in studio alla
prima progressione di malattia o morte dovuta a qualunque causa, qualunque accada prima.
•sopravvivenza globale (OS) in tutti i soggetti entrati in studio : definita come il tempo dall’ingresso in studio alla data della morte
per qualunque causa. I dati di OS verranno registrati continuamente durante il trattamento e ogni 2 mesi fino a un anno, poi ogni 3
mesi fino a 5 anni.
•Tempo a progressione (TTP) [definito come l’intervallo di tempo dalla data di ingresso in studio alla data della prima progressione
documentata (secondo RECIST 1.1) o la data della morte per qualunque causa]. TTP verrà valutato per la malattia stabile (SD).
•Correlazione tra la stato mutazionale di BRAF e ORR, PFS e OS ;
•Questionario di valutazione dello stato di benessere del paziente derivante dal trattamento verrà somministrato solo una volta
entro 2 settimane dall’ultimo trattamento.
•Costi del trattamento (farmaci, procedure diagnostiche e ricoveri) saranno confrontati con quelli sostenuti nel 2015 nei pazienti
trattati con solo ipilimumab e messi in relazione a ORR, PFS e OS. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1 year, 3 years, 5 years |
| 1 anno, 3 anni, 5 anni |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | 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.8.3 |
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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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