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    Summary
    EudraCT Number:2021-003208-42
    Sponsor's Protocol Code Number:CA209-6GE
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-09-13
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2021-003208-42
    A.3Full title of the trial
    A Phase 3, Open Label, Randomized, Non-Inferiority Pharmacokinetic Study of Nivolumab Administered Subcutaneously (Nivo SC) Versus Intravenous Administration of Nivolumab in Participants with Stage IIIA/B/C/D or Stage IV Adjuvant Melanoma Following Complete Resection
    Studio di fase 3, in aperto, randomizzato, di non inferiorità di farmacocinetica su Nivolumab somministrato per via sottocutanea (Nivo SC) rispetto alla somministrazione endovenosa di Nivolumab in partecipanti con melanoma, in trattamento adiuvante, allo stadio IIIA/B/C/D o allo stadio IV dopo resezione completa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Pharmacokinetic Study of Nivolumab Administered Subcutaneously vs Intravenous Nivolumab in Participants with Stage III A/B/C/D or Stage IV Melanoma Following Complete Resection
    Studio farmacocinetico di nivolumab somministrato per via sottocutanea vs nivolumab per via endovenosa in partecipanti con melanoma di stadio III A/B/C/D o stadio IV dopo resezione completa
    A.3.2Name or abbreviated title of the trial where available
    CheckMate-6GE: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 6GE
    CheckMate-6GE: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 6GE
    A.4.1Sponsor's protocol code numberCA209-6GE
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1266-6116
    A.5.4Other Identifiers
    Name:INDNumber:150,904
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBRISTOL-MYERS SQUIBB INTERNATIONAL CORPORATION
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Myers Squibb International Corporation
    B.5.2Functional name of contact pointGSM-CT
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance - Avenue de Finlande, 4
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNivolumab Subcutaneous coformulated with excipient rHuPH20
    D.3.2Product code [BMS-986298-01]
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-986298
    D.3.9.3Other descriptive nameBMS936558
    D.3.9.4EV Substance CodeSUB32944
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Opdivo (100 mg/10 ml)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNivolumab-10 ml vial-COMMERCIAL
    D.3.2Product code [BMS-936558]
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameBMS936558
    D.3.9.4EV Substance CodeSUB32944
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Resected Stage IIIA/B/C/D or Stage IV melanoma in an adjuvant setting
    Melanoma asportato di stadio IIIA/B/C/D o di stadio IV in trattamento adiuvante
    E.1.1.1Medical condition in easily understood language
    Melanoma Stage III or Stage IV
    Melanoma Stadio III o Stadio IV
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10025671
    E.1.2Term Malignant melanoma stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1:
    - To demonstrate PK (pharmacokinetics) non-inferiority of nivolumab SC coformulated with rHuPH20 (recombinant human hyaluronidase PH20 enzyme) versus nivolumab IV (intravenous administration).
    Part 2:
    - To characterize the PK of nivolumab SC coformulated with rHuPH20.
    Parte1:
    - Dimostrare la non inferiorità della PK (farmacocinetica) di Nivolumab SC coformulato con rHuPH20 (ialuronidasi umana ricombinante PH20) rispetto a Nivolumab EV (endovenosa).
    Parte 2:
    - Caratterizzare la PK di Nivolumab SC coformulato con rHuPH20.
    E.2.2Secondary objectives of the trial
    Part 1, Key secondary:
    - To assess the safety and tolerability of nivolumab SC coformulated with rHuPH20 and nivolumab IV.
    - To assess the efficacy of nivolumab SC coformulated with rHuPH20 and nivolumab IV.
    Part 1, Other Secondary:
    - To characterize additional PK parameters following nivolumab SC coformulated with rHuPH20 and nivolumab IV.
    - To evaluate the immunogenicity of nivolumab SC coformulated with rHuPH20 and nivolumab IV and the impact of anti-nivolumab antibodies on safety.
    - To assess satisfaction with route of treatment administration.
    Part 2:
    - To characterize additional PK parameters following nivolumab SC coformulated with rHuPH20.
    - To assess the safety and tolerability profile of nivolumab SC injection with rHuPH20.
    - To assess the immunogenicity of nivolumab SC and the impact of anti-nivolumab antibodies on safety.
    Parte 1, secondari principali:
    - Valutare la sicurezza e la tollerabilità di Nivolumab SC coformulato con rHuPH20 e Nivolumab EV.
    - Valutare l’efficacia di Nivolumab SC coformulato con rHuPH20 e Nivolumab EV.

    Parte 1, altri secondari:
    - Caratterizzare ulteriori parametri di PK in seguito alla coformulazione di Nivolumab SC con rHuPH20 e Nivolumab EV.
    - Valutare l’immunogenicità di Nivolumab SC coformulato con rHuPH20 e Nivolumab EV e l’impatto degli anticorpi anti-Nivolumab sulla sicurezza.
    - Valutare la soddisfazione con la via di somministrazione del trattamento.

    Part 2:
    - Caratterizzare ulteriori parametri PK successivamente alla somministrazione di Nivolumab SC coformulato con rHuPH20.
    - Valutare il profilo di sicurezza e tollerabilità dell’iniezione SC di Nivolumab coformulato con rHuPH20.
    - Valutare l’immunogenicità di Nivolumab SC e l’impatto degli anticorpi anti-Nivolumab sulla sicurezza.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -All participants must have been diagnosed with either Stage IIIA (>1mm tumor in lymph node)/B/C/D or Stage IV melanoma by AJCC 8th edition and have histologically confirmed melanoma (as documented in the pathology report) that is completely surgically resected (free of disease) with negative margins in order to be eligible. All melanomas, except uveal and mucosal melanoma, regardless of primary site of disease, will be allowed.
    - Complete resection must be performed within 12 weeks prior to randomization (Part 1) or treatment assignment (Part 2). Management of residual lymph nodes after positive sentinel lymph node biopsy (ie, completion lymph node dissection) will be as per local standards and recommendations for the individual participant.
    - Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of < and = 1.
    -Per essere idonei, tutti i partecipanti devono aver ricevuto una diagnosi di melanoma di stadio IIIA (tumore >1 mm nei linfonodi)/B/C/D o stadio IV, secondo l’AJCC 8a edizione, e presentare un melanoma confermato istologicamente (come documentato nel referto patologico) che sia completamente resecato chirurgicamente (libero da malattia) con margini negativi. Saranno consentiti tutti i melanomi, ad eccezione del melanoma uveale e mucosale, a prescindere dal sito primario di malattia.
    - La resezione completa deve essere eseguita entro 12 settimane prima della randomizzazione (Parte 1) o dell’assegnazione del trattamento (Parte 2). La gestione dei linfonodi residui dopo biopsia positiva del linfonodo sentinella (ovvero, dissezione completa del linfonodo) avverrà secondo gli standard e le raccomandazioni locali per il singolo partecipante.
    - I partecipanti devono presentare uno stato di performance < e =1 nella scala dell’Eastern Cooperative Oncology Group (gruppo orientale cooperativo di oncologia).
    E.4Principal exclusion criteria
    -History of uveal or mucosal melanoma.
    -Untreated/unresected CNS metastases or leptomeningeal metastases.
    -Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    - Participants with serious or uncontrolled medical disorders within 4 weeks prior to screening.
    - Additionally, in the case of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, acute symptoms must have resolved and based on investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.
    - Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to randomization (Part 1) or treatment assignment (Part 2) (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before randomization/treatment assignment and the patient has no evidence of disease). Participants with history of prior early stage basal/squamous cell skin cancer or noninvasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
    - Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
    - Any condition that according to investigator criteria makes a participant ineligible from participation in the study, including but not limited to medical conditions (including psychological, psychiatric), or social conditions; or conditions that can impact ability to comply with protocol requirements (eg, conditions that preclude the use of IV or subcutaneous [SC] route of study drug administration) or that can put the participant at risk. Participants with history of self-harm including suicidal attempts will be excluded from the study.
    - Prior immunotherapy treatments for any prior malignancies are not permitted (such as, but not limited to anti-programmed death-1, antiprogrammed death-ligand 1, anti-programmed death-ligand 2, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
    -Participants treated with anti-cancer therapy directed against the resected melanoma (for example, but not limited to, systemic, local, radiation, and radiopharmaceuticals) except:- Surgery for the melanoma lesion(s);- Adjuvant radiation therapy after neurosurgical resection for CNS lesions;- Prior adjuvant interferon completed > and = 6 months prior to randomization (Part 1) or treatment assignment (Part 2).
    Other protocol-defined exclusion criteria apply.
    -Anamnesi di melanoma uveale o mucosale.
    -Metastasi del SNC non trattate/non resecate o metastasi leptomeningee.
    -Partecipanti con una malattia autoimmune in fase attiva, nota o sospetta. È consentito l’arruolamento di partecipanti con diabete mellito di tipo I, ipotiroidismo che richieda soltanto la sostituzione ormonale, patologie cutanee (come vitiligine, psoriasi o alopecia) che non richiedano trattamento sistemico o condizioni di cui non si preveda la recidiva in assenza di un fattore scatenante esterno.
    -Partecipanti con disturbi medici gravi o non controllati nelle 4 settimane precedenti lo screening.
    -Inoltre, in caso di precedente infezione con sindrome respiratoria acuta grave da coronavirus 2 (SARS-CoV-2), i sintomi acuti devono essersi risolti e in base alla valutazione dello sperimentatore in consultazione con il medical monitor, non vi devono essere sequele che metterebbero il partecipante a un rischio più elevato nel ricevere il trattamento sperimentale.
    -Malattia maligna concomitante (presente durante lo screening) che richieda trattamento o anamnesi di precedente malattia maligna attiva nei 2 anni precedenti la randomizzazione (Parte 1) o l’assegnazione del trattamento (Parte 2) (ovvero i partecipanti con anamnesi di precedente malignità sono idonei se il trattamento è stato completato almeno 2 anni prima della randomizzazione/assegnazione del trattamento e il paziente non ha alcuna evidenza di malattia). I partecipanti con anamnesi di precedente tumore cutaneo a cellule basali/squamose in stadio precoce o carcinomi in situ non invasivi o che siano stati sottoposti a trattamento definitivo in qualsiasi momento sono anch’essi idonei.
    -Partecipanti che presentano una condizione che richieda trattamento sistemico con corticosteroidi (>10 mg una volta al giorno di equivalente del prednisone) entro 14 giorni o altri farmaci immunosoppressori entro 30 giorni dall’avvio del trattamento dello studio. Gli steroidi per via inalatoria o topica e dosi di steroidi per terapia sostitutiva surrenalica >10 mg al giorno di un equivalente del prednisone sono consentiti in assenza di malattia autoimmune in fase attiva.
    -Qualsiasi condizione che, secondo i criteri dello sperimentatore, rende un partecipante non idoneo alla partecipazione allo studio, incluse, a titolo esemplificativo ma non esaustivo, condizioni mediche (comprese condizioni psicologiche, psichiatriche) o sociali; o condizioni che possono influire sulla capacità di rispettare i requisiti del protocollo (ad es., condizioni che precludono l’uso della via di somministrazione del farmaco dello studio EV o sottocutanea [SC]) o che possono mettere a rischio il partecipante. I partecipanti con anamnesi di autolesionismo, compresi i tentativi di suicidio, saranno esclusi dallo studio.
    -Non sono consentiti precedenti trattamenti immunoterapici per tumori maligni pregressi (come, a titolo esemplificativo ma non esaustivo anticorpi inibitori della proteina di morte cellulare programmata-1, anticorpi inibitori del ligando della proteina di morte cellulare programmata 1, anticorpi inibitori del ligando della proteina di morte programmata-2 o qualsiasi altro anticorpo o farmaco specificamente mirato alla co-stimolazione delle cellule T o alle vie del checkpoint immunitario).
    -Partecipanti trattati con terapia antitumorale diretta contro il melanoma resecato (per esempio, a titolo esemplificativo ma non esaustivo, terapia sistemica, locale, radioterapia e radiofarmaci), ad eccezione di: -Intervento chirurgico per la/le lesione(i) del melanoma; -Radioterapia adiuvante dopo resezione neurochirurgica per lesioni del SNC;-Precedente interferone adiuvante se completato > e =6 mesi prima della randomizzazione (Parte 1) o assegnazione del trattamento (Parte 2)
    Si applicano altri criteri di esclusione definiti dal protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    -Cavgd28 (Time averaged nivolumab serum concentration over the first 28 days)
    - Cminss (Minimum nivolumab serum concentration at steady-state)
    Part 2
    -Cavgd28
    Parte1
    -Cavgd28 (concentrazione sierica mediata nel tempo di Nivolumab nei primi 28 giorni)
    - Cminss (concentrazione sierica minima di Nivolumab allo stato stazionario)
    Part 2
    -Cavgd28
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1
    -Cavgd28 : First 28 days of treatment
    -Cminss : 17 weeks after the start of treatment
    Part 2
    -Cavgd28 : First 28 days of treatment
    Parte 1
    -Cavgd28 : Primi 28 giorni di trattamento
    -Cminss : 17 settimane dopo l'inizio del trattamento
    Parte 2
    -Cavgd28 : Primi 28 giorni di trattamento
    E.5.2Secondary end point(s)
    Part 1, Key secondary:
    a) Incidence of all AEs/SAEs, treatment-related AEs, including IMAEs, SAEs, AEs (including device-related adverse reactions, injection/infusion-related AEs) leading to discontinuation or death, and laboratory abnormalities for each treatment group.
    b) RFS (recurrence-free survival) per investigator - rates at 12, 18, 24, and 36 months follow-up.
    c) OS (overall survival) rates at 12, 18, 24, and 36 months follow-up.
    Part 1, other secondary:
    d) Cmind28 (minimum nivolumab serum concentration on Day 28), Cmax1 (maximum nivolumab serum concentration after the first dose), Tmax (time to maximum nivolumab serum concentration after the first dose.)
    e) Cmaxss (maximum nivolumab serum concentration at steady-state), and Cavgss (time-averaged nivolumab serum concentration at steadystate).
    f) Percentage of participants who develop anti-nivolumab antibodies and neutralizing antibodies, if applicable, and the impact of anti-nivolumab antibodies on AEs, administration-related reactions, and events within MedDRA SMQ Anaphylactic reactions
    g) Mean CTSQ (Cancer Treatment Satisfaction Questionnaire) Satisfaction domain scores and score change from baseline at each assessment time point.
    Part 2
    h) Cmind28, Cmax1, Tmax
    i) Cmaxss, Cavgss, and Cminss.
    j) Incidence of AEs/SAEs, treatment-related AEs, including IMAEs, SAEs, AEs (including device-related adverse reactions, injection/infusionrelated AEs) leading to discontinuation or death, and laboratory abnormalities.
    k) Percentage of participants who develop anti-nivolumab antibodies and neutralizing antibodies, if applicable, and the impact of antinivolumab antibodies on AEs, administration-related reactions, and events within MedDRA SMQ Anaphylactic reactions.
    Parte 1, secondari principali:
    a) Incidenza di tutti gli AE/SAE, AE correlati al trattamento, compresi IMAE, SAE, AE (incluse reazioni avverse correlate al dispositivo, AE correlati all’iniezione/infusione) che portano all’interruzione o al decesso e valori anomali di laboratorio per ciascun gruppo di trattamento.
    b) Tassi di RFS (secondo lo sperimentatore) al follow-up a 12, 18, 24 e 36 mesi.
    c) Tassi di OS al follow-up a 12, 18, 24 e 36 mesi.
    Parte 1, altri secondari:
    d) Cmind28 (concentrazione sierica minima di Nivolumab al Giorno 28), Cmax1 (concentrazione sierica massima di Nivolumab dopo la prima dose), Tmax (tempo alla concentrazione sierica massima di Nivolumab dopo la prima dose)
    e) Cmaxss (concentrazione sierica massima di Nivolumab allo stato costante) e Cavgss (concentrazione sierica di Nivolumab allo stato di equilibrio mediata nel tempo).
    f) Percentuale di partecipanti che sviluppano anticorpi anti-Nivolumab e anticorpi neutralizzanti, se pertinente, e l’impatto degli anticorpi anti-Nivolumab su EA, reazioni correlate alla somministrazione ed eventi all’interno delle reazioni anafilattiche dell’SMQ MedDRA.
    g) Punteggi medi del dominio di Soddisfazione CTSQ e variazione del punteggio dal basale a ogni punto temporale di valutazione.
    Parte 2
    h) Cmind28, Cmax1, Tmax
    i) Cmaxss, Cavgss e Cminss.
    j) Incidenza di tutti gli AE/SAE, AE correlati al trattamento, compresi IMAE, SAE, AE (incluse reazioni avverse correlate al dispositivo, AE correlati all’iniezione/infusione) che portano all’interruzione o al decesso e valori di laboratorio non normali.
    k) Percentuale di partecipanti che sviluppano anticorpi anti-Nivolumab e anticorpi neutralizzanti, se pertinente, e l’impatto degli anticorpi anti-Nivolumab su AE, reazioni correlate alla somministrazione ed eventi all’interno delle reazioni anafilattiche dell’SMQ MedDRA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    a) Up to 100 days after the last treatment of study intervention or up to discontinuation of study treatment
    b) Until recurrence event, up to minimum follow-up of 12 months from last participant randomized in the study or death whichever is earlier
    c) Until death, up to 36 months
    d) First 28 days of treatment
    e) 17 weeks after the start of treatment
    f) Up to 100 days after the last study treatment or up to discontinuation of study treatment
    g) At each assessment time Point
    h) First 28 days of treatment
    i) 17 weeks after the start of treatment
    j) Up to 100 days after the last treatment of study intervention or up to discontinuation of study treatment
    k) Up to 100 days after the last study treatment or up to discontinuation of study treatment
    a)Fino a 100 giorni dopo l'ultimo trattamento dell'intervento in studio o fino all'interruzi. del trattamento b)Fino alla ricorrenza dell'evento,fino al follow-up minimo di 12 mesi dall'ultimo partecipante randomiz. allo studio o al decesso,se precedente c)Fino alla morte,fino a 36 mesi d)Primi 28 giorni di trattamento e)17 settimane dopo l'inizio del trattamento f)Fino a 100 giorni dopo l'ultimo trattamento in studio o fino all'interruz. del trattamento in studio g)Ad ogni punto temporale di valutazione
    h)Primi 28 giorni di trattamento i)17 settimane dopo l'inizio del trattamento j)Fino a 100 giorni dopo l'ultimo trattamento dell'intervento in studio o fino all'interruz. del trattamento in studio k)Fino a 100 giorni dopo l'ultimo trattamento in studio o fino all'interruz. del trattamento
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability, Immunogenicity
    Tollerabilità, immunogenicità
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA31
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    United States
    France
    Poland
    Spain
    Germany
    Italy
    Belgium
    United Kingdom
    E.8.7Trial 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
    End of trial is defined as the last participant last visit or completion of Follow-up Visit 2.
    La fine dello studio è definita come l'ultima visita del partecipante o il completamento della visita di follow-up 2.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 276
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 103
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    In situations where consent cannot be given by participants, consent can be given by their legally acceptable representatives (as per country regulation) in accordance with ICH GCP Guidelines.
    Nelle situazioni in cui il consenso non può essere fornito dai partecipanti, il consenso può essere fornito dai loro rappresentanti legalmente accettabili (come da regolamento nazionale) in conformità con le linee guida ICH GCP.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 235
    F.4.2.2In the whole clinical trial 379
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the study, BMS will not continue to provide BMS-supplied study intervention to participants/investigators unless BMS chooses to extend the study. The investigator should ensure that the participant receives appropriate standard of care to treat the condition under study.
    Al termine dello studio, BMS non continuerà a fornire il farmaco BMS fornito per lo studioai partecipanti/sperimentatori a meno che BMS non decida di far estendere lo studio. Lo sperimentatore dovrebbe assicurarsi che il partecipante riceva un adeguato standard di cura per trattare la condizione in cui si trova.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-07-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-13
    P. End of Trial
    P.End of Trial StatusOngoing
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