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    Summary
    EudraCT Number:2015-004992-62
    Sponsor's Protocol Code Number:A-US-52030-328
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-11-04
    Trial results View 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 number2015-004992-62
    A.3Full title of the trial
    A PHASE 3, PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, MULTI-CENTER, STUDY OF THE EFFICACY AND SAFETY OF LANREOTIDE AUTOGEL/ DEPOT 120 MG PLUS BSC VS. PLACEBO PLUS BSC FOR TUMOR CONTROL IN SUBJECTS WITH WELL DIFFERENTIATED, METASTATIC AND/OR UNRESECTABLE TYPICAL OR ATYPICAL LUNG NEUROENDOCRINE TUMORS
    STUDIO PROSPETTICO, MULTICENTRICO, RANDOMIZZATO, IN DOPPIO CIECO DI FASE 3 SULL’EFFICACIA E LA SICUREZZA DI LANREOTIDE AUTOGEL/DEPOT 120 MG PIÙ BSC VS. PLACEBO PIÙ BSC PER IL CONTROLLO DEL TUMORE IN SOGGETTI AFFETTI DA TUMORI NEUROENDOCRINI POLMONARI TIPICI O ATIPICI, BEN DIFFERENZIATI, METASTATICI E/O NON RESECABILI
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A PHASE 3, PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, MULTI-CENTER, STUDY OF THE EFFICACY AND SAFETY OF LANREOTIDE AUTOGEL/ DEPOT 120 MG PLUS BSC VS. PLACEBO PLUS BSC FOR TUMOR CONTROL IN SUBJECTS WITH WELL DIFFERENTIATED, METASTATIC AND/OR UNRESECTABLE TYPICAL OR ATYPICAL LUNG NEUROENDOCRINE TUMORS
    STUDIO PROSPETTICO, MULTICENTRICO, RANDOMIZZATO, IN DOPPIO CIECO DI FASE 3 SULL’EFFICACIA E LA SICUREZZA DI LANREOTIDE AUTOGEL/DEPOT 120 MG PIÙ BSC VS. PLACEBO PIÙ BSC PER IL CONTROLLO DEL TUMORE IN SOGGETTI AFFETTI DA TUMORI NEUROENDOCRINI POLMONARI TIPICI O ATIPICI, BEN DIFFERENZIATI, METASTATICI E/O NON RESECABILI
    A.3.2Name or abbreviated title of the trial where available
    SPINET
    SPINET
    A.4.1Sponsor's protocol code numberA-US-52030-328
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02683941
    A.5.4Other Identifiers
    Name:SPINETNumber:SPINET
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/302/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIPSEN PHARMA SAS
    B.1.3.4CountryFrance
    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 supportIpsen Biopharmaceuticals, Inc.
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIpsen Pharma SAS
    B.5.2Functional name of contact pointSpeciality Franchise Clin Ops
    B.5.3 Address:
    B.5.3.1Street Address65 Quai George Gorse
    B.5.3.2Town/ cityBoulogne Billancourt
    B.5.3.3Post code92100
    B.5.3.4CountryFrance
    B.5.4Telephone number+3358335000
    B.5.5Fax number+3358335001
    B.5.6E-mailbeloo.mirakhur@ipsen.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 Yes
    D.2.1.1.1Trade name IPSTYL - 120 MG SOLUZIONE INIETTABILE PER USO SOTTOCUTANEO 1 SIRINGA PRERIEMPITA
    D.2.1.1.2Name of the Marketing Authorisation holderIPSEN S.P.A
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameSomatuline® Autogel® 120mg
    D.3.2Product code [PL 34926/0007]
    D.3.4Pharmaceutical form Solution for injection
    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 INNLANREOTIDE ACETATO
    D.3.9.1CAS number 127984-74-1
    D.3.9.2Current sponsor codeSomatuline® Autogel®
    D.3.9.3Other descriptive nameLANREOTIDE ACETATE
    D.3.9.4EV Substance CodeSUB14326MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Lung Neuroendocrine Tumours
    Lung Neuroendocrine Tumours
    E.1.1.1Medical condition in easily understood language
    Lung Neuroendocrine Tumours
    Lung Neuroendocrine Tumours
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10057270
    E.1.2Term Neuroendocrine carcinoma
    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
    To compare the antitumour efficacy of LAN plus BSC every 28 days
    monotherapy versus placebo plus BSC, in terms of progression-free
    survival (PFS), measured by central review using Response Evaluation
    Criteria in Solid Tumours (RECIST) v1.1 criteria, every 12 weeks, in
    subjects with unresectable and/or metastatic well differentiated, typical
    or atypical lung NETs.
    Obiettivo primario
    • Confrontare l’efficacia antitumorale della monoterapia con LAN più BSC ogni 28 giorni rispetto al placebo più BSC, in termini di sopravvivenza libera da progressione (PFS), misurata mediante revisione centrale utilizzando i criteri RECIST (Response Evaluation Criteria in Solid Tumours) v1.1 ogni 12 settimane, in soggetti con tumori neuroendocrini polmonari tipici o atipici, ben differenziati, non resecabili e/o metastatici.
    E.2.2Secondary objectives of the trial
    • To compare the objective response rate (ORR) of LAN monotherapy plus BSC every 28 days versus placebo plus BSC, as assessed by RECIST v 1.1 criteria (proportion of subjects with a best overall response of partial response (PR) or complete response (CR)),
    • To compare the overall survival (OS) of subjects randomised to LAN monotherapy plus BSC every 28 days versus subjects randomised to placebo plus BSC,
    • To compare time to treatment failure (Kaplan Meier estimates) of LAN monotherapy plus BSC every 28 days versus placebo plus BSC,
    • To compare the changes from Baseline in the biomarker chromogranin A (CgA),
    • To compare the proportion of subjects with a decrease of CgA=30% at week 8 in the population of subjects with an elevated CgA (=2 x ULN) at Baseline,
    • To describe the change in Quality of Life (QoL) from baseline, as assessed by the EORTC QLQ-C30 questionnaire,
    • To describe the time to deterioration of QoL (using EORTC QLQ-C30),
    • To describe the changes in urinary 5-HIAA
    • Confrontare il tasso di risposta obiettiva (ORR) della monoterapia con LAN più BSC ogni 28 giorni rispetto al placebo più BSC, valutata in base ai criteri RECIST v1.1 [proporzione di soggetti con miglior risposta complessiva in termini di risposta parziale (PR) o risposta completa (CR)];
    • Confrontare la sopravvivenza complessiva (OS) dei soggetti randomizzati a monoterapia con LAN più BSC ogni 28 giorni rispetto ai soggetti randomizzati al placebo più BSC;
    • Confrontare il tempo al fallimento terapeutico (stime di Kaplan Meier) con la monoterapia con LAN più BSC ogni 28 giorni rispetto al placebo più BSC;
    • Confrontare le variazioni del biomarker cromogranina A (CgA) rispetto al basale;
    • Confrontare la percentuale di soggetti che presentano una diminuzione = 30% della CgA alla settimana 8 nella popolazione di soggetti con valori elevati di CgA [= 2 volte il limite superiore della norma (ULN)] al basale;
    • Descrivere la variazione della qualità di vita (QoL) dal basale,
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    (1) Provision of written informed consent prior to any study related procedures,
    (2) Subjects aged = 18 years,
    (3) Have metastatic and/or unresectable pathologically confirmed well-differentiated, typical or atypical neuroendocrine tumour of the lung,
    (4) Histologic evidence of well differentiated NETs of the lung (typical and atypical according to the WHO criteria evaluated locally),
    (5) Has a mitotic index <2 mitoses/2 mm2 for typical carcinoid (TC) and <10 mitoses/2 mm2 and/or foci of necrosis for atypical carcinoid (AC),
    (6) At least one measurable lesion of the disease on imaging (CT or MRI; RECIST v1.1),
    (7) Positive somatostatin receptor imaging (SRI) (Octreoscan® = grade 2 Krenning scale; Ga-PET scan: uptake greater than liver background),
    (8) ECOG performance status 0-1,
    (9) Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required,
    (10) Female subjects who are at risk of becoming pregnant must agree to use an effective method of contraception such as double barrier contraception, an injectable, combined oral contraceptive or an intra-uterine device (IUD). The subject must agree to use the contraception during the whole period of the study and for eight months after the last study drug administration. Non childbearing potential is defined as being postmenopausal for at least 1 year, or permanently sterilized at least 3 months before study entry,
    (11) Male subjects must agree that, if their partner is at risk of becoming pregnant, they will use an effective method of contraception (see above). The subject must agree to use the contraception during the whole period of the study and for eight months after the last study drug administration,
    (12) Signed HIPAA authorization where required,
    (13) Subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the study site for the follow-up evaluation as specified in the protocol.

    (1) Consenso informato scritto, accordato prima di procedere alle indagini previste dallo studio;
    (2) Età pari o superiore a 18 anni;
    (3) Presenza di tumore neuroendocrino polmonare tipico o atipico, ben differenziato, metastatico e/o non resecabile, patologicamente confermato;
    (4) Evidenza istologica di NET polmonare ben differenziato (tipico e atipico, valutato a livello locale secondo i criteri dell’OMS);
    (5) Indice mitotico < 2 mitosi/2 mm2 per il carcinoide tipico (TC) e < 10 mitosi/2 mm2 e/o focolai di necrosi per il carcinoide atipico (AC);
    (6) Almeno una lesione misurabile della malattia all’imaging (TC o RM; criteri RECIST v1.1);
    (7) Imaging positivo per i recettori della somatostatina (SRI) (Octreoscan® di grado = 2 sulla scala di Krenning, scansione PET-Ga: assorbimento maggiore del livello di sottofondo del fegato);
    (8) Performance Status 0 1 secondo la scala ECOG;
    (9) I soggetti femmine in età fertile devono risultare negative al test di gravidanza su urine o siero nelle 72 ore precedenti alla randomizzazione. Se il test delle urine è positivo o se è impossibile confermarne la negatività, il test di gravidanza deve essere ripetuto nel siero;
    (10) I soggetti femmine potenzialmente fertili devono acconsentire a far uso di un metodo contraccettivo efficace, come un metodo a doppia barriera, un anticoncezionale iniettabile, combinato orale o un dispositivo intrauterino (IUD). Il soggetto deve accettare di far uso del metodo anticoncezionale per l’intera durata dello studio e negli otto mesi successivi all’ultima somministrazione del farmaco in studio. Per donne in età non fertile si intendono le donne in postmenopausa da almeno un anno o sottoposte a sterilizzazione permanente da almeno tre mesi prima dell’ammissione allo studio;
    (11) I soggetti maschi e la loro partner se potenzialmente fertile devono acconsentire a far uso di un metodo contraccettivo efficace (vedere sopra). Il soggetto deve acconsentire ad usare la contraccezione durante l’intero periodo dello studio e per otto mesi dopo l’ultima somministrazione del farmaco in studio;
    (12) Laddove necessario, autorizzazione firmata alla divulgazione dei dati sanitari ai sensi della legge statunitense sulla Privacy dell’Health Insurance Portability and Accountability Act (HIPAA);
    (13) I soggetti devono essere disposti e in grado di rispettare le limitazioni richieste dallo studio e restare in clinica per il tempo necessario durante il periodo di studio, nonché essere disposti a tornare presso il centro sperimentale per la valutazione di follow up, come specificato nel protocollo.
    E.4Principal exclusion criteria
    (1) Poorly differentiated or high grade carcinoma, or subjects with neuroendocrine tumours not of lung origin are excluded,
    (2) Subjects with Multiple endocrine neoplasia type 1 (MEN 1),
    (3) Has been treated with an SSA at any time prior to randomization, except if that treatment was for less than 15 days (e.g. peri-operatively) of short acting SSA or one dose of long acting SSA and the treatment was received more than 6 weeks prior to randomization,
    (4) Has been treated with Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization,
    (5) Has been treated for Lung NET with chemotherapy* within 4 weeks of randomization (whatever the number of cycles),
    (6) Has been treated with more than two lines of chemotherapy* for Lung NET,
    * cytotoxic chemotherapy or molecular targeted therapy or interferon.

    (7) Treated with surgery within 6 weeks prior to randomization,
    (8) Previous local therapy (e.g. chemo-embolization, bland, or radio-embolization) is allowed if completed > 6 weeks prior to randomization. For subjects who received local therapy prior to randomization, there must be documented growth of measurable disease within the embolization field prior to study,
    (9) Symptomatic subjects requiring SSA for symptom management (please also note the exclusion criteria 3),
    (10) Subjects with known ectopic production of adrenocorticotropic hormone (ACTH) or other hormonal secreting subjects allowed – ONLY if symptoms adequately controlled without SSAs,
    (11) Subjects on concomitant Growth Hormone (GH) antagonist, cyclosporine or bromocriptine
    (12) Inadequate bone marrow function as per investigator’s judgement
    (13) Severe renal insufficiency as defined by a calculated creatinine clearance <30 mL/min,
    (14) Total bilirubin >2x ULN, AST, ALT or Alk Ph >5xN, lipase, amylase >2xN,
    (15) Serum albumin <3.0 g/dL unless prothrombin time is within the normal range,
    (16) Known hypersensitivity to the study drug,
    (17) Present cholecystitis,
    (18) Uncontrolled congestive heart failure
    (19) Glycosylated hemoglobin (HbA1c) > 8.5%,
    (20) Abnormal findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, would compromise the subject’s safety or the outcome of the study,
    (21) Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years,
    (22) Pregnant or lactating women or those of childbearing potential age and not practicing a medically acceptable method for birth control,
    (23) Subjects who have participated in any therapeutic clinical study/received any investigational agent within 30 days of randomization.
    (24) Clinically significant cardiac arrhythmia, bradycardia, tachycardia that would compromise patient safety or the outcome of the study
    (25) Uncontrolled hypothyroidism
    (26) Has been previously screened (i.e. informed consent signed) in this study.

    (1) Sono esclusi i soggetti con carcinoma scarsamente differenziato o di grado elevato oppure con tumori neuroendocrini di origine non polmonare;
    (2) Soggetti con neoplasia endocrina multipla tipo 1 (MEN 1);
    (3) Soggetti trattati con un SSA in un momento qualsiasi precedente alla randomizzazione, tranne nei casi in cui la durata del trattamento con SSA a breve durata d’azione fosse stata inferiore a 15 giorni (ad es. nel perioperatorio) o fosse stata somministrata una dose di SSA a lunga durata d’azione e il trattamento fosse stato somministrato più di 6 settimane prima della randomizzazione;
    (4) Soggetti trattati con terapia radionuclide del recettore del peptide (PRRT) in un momento qualsiasi precedente alla randomizzazione;
    (5) Soggetti trattati con chemioterapia* per NET polmonare nelle 4 settimane precedenti alla randomizzazione (a prescindere dal numero di cicli);
    (6) Pazienti trattati con più di due linee di chemioterapia* per NET polmonare;
    * chemioterapia citotossica o terapia molecolare mirata o interferone.

    (7) Soggetti trattati con terapia chirurgica nelle 6 settimane precedenti alla randomizzazione;
    (8) È ammessa una precedente terapia locale (ad es., chemioembolizzazione, lieve embolizzazione o radioembolizzazione) se completata più di 6 settimane prima della randomizzazione. I soggetti trattati con terapia localizzata prima della randomizzazione devono presentare una crescita documentata della malattia misurabile entro il campo di embolizzazione prima dello studio;
    (9) Soggetti sintomatici necessitanti di SSA per la gestione dei sintomi (nota: si rinvia al criterio di esclusione 3);
    (10) Sono ammessi i soggetti con nota produzione ectopica di ormone adrenocorticotropo (ACTH) o soggetti con altra secrezione ormonale, A CONDIZIONE che i sintomi siano adeguatamente controllati senza l’uso di SSA;
    (11) Soggetti in terapia concomitante con antagonisti dell’ormone della crescita (GH), ciclosporina o bromocriptina;
    (12) Funzione midollare inadeguata, secondo l’opinione dello sperimentatore;
    (13) Severa insufficienza renale definita da una clearance della creatinina calcolata < 30 mL/min;
    (14) Bilirubina totale > 2 x ULN, AST, ALT o fosfatasi alcalina > 5 volte la norma, lipasi, amilasi > 2 volte la norma;
    (15) Albumina sierica 3,0 g/dL a meno che il tempo di protrombina non rientri nei limiti della norma;
    (16) Nota ipersensibilità al farmaco in studio;
    (17) Presenza di colecistite;
    (18) Insufficienza cardiaca congestizia non controllata;
    (19) Emoglobina glicosilata (HbA1c) > 8,5%;
    (20) Parametri anormali, qualsiasi altra patologia medica/ patologie mediche o risultati degli esami di laboratorio che, a parere dello sperimentatore, comprometterebbero la sicurezza del soggetto o l’esito dello studio;
    (21) Altre note neoplasie maligne coesistenti, con l’eccezione di tumori non melanomatosi della cute e carcinoma in situ della cervice uterina, a meno che non siano stati trattati in maniera definitiva e documentata, senza evidenza di recidiva in un periodo di 5 anni;
    (22) Donne in gravidanza o che allattano o donne in età fertile che non adottano un metodo contraccettivo accettabile;
    (23) Soggetti che hanno partecipato a un qualsiasi studio clinico terapeutico o hanno ricevuto un agente sperimentale nei 30 giorni precedenti alla randomizzazione;
    (24) Aritmia cardiaca, bradicardia, tachicardia clinicamente significative che comprometterebbero la sicurezza del paziente o l’esito dello studio;
    (25) Ipotiroidismo non controllato;
    (26) Paziente precedentmente sottoposto a screening (cioè ha firmato il consenso informato) in questo studio.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) will be measured from the date of randomization to the documented date of centrally confirmed progressive disease (PD) or death (from any cause), whichever occurs first. PFS will be analyzed for the intention-to-treat (primary analysis) and Per Protocol populations. Subjects who start a new cancer therapy, who are lost to follow-up, and those who are alive at the date of data cut-off without documented PD will be censored at the date of the last evaluable response assessment (prior to initiation of a new cancer therapy).

    As a sensitivity analysis of the primary endpoint, a similar PFS analysis will be performed using the local assessment of progression.
    La sopravvivenza libera da progressione (PFS) sarà misurata a partire dalla data di randomizzazione fino alla data documentata di malattia progressiva (PD) confermata a livello centrale o morte (per ogni causa), a seconda di quale evento si verifichi per primo. La PFS sarà analizzata nelle popolazioni intent to treat (analisi primaria) e per protocol. I soggetti che iniziano una nuova terapia antitumorale, quelli persi al follow up e quelli ancora viventi alla data di cut off dei dati senza PD documentata saranno censurati alla data in cui è stata determinata l’ultima risposta valutabile (prima dell’avvio della nuova terapia antitumorale).

    Come analisi di sensibilità dell’endpoint primario, sarà eseguita un’analisi PFS simile usando la valutazione locale della progressione.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Refer to protocol
    Refer to protocol
    E.5.2Secondary end point(s)
    • The ORR in each treatment arm, with their corresponding exact 95% CIs, will be estimated. A Cochran-Mantel-Haenszel test will be used to compare the treatment arms and estimate the odds ratios and their 95% CIs, controlling for the stratification factors. These analyses will be performed using data from local and central review of RECIST v1.1.
    • OS is defined as the time from randomization to death from any causes. The distribution of OS times will be estimated using the Kaplan Meier method within each treatment arm, and treatment effect will be compared using a two sided stratified log rank test, controlling for the stratification factors. The median OS and associated 95% CI will be computed for each treatment arm. A stratified Cox proportional hazards model will be used to estimate the HRs and their two sided 95% CIs.
    • Treatment failure is defined as progression [defined as the minimum (time to event according to central review, time to event according to local review)] using RECIST v1.1, death, consent withdrawn, an AE, protocol deviations, lost to follow-up, the appearance of carcinoid syndrome or other hormone related syndrome necessitating the initiation of SSAs (rescue octreotide and/or LAR SSA), or initiation of anticancer treatment. Time to treatment failure will be defined as the time from randomization to treatment failure. The distribution of times to treatment failure for each treatment arm will be estimated using the Kaplan Meier method and the effect will be compared using a two sided stratified log rank test. A stratified Cox proportional hazards model will be used to estimate the HRs, and their two sided CIs.
    • Mean changes from Baseline in biomarker CgA will be presented descriptively by time point and treatment group, using summary statistics. Raw values and change from Baseline will be presented. A repeated mixed ANCOVA model including the stratification factors will be used to assess the treatment effect during the double blind phase.
    • The proportion of subjects with a decrease of CgA=30% from baseline from Baseline to Week 8 will be estimated, with the corresponding 95% CI in each treatment arm. A Cochran-Mantel-Haenszel test will be used to compare the treatment arms and estimate the odds ratios and their 95% CIs, controlling for the stratification factors.
    • EORTC QLQ-C30 will be described at Baseline, and every 12 Weeks, for double blind and OL extension (both treatment and follow-up phases). Raw values and change from Baseline will be presented. A repeated mixed ANCOVA model including the stratification factors will be used to assess the treatment effect during the double blind phase.
    • Time to EORTC QLQ-C30 deterioration will be analyzed in a similar fashion to time to treatment failure. EORTC QLQ-C30 deterioration is defined as a reduction of at least 10 points between baseline and the given assessment.
    • Mean changes from Baseline in urinary 5-HIAA levels in subjects with elevated urinary 5-HIAA (=2 x ULN) at Base
    • Sarà stimata la ORR in ogni braccio di trattamento unitamente ai rispettivi IC esatti al 95%. Un test di Cochran Mantel Haenszel verrà utilizzato per confrontare i bracci di trattamento e stimare gli odds ratio e i rispettivi IC al 95%, tenendo conto dei fattori di stratificazione. Queste analisi saranno effettuate utilizzando i dati ottenuti dalla revisione locale e centrale dei criteri RECIST v1.1.
    • La sopravvivenza complessiva (OS) è definita come il tempo che intercorre tra la randomizzazione e il decesso per ogni causa. La distribuzione dei tempi di OS sarà stimata utilizzando il metodo di Kaplan Meier in ogni braccio di trattamento e l’effetto del trattamento sarà confrontato utilizzando un test dei ranghi logaritmici stratificato, bilaterale, tenendo conto dei fattori di stratificazione. L’OS mediana e l’IC al 95% ad essa associato saranno calcolati per ogni braccio di trattamento. Un modello di Cox a rischi proporzionali stratificato sarà utilizzato per stimare gli HR e i corrispondenti IC bilaterali al 95%.
    • Il fallimento terapeutico è definito come progressione [definito come il minimo (tempo all’evento secondo la revisione centrale, tempo all’evento secondo la revisione locale)], secondo RECIST v1.1., decesso, ritiro del consenso, AE, deviazioni dal protocollo, perdita al follow-up comparsa di sindrome da carcinoide o altra sindrome legata agli ormoni necessitante di trattamento con SSA (octreotide e/o LAR SSA di soccorso) o inizio di trattamento antitumorale. Il tempo al fallimento terapeutico sarà definito come il tempo che intercorre tra la randomizzazione e l’insuccesso del trattamento. La distribuzione dei tempi al fallimento terapeutico per ogni braccio di trattamento sarà stimata utilizzando il metodo di Kaplan Meier e l’effetto sarà confrontato utilizzando un test dei ranghi logaritmici stratificato, bilaterale. Un modello di Cox a rischi proporzionali stratificato sarà utilizzato per stimare gli HR e i corrispondenti IC bilaterali.
    • Le variazioni medie del biomarker CgA rispetto al basale saranno presentate in modo descrittivo in base al punto di rilevazione temporale e gruppo di trattamento, utilizzando la statistica riepilogativa. Saranno presentati i valori grezzi e la variazione dal basale. Un modello ANCOVA misto, ripetuto che include i fattori di stratificazione sarà adottato per valutare l’effetto del trattamento durante la fase in doppio cieco.
    • Sarà stimata la percentuale di soggetti che presentano una diminuzione = 30% della CgA rispetto al basale a partire dalla visita basale fino alla Settimana 8, unitamente al corrispondente IC al 95% in ciascun braccio di trattamento. Un test di Cochran Mantel Haenszel verrà utilizzato per confrontare i bracci di trattamento e stimare gli odds ratio e i rispettivi IC al 95%, tenendo conto dei fattori di stratificazione.
    • EORTC QLQ C30 sarà descritto al basale e ogni 12 settimane durante le fasi in doppio cieco e di estensione in aperto (entrambi i periodi di trattamento e
    E.5.2.1Timepoint(s) of evaluation of this end point
    Refer to study protocol
    Refer to study protocol
    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 No
    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
    Quality of Life and Patient satisfaction
    Qualità della vita e soddisfazione del paziente
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Austria
    Belgium
    France
    Germany
    Italy
    Spain
    United Kingdom
    United States
    E.8.7Trial 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years2
    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: 166
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 216
    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)
    None
    None
    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 Decision2016-07-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-07
    P. End of Trial
    P.End of Trial StatusCompleted
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