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    Summary
    EudraCT Number:2012-001266-15
    Sponsor's Protocol Code Number:BRF115532
    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:2012-12-19
    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 number2012-001266-15
    A.3Full title of the trial
    COMBI-AD: A phase III randomized double blind study of dabrafenib(GSK2118436) in COMBInation with trametinib(GSK1120212)versus two placebos in the ADjuvant treatment of high-risk BRAF V600 mutationpositive melanoma after surgical resection.
    COMBI-AD:Studio di Fase III randomizzato, in doppio cieco di confronto tra l'associazione di dabrafenib (GSK2118436) e trametinib (GSK1120212)verso due placebo nella terapia adiuvante del melanoma ad alto rischio con mutazione V600 dopo resezione chirurgica.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib compared to two placebos (inactive drugs) in the treatment of BRAF V600E/K mutation-positive melanoma after surgery.
    Uno studio del dabrafenib inibitore BRAF in combinazione con il MEK trametinib inibitore rispetto al placebo (due farmaci inattivi) nella trattamento di BRAF V600E / K positivi alla mutazione melanoma dopo l'intervento chirurgico.
    A.3.2Name or abbreviated title of the trial where available
    COMBI-AD
    COMBI-AD
    A.4.1Sponsor's protocol code numberBRF115532
    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 SponsorGLAXOSMITHKLINE RESEARCH & DEVELOPMENT LTD.
    B.1.3.4CountryUnited Kingdom
    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 supportGlaxoSmithKline
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline
    B.5.2Functional name of contact pointClinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road
    B.5.3.2Town/ cityUxbridge
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 020 8990 4466
    B.5.5Fax number+44 020 8990 1234
    B.5.6E-mailGSKClinicalSupportHD@gsk.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 namedabrafenib
    D.3.2Product code GSK2118436
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdabrafenib
    D.3.9.1CAS number 1195765-45-7
    D.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameDABRAFENIB
    D.3.9.4EV Substance CodeSUB45696
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.IMP: 2
    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 namedabrafenib
    D.3.2Product code GSK2118436
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdabrafenib
    D.3.9.1CAS number 1195765-45-7
    D.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameDABRAFENIB
    D.3.9.4EV Substance CodeSUB45696
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.IMP: 3
    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 nametrametinib
    D.3.2Product code GSK1120212
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtrametinib
    D.3.9.2Current sponsor codeGSK1120212
    D.3.9.3Other descriptive nametrametinib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number.5
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.IMP: 4
    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 nametrametinib
    D.3.2Product code GSK1120212
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTRAMETINIB
    D.3.9.2Current sponsor codeGSK1120212
    D.3.9.3Other descriptive nameTRAMETINIB
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High-risk BRAF V600 mutation-positive melanoma after surgical resection.
    Soggetti dd alto rischio BRAF V600 positivi alla mutazione melanoma dopo resezione chirurgica.
    E.1.1.1Medical condition in easily understood language
    A certain type of skin cancer (after removal by surgery)
    cancro della pelle (dopo la rimozione da un intervento chirurgico)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLT
    E.1.2Classification code 10027156
    E.1.2Term Skin melanomas (excl ocular)
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of dabrafenib and trametinib combination therapy compared to two placebos with respect to relapse-free survival (RFS) in patients with completely resected, histologically confirmed,BRAF V600E/K high-risk, stage III cutaneous melanoma
    Valutare l'efficacia della terapia di associazione dabrafenib e trametinib rispetto ai due placebo in termini di sopravvivenza libera da recidiva(RFS) in pazienti completamente resecati, con conferma istologica di melanoma cutaneo ad alto rischio di stadio III positivo alle mutazioni di BRAF V600E/K
    E.2.2Secondary objectives of the trial
    - To compare overall survival (OS) of dabrafenib and trametinib as a combination therapy versus two placebos. - To compare distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus two placebos. - To compare freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus two placebos. - To evaluate the safety of dabrafenib and trametinib as a combination therapy in the overall study population including incidences of squamous cell carcinoma (SCC), new cancers in other sites, and other proliferative cutaneous lesions.
    - Confrontare la terapia di associazione dabrafeninb -trametinib rispetto ai due placebo in termini di sopravvivenza globale (OS). - Confrontare la terapia di associazione dabrafeninb -trametinib rispetto ai due placebo in termini di sopravvivenza libera da metastasi a distanza (DMFS). -Confrontare la terapia di associazione dabrafeninb -trametinib rispetto ai due placebo in termini di Intervallo libero da recidiva (FFR). - Determinare la sicurezza della terapia di associazione dabrafeninb-trametinib nella popolazione complessiva dello studio inclusa l'incidenza di carcinoma a cellule squamose (SCC), nuovi tumori in altri siti, e altre lesioni cutanee proliferative.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Is 18 years of age or older. 2. Has signed written informed consent. 3. Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis >1 mm),IIIb or IIIc; cutaneous melanoma determined to be V600E/K mutation positive using the bioMerieux (bMX)investigational use only (IUO) THxID BRAF Assay (IDE: G120011).Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. 4. Must be surgically rendered free of disease no more than 12 weeks before randomization. 5. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains). 6. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 [Oken, 1982] 8. Must have adequate organ function 9. Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, as defined in Section 7.3.3 from 14 days prior to randomization, throughout the treatment period and for 30 days after the last dose of study treatment. 10. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from the day of randomization, throughout the treatment period and for 16 weeks after the last dose of study treatment. 11. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
    1.Età &gt;/= 18 anni. 2.Firma del consenso informato scritto. 3.Conferma istologica di melanoma cutaneo ad alto rischio completamente resecato [Stage IIIa (metastasi LN &gt;1 mm), IIIb o IIIc; fare riferimento all'Appendice 1 per le Linee Guida di Staging] positivo alla mutazione V600E/K determinata con il saggio bioMerieux (bMX) per uso esclusivamente sperimentale (investigational use only (IUO) THxID BRAF Assay (IDE: G120011)). Il test sarà condotto presso un laboratorio centrale di riferimento. Sono eleggibili i soggetti che dopo una diagnosi di melanoma di Stadio I o II presentano a livello linfonodale una iniziale ricomparsa di malattia resecabile. 4.Devono essere resi liberi da malattia non più di 12 settimane prima della randomizzazione. 5.Recupero post-operatorio dopo chirurgia definitiva (per esempio, non sono presenti infezioni non controllate delle ferite, o cateteri per il drenaggio). 6.Il soggetto deve essere in grado di deglutire e trattenere farmaci orali e non deve presentare anomalie gastrointestinali clinicamente significative che possono alterare l'assorbimento, come sindrome da malassorbimento o resezione maggiore dello stomaco o dell’intestino. 7.ECOG Performance Status 0-1 [Oken, 1982]. 8.Funzionalità d'organo adeguata, al momento dello screening. 9.Le donne in età fertile devono presentare un test di gravidanza negativo, eseguito nei 7 giorni precedenti la prima dose del trattamento in studio, e accettare di utilizzare un metodo contraccettivo efficace, da 14 giorni prima della randomizzazione e continuando per tutta la durata della terapia dello studio e per i 30 giorni successivi all'assunzione dell'ultima dose del trattamento in studio. 10.Gli uomini con partner femminili in età fertile, se non vasectomizzati, devono accettare di utilizzare un metodo contraccettivo efficace, iniziando 14 giorni prima della randomizzazione e continuando per tutta la durata della terapia dello studio e per 6 mesi dopo l’ultima dose.
    E.4Principal exclusion criteria
    1. Known mucosal or ocular melanoma or the presence of unresectable in-transit metastases. 2. Evidence of distant metastatic disease on screening evaluation. 3. Prior systemic anti-cancer treatment (chemotherapy,immunotherapy, biologic therapy, vaccine therapy, or investigational treatment)and radiotherapy for melanoma. Prior surgery for melanoma is allowed. 4. Taken an investigational drug within 28 days or 5 half-lives,whichever is longer, prior to randomization. 5. Current or expected use of a prohibited medication 6. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO). 7. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection(with the exception of chronic or cleared HBV and HCV infection which are allowed). 8. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency. 9. History of another malignancy or a concurrent malignancy including prior malignant melanoma except as noted below;Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas, or other malignancies for which the patient has been disease free for > 5 years except those known to have had a KRAS mutation. 10. A history or evidence of cardiovascular risk including any of the following: a. A QT interval corrected for heart rate using the Bazett's formula (QTcB; Appendix 5) ≥ 480 msec; b. A history or evidence of current clinically significant uncontrolled arrhythmias; c. A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization d. A history or evidence of current > Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines e. Patients with intra-cardiac defibrillators or permanent pacemakers. f. Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study. g. Treatment refractory hypertension defined as a blood pressure of systolic >140 mm HgmmHg and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy 11. A history or current evidence/risk of retinal vein occlusion(RVO) or central serous retinopathy(CSR) including: a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or b. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: i. Evidence of new optic disc cupping; ii. Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure >21 mm mmHg as measured by tonography. 13. History of interstitial lung disease or pneumonitis. 14. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the investigator, could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures. 15. Pregnant or nursing females.
    1.Pazienti affetti da melanoma mucosale oppure oculare o presenza di metastasi in-transit non resecabili. 2.Evidenza alla valutazione di screening di malattia con metastasi a distanza. 3.Precedente trattamento anti-tumorale sistemico (chemioterapia,immunoterapia, terapia biologica, vaccinoterapia, o trattamento sperimentale) e radioterapia per il melanoma. E’ permessa una precedente chirurgia per il melanoma. 4.Somministrazione di un prodotto sperimentale nei 28 giorni o 5 emivite (si applica il periodo più lungo) prima della randomizzazione. 5.Terapia in atto o che ci si attende che sarà necessaria con farmaci non consentiti dal protocollo. 6.Nota reazione di ipersensibilità immediata o ritardata o idiosincrasia a farmaci chimicamente correlati ai trattamenti in studio, ai loro eccipienti, e/o dimetilsolfossido (DMSO). 7.Infezione diagnosticata da virus dell’immunodeficienza umana(HIV). 8.Deficit di glucosio-6-fosfato deidrogenasi(G6PD). 9.Storia o simultaneità di altra malignità incluso precedente melanoma maligno. Eccezione: sono eleggibili i soggetti che sono stati liberi da malattia per 5 anni, o i soggetti con una storia di carcinoma cutaneo non melanomatoso completamente resecato o carcinoma in situ trattato con successo, per esempio carcinoma in situ della cervice, iperplasia melanocitica atipica o melanoma in situ, melanomi primari multipli, o altre malignità per le quali il paziente è stato libero da malattia per &gt; 5 anni. 10.Anamnesi o evidenze di rischio cardiovascolare, tra cui una delle seguenti condizioni: a.Intervallo QT corretto per la frequenza con la formula di Bazett (QTcB; Appendice 5) &gt;/=480 ms; b.Aritmie non controllate, clinicamente significative, pregresse o in atto; c.Pregresse (nei 6 mesi precedenti la randomizzazione)sindromi coronariche acute(infarto miocardico o angina instabile), angioplastica coronaria o stent; d.Scompenso cardiaco congestizio pregresso o in atto di Classe &gt;=II secondo le linee guida della NYHA (New York Heart Association)(Appendice 6); e.Pazienti con defibrillatori intracardiaci o pacemakers permanenti; f.Valvulopatie (grado ≥2) documentate ecocardiograficamente(sono eleggibili i soggetti con alterazioni di grado 1 [stenosi/insufficienza lieve]).Non sono eleggibili i soggetti con ispessimenti valvolari moderati. g.Ipertensione refrattaria, definita come PA sistolica(PAS) &gt;140 mmHg e/o diastolica(PAD) &gt;90 mmHg non controllabile con la terapia anti-ipertensiva; 11.Anamnesi positiva o segni clinici/rischio di occlusione venosa retinica(RVO) o retinopatia centrale sierosa(CSR),quali: a.Fattori predisponenti per RVO o CSR (ad es. ipertensione oculare o glaucoma non controllato, ipertensione non controllata, diabete mellito non controllato, sindromi da iperviscosità o ipercoagulabilità); b.Patologie retiniche visibili diagnosticate mediante oftalmoscopia e considerate fattori di rischio per RVO o CSR, quali: i.Cupping del disco ottico (neuropatia ottica compressiva); ii.Difetti del campo visivo misurati con perimetria automatizzata; iii.Ipertensione oculare &gt;21 mmHg misurata mediante tonometria. 12.Storia di malattia polmonare interstiziale o polmonite. 13.Condizioni mediche, psichiatriche o di altro genere gravi e/o instabili preesistenti(fatta eccezione per le malignità di cui sopra)che potrebbero interferire con la sicurezza del soggetto, l’ottenimento del consenso informato o il rispetto delle procedure dello studio. 14.Donne incinte o in allattamento.
    E.5 End points
    E.5.1Primary end point(s)
    Relapse Free Survival (RFS), defined as the time from randomization to disease recurrence or death from any cause.
    Sopravvivenza libera da recidiva (RFS), definita come l’intervallo di tempo tra la data di randomizzazione e la data di ricomparsa della malattia o decesso per qualsiasi motivo. Sono considerati eventi la ricomparsa della malattia o il decesso causato dallo stesso tumore e tutti i decessi per altre cause. Le neoplasie maligne che possono emergere in seguito al trattamento, eccetto il melanoma secondario, non saranno considerati eventi. In pazienti persi al Follow up verranno censiti alla data dell’ultimo follow-up. I pazienti senza eventi RFS verranno censurati all’ultima valutazione adeguata.
    E.5.1.1Timepoint(s) of evaluation of this end point
    every 3 months
    ogni 3 mesi
    E.5.2Secondary end point(s)
    -Overall survival (OS) -Distant metastasis-free survival (DMFS) -Freedom from relapse (FFR) -Safety including incidences of squamous cell carcinoma (SCC), and other proliferative cutaneous lesions
    -OS, definita come l’intervallo di tempo tra la data di randomizzazione e la data del decesso, indipendentemente dalla causa; i pazienti che saranno ancora vivi saranno valutati alla data dell’ultimo contatto. -DMFS, definita come l’intervallo di tempo tra la data di randomizzazione e la data della prima metastasi a distanza o la data del decesso, a seconda di quale delle due ipotesi si verifica per prima. I pazienti vivi e senza metastasi a distanza saranno valutati alla data dell’ultimo contatto. -FFR definita come l’intervallo di tempo tra la data di randomizzazione e la data della recidiva locale o a distanza e verranno censurati i pazienti deceduti, per cause diverse dal melanoma o tossicità correlate al trattamento, alla data del decesso. I pazienti vivi senza recidiva con un secondo tumore primario saranno censurati alla data dell’ultima valutazione. -Sicurezza in base alla valutazione clinica: segni vitali e esame obiettivo, ECG a 12 derivazioni (ECG), ecocardiogramma (ECO), visita oculistica, valori dei parametri ematologici e di chimica clinica e eventi avversi (AEs).
    E.5.2.1Timepoint(s) of evaluation of this end point
    -OS: every 3 months, then every 6 months after 2 years -DMFS: every 3 months -FFR: every 3 months -Safety: every month for the first 12 months, then every 3 months until month 24, then every 6 months until relapse.
    -OS:ogni 3 mesi, poi ogni 6 mesi dopo 2 anni -DMFS:ogni 3 mesi -FFR:ogni 3 mesi -SAFETY:ogni mese per i primi 12 mesi, poi ogni 3 mesi fino al mese 24, poi ogni 6 mesi fino a ricaduta.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    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 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) 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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA125
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Israel
    New Zealand
    Russian Federation
    Switzerland
    Taiwan
    United States
    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
    The study will be considered complete, and the final OS analysis will be conducted when approximately 70% of the total number of randomized subjects have died
    Lo studio sarà considerato completo, e l'analisi finale della OS sarà condotta quando circa il 70% del numero totale di soggetti randomizzati saranno deceduti.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months65
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months65
    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.1.1Number of subjects for this age range: 0
    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: 682
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 170
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 483
    F.4.2.2In the whole clinical trial 852
    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
    n.a.
    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 Decision2013-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-17
    P. End of Trial
    P.End of Trial StatusOngoing
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