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    Summary
    EudraCT Number:2010-024568-16
    Sponsor's Protocol Code Number:CV181-147
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-03-05
    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 number2010-024568-16
    A.3Full title of the trial
    A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Saxagliptin (BMS-477118) in Combination with Metformin IR or Metformin XR in Pediatric Patients with Type 2 Diabetes who have Inadequate Glycemic control on Metformin Alone
    Studio multicentrico, randomizzato, in doppio cieco, controllato verso placebo, teso a valutare l'efficacia e la sicurezza di saxagliptin (BMS-477118) somministrato in combinazione con metformina IR o metformina XR a pazienti pediatrici con diabete di tipo 2 che presentano controllo glicemico inadeguato con l'assunzione di sola metformina
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate the Efficacy and Safety of Saxagliptin (BMS-477118) in combinaton with Metformin IR or Metformin XR therapy in Pediatric Patients with Type 2 Diabetes who have inadequate Glycemic Control on Metformin Alone
    Studio per valutare l’efficacia e la sicurezza di saxagliptin (BMS-477118) somministrato in combinazione con metformina IR o metformina XR a pazienti pediatrici con diabete di tipo 2 che presentano controllo glicemico inadeguato con l’assunzione di sola metformina
    A.4.1Sponsor's protocol code numberCV181-147
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01434186
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/097/2011
    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 pointEU Study Start Up Unit
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance - Avenue de Finlande, 8
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.4Telephone number32 2 3527876
    B.5.5Fax number32 2 3527164
    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 namesaxagliptin
    D.3.2Product code BMS-477118-11
    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 INNSAXAGLIPTIN
    D.3.9.1CAS number 361442-04-8
    D.3.9.2Current sponsor codeBMS-477118-11
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB25220
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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: 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 namesaxagliptin
    D.3.2Product code BMS-477118-11
    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 INNSAXAGLIPTIN
    D.3.9.1CAS number 361442-04-8
    D.3.9.2Current sponsor codeBMS-477118-11
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB25220
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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 Glucophage 500 mg film-coated tablet
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical 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 INNMETFORMIN HYDROCHLORIDE
    D.3.9.1CAS number 1115-70-4
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB03200MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 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 Glucophage SR 500 mg prolonged release tablets
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Prolonged-release 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 INNMETFORMIN HYDROCHLORIDE
    D.3.9.1CAS number 1115-70-4
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB03200MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 placeboFilm-coated tablet
    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
    diabetes type 2
    Diabete Tipo-2
    E.1.1.1Medical condition in easily understood language
    diabetes
    Diabete
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level SOC
    E.1.2Classification code 10027433
    E.1.2Term Metabolism and nutrition disorders
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    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 after 16 weeks of oral double-blind treatment the mean change from baseline in HbA1c achieved with saxagliptin and placebo as add on therapy to metformin IR or metformin XR.
    Confrontare, dopo 16 settimane di trattamento orale in doppio cieco, la variazione media dal basale di HbA1c conseguita con saxagliptin e placebo come terapia aggiuntiva alla metformina a rilascio immediato o alla metformina XR
    E.2.2Secondary objectives of the trial
    To compare after 16 weeks of oral double-blind treatment the effects of saxagliptin versus placebo as add on therapy to metformin IR or metformin XR on: 1) The AUC change from baseline in 2-hour PPG levels, as determined from samples obtained during Mixed Meal Tolerance Test (MMTT) 2) The change from baseline in FPG 3) The percent of subjects who achieved HbA1c < 7%.
    Confrontare, dopo 16 settimane di trattamento orale in doppio cieco, gli effetti di saxagliptin rispetto al placebo come terapia aggiuntiva alla metformina IR o alla metformina XR in termini di: 1) Variazione dal basale della AUC dei livelli di PPG a 2 ore, stabilita su campioni ottenuti durante test di tolleranza dopo pasto misto (MMTT, Mixed-Meal Tolerance Test) 2) Variazione del valore FPG rispetto ai valori basali 3) Percentuale di soggetti che hanno conseguito un livello di HbA1c &lt; 7%.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Signed Written Informed Consent a) Freely given informed consent must be obtained prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the trial. Minor's parents or legally acceptable representatives must give fully informed written consent. Assent should be obtained according to local regulations and if child is mentally capable. 2) Target Population a) Male and female patients 10 years of age, up to 17 years and 30 weeks of age at the time of screening. b) Previously diagnosed as having type 2 diabetes for at least 2 months by WHO/ADA diagnostic criteria for glucose levels (FPG >7.0 mmol/L [126 mg/dL] or plasma glucose levels 2-hours after 75-mg oral glucose load of >11.1 mmol/L; [200 mg/dL] or a casual plasma > 200 mg/dL with symptoms WHO 1999; WHO 2006; ADA 2010).c) HbA1c ≥ 7.0% and ≤ 10.5% obtained at screening visit followed by randomization HbA1c ≥ 6.5% and ≤ 10.5% obtained during lead in. d) Body weight ≥ 30 kg. e) BMI > 85th percentile. f) Stable dose of metformin (≥ 1000mg - ≤ 2000mg) for a minimum of 2 months. 3) Age and Reproductive Status a) Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of WOCBP. The decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject. b) Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product. c) Women must not be breastfeeding d) Sexually active fertile men must use effective birth control if their partners are WOCBP.
    1) Firma del consenso informato scritto: a) Prima della partecipazione allo studio clinico si dovrà ottenere un consenso informato liberamente rilasciato dai pazienti, incluso il consenso informato per eventuali procedure di screening condotte per stabilire l'eleggibilità del soggetto per lo studio. I genitori o i rappresentanti legalmente autorizzati dei minori dovranno rilasciare un consenso informato scritto completo. Se il bambino è mentalmente capace, si dovrà ottenere il suo assenso secondo quanto stabilito dalle normative locali. 2) Popolazione bersaglio: a) Pazienti di ambo i sessi, di età compresa tra i 10 e i 17 anni e 30 settimane al momento dello screening. b) Diagnosi di diabete di tipo 2 da almeno due mesi, formulata in base a: criteri diagnostici OMS/ADA per la glicemia (FPG &gt; 7,0 mmol/l [126 mg/dl] o livelli plasmatici del glucosio 2 ore dopo un carico orale di glucosio da 75 mg &gt;11,1 mmol/l [200 mg/dl] o glicemia estemporanea &gt; 200 mg/dl con sintomi. OMS 1999; OMS 2006; ADA 2010). c) Livello di HbA1c &gt;= 7,0% e &lt;=10,5% rilevato alla visita di screening, seguito da un livello HbA1c &gt;= 6,5% alla randomizzazione e un livello &lt;= 10,5% nella fase iniziale della terapia. d) Peso corporeo &gt;= 30 kg. e) IMC &gt; 85 percentile. f) Dose stabile di metformina (&gt;= 1.000 mg - &lt;= 2.000 mg) da almeno 2 mesi. 3) Età e stato riproduttivo: a) Le donne potenzialmente fertili (WOCBP, Women Of Childbearing Potential) e gli uomini potenzialmente fertili dovranno utilizzare un metodo di contraccezione accettabile per evitare la gravidanza durante l'intero studio e per le 4 settimane successive all'ultima dose del prodotto sperimentale, in modo da ridurre al minimo il rischio di gravidanza. Per la definizione di WOCBP, vedere paragrafo 3.3.3. La decisione relativa al metodo adeguato di prevenzione della gravidanza deve essere presa attraverso una discussione tra sperimentatore e paziente in studio. b) Le donne devono ottenere un risultato negativo al test di gravidanza sul siero o sulle urine (sensibilità minima 25 UI/l o unità equivalenti di HCG) nelle 72 ore precedenti l'avvio del prodotto sperimentale. c) Le donne non devono essere in fase di allattamento d) Gli uomini fertili e sessualmente attivi devono utilizzare un metodo di controllo delle nascite efficace se hanno partner WOCBP.
    E.4Principal exclusion criteria
    1) Target Disease Exceptions a) Current use of the following medications for the treatment of diabetes, or use within the specified timeframe prior to screening for the main study: • 6 months: insulin (Exceptions: Short-term insulin therapy during hospitalization for causes other than diabetes should be discussed with the Medical Monitor). • 4 months: thiazolidinediones. • 2 months: any other antidiabetic treatment including, but not limited to, sulfonylureas, alpha glucosidase inhibitors, metiglinide, oral or injectable incretins or incretin mimetics. • Any previous use of DPP4-inhibitor and/or incretin mimetics • Exceptions: metformin monotherapy for 2 months or longer b) Current use of weight loss drugs and their use within 3 months of screening. 2) Medical History and Concurrent Diseases a) Significant co-morbidity that would preclude participation in the study. b) Previous diagnosis of monogenic etiology of type 2 diabetes such as MODY, genetic disorders with strong associations with insulin resistance/diabetes and/or obesity (Turner’s Syndrome, Prader-Willi),or secondary diabetes (steroid use, Cushing’s disease, acromegaly). c) Significant cardiovascular history. d) History of hemoglobinopathies e) History of unstable or rapidly progressive renal disease. f) History of alcohol or drug abuse. g) Psychiatric cognitive disorder that will limit the patient’s ability to comply with the study. h) Administration of any other study drug or participation in a clinical research trial within 30 days of planned enrollment to this study (or a longer period if dictated by local regulatory authorities). i) Any condition may render the subject unable to complete the study or may pose significant risk. j) Immunocompromised individuals such as subjects that have undergone organ transplantation or subjects diagnosed with HIV k) Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program. 3) Physical and Laboratory Test Findings a) FPG > 255 mg/dL (14.2 mmol/L) at screening b) DKA within 6 months of study entry c) Abnormal renal function, defined as an abnormal creatinine clearance rate. d) Presence of one or more of the following: antibodies to GAD, ICA or IA-2. e) Active liver disease and/or significant abnormal liver function defined as AST and/or ALT> 2 times upper limits of normal, and/or serum total bilirubin > 2.0 mg/dL. f) […] g) […] 4) Allergies and Adverse Drug Reaction […] 5) Prohibited Therapies and/or Medications […] 6) Sex and Reproductive Status […] 7) Other Exclusion Criteria […] FOR THE WHOLE LIST OF EXCLUSION CRITERIA PLEASE REFER TO PARAGRAPH 3.3.2 OF THE STUDY PROTOCOL
    1) Eccezioni relative alla malattia bersaglio: a) Utilizzo concomitante dei seguenti farmaci per il trattamento del diabete, o utilizzo nella finestra temporale specificata, precedente lo screening per lo studio principale. i) Sei mesi: insulina (eccezioni: la terapia insulinica a breve termine durante il ricovero ospedaliero per cause diverse dal diabete deve essere preventivamente autorizzata dal responsabile del monitoraggio clinico). ii) Quattro mesi: tiazolidinedioni. iii) Due mesi: qualsiasi altro trattamento antidiabetico inclusi, a titolo esemplificativo e non esaustivo, sulfoniluree, inibitori dell'alfa-glucosidasi, metiglinide, incretine orali o iniettabili o incretino-mimetici. iv) Eventuale utilizzo precedente di inibitori della DPP4 e o di incretino-mimetici. v) eccezioni: è consentita la partecipazione ai pazienti in monoterapia con metformina da 2 o più mesi. b) Utilizzo concomitante di farmaci per la perdita di peso, dietro prescrizione o da banco, e loro utilizzo nei 3 mesi precedenti lo screening. 2) Anamnesi e malattie concomitanti: a) Significativa comorbilità che, secondo il parere dello sperimentatore, precluderebbe la partecipazione allo studio b) Precedente diagnosi di diabete di tipo 2 a eziologia monogenica come il MODY (Maturity Onset of Diabetes in Youth), disordini genetici fortemente associati a resistenza insulinica/diabete e/o obesità, come la sindrome di Turner e di Prader-Willi, oppure diabete secondario (uso di steroidi, sindrome di Cushing, acromegalia). c) Anamnesi cardiovascolare significativa. d) Anamnesi di emoglobinopatie (anemia a cellule falciformi o talassemia, anemia sideroblastica). e) Anamnesi di nefropatia instabile o in rapida progressione. f) Anamnesi di abuso di alcol o di droga. g) Disordine psichiatrico o cognitivo che, secondo il parere dello sperimentatore, limiterebbe le capacità del paziente di rispettare i requisiti dello studio in termini di assunzione dei farmaci e monitoraggio. h) Somministrazione di qualsiasi altro farmaco sperimentale o partecipazione a uno studio clinico di ricerca nei 30 giorni precedenti la data di arruolamento nello studio programmata (o un periodo maggiore se imposto dalle autorità di controllo locali). i) Qualsiasi patologia che, secondo il parere dello sperimentatore, renderebbe il soggetto non in grado di completare lo studio o lo esporrebbe a un rischio significativo. j) Soggetti immunocompromessi, ad esempio per trapianto d'organo o diagnosi di virus dell'immunodeficienza umana. k) Soggetti coinvolti in un programma commerciale per la perdita di peso con perdita di peso in atto, oppure impegnati in un programma di attività fisica intensa. 3) Risultati dell'esame obiettivo e delle analisi di laboratorio: a) Una glicemia a digiuno (FPG) &gt; 255 mg/dl (14,2 mmol/l) allo screening. b) Chetoacidosi diabetica (DKA) nei 6 mesi precedenti l'ingresso nello studio c) Funzione renale anomala, definita da una anormale velocità di clearance della creatinina d) Presenza di uno o più dei seguenti elementi: anticorpi anti-decarbossilasi dell'acido glutammico (GAD), autoanticorpi anti-cellule insulari (ICA), o anticorpi anti- protein tirosin fosfatasi-simili (IA-2). e) Epatopatia attiva e/o significativa anomalia della funzione epatica, definita dai seguenti valori: Aspartato aminotransferasi (AST) e/o alanina aminotransferasi (ALT) &gt; 2 volte il limite superiore della norma, e/o bilirubina totale sierica &gt; 2,0 mg/dl. f) […] g) […] 4) Allergie e reazione avversa al farmaco […] 5) Terapie o medicinali proibiti […] 6) Sesso e stato riproduttivo […] 7) Altri criteri di esclusione […] PER LA LISTA COMPLETA DEI CRITERI DI ESCLUSIONE SI PREGA DI FARE RIFERIMENTO AL PARAGRAFO 3.3.2 DEL PROTOCOLLO
    E.5 End points
    E.5.1Primary end point(s)
    Mean change in HbA1c from baseline to Week 16 (or the last postbaseline measurement prior to Week 16, if no Week 16 assessment is available) in the short term treatment period.
    Confrontare la variazione media di HbA1c dal basale ottenuta con saxagliptin e placebo in terapia aggiuntiva a metformina IR o metformina XR dopo 16 settimane di trattamento orale in doppio cieco
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analyses at Week 16 of the primary and secondary efficacy endpoints will be based on measurements available at that time point or the last post-baseline measurement prior to the time-point, if no measurement is available at that time point, ie, LOCF. For subjects who meet the pre-specified rescue criteria, their last post-baseline measurement prior to initiation of rescue medication will be used, unless otherwise specified. All efficacy analyses will be performed using the Randomized Dataset. In addition the Primary efficacy analysis will be performed using the Evaluable Dataset as a sensitivity analysis.
    Le analisi primarie per gli endpoint di efficacia primaria e secondaria effettuate alla Settimana 16 si baseranno sulle rilevazioni disponibili al momento o, in loro assenza, sull’ultima rilevazione post-basale prima della Settimana 16, ovvero l’ultima osservazione effettuata (LOCF). Per i soggetti che soddisfano i criteri di emergenza prestabiliti, salvo diversamente specificato, si farà riferimento all’ultima valutazione post-basale prima di iniziare il farmaco di emergenza. Tutte le analisi di efficacia saranno eseguite utilizzando il “Randomized Dataset” come definito nel Protocollo. In aggiunta, le analisi di efficacia primaria saranno effettuate utilizzando l’“Evaluable Dataset” –secondo definizione data nel Protocollo , come analisi di sensitività.
    E.5.2Secondary end point(s)
    To compare after 16 weeks of oral double-blind treatment the effects of saxagliptin versus placebo as add on therapy to metformin IR or metformin XR on: . Mean change in 2-hour PPG AUC from baseline to Week 16 (or the last postbaseline measurement prior to Week 16, if no Week 16 assessment is available) in the short term treatment period. • Mean change in FPG from baseline to Week 16 (or the last postbaseline measurement prior to Week 16, if no Week 16 assessment is available) in the short term treatment period. • Percent of subjects with HbA1c < 7% at Week 16 (or the last postbaseline measurement prior to Week 16, if no Week 16 assessment is available) in the short term treatment period
    Confrontare, dopo 16 settimane di trattamento orale in doppio cieco, gli effetti di saxagliptin rispetto al placebo come terapia aggiuntiva alla metformina IR o alla metformina XR in termini di: o Variazione media nella AUC-PPG a 2 ore dal basale alla Settimana 16 (o ultima rilevazione post-basale prima della Settimana 16, se in quell’occasione non sono state effettuate misurazioni) del periodo di trattamento a breve termine. o Variazione media nella FPG dal basale alla Settimana 16 (o ultima rilevazione post-basale prima della Settimana 16, se in quell’occasione non sono state effettuate misurazioni) del periodo di trattamento a breve termine. o Percentuale di soggetti con HbA1c < 7% alla Settimana 16 (o ultima rilevazione post-basale prima della Settimana 16, se in quell’occasione non sono state effettuate misurazioni) del periodo di trattamento a breve termine
    E.5.2.1Timepoint(s) of evaluation of this end point
    The analyses at Week 16 of the primary and secondary efficacy endpoints will be based on measurements available at that time point or the last post-baseline measurement prior to the time-point, if no measurement is available at that time point, ie, LOCF. For subjects who meet the pre-specified rescue criteria, their last post-baseline measurement prior to initiation of rescue medication will be used, unless otherwise specified. All efficacy analyses will be performed using the Randomized Dataset. In addition the Primary efficacy analysis will be performed using the Evaluable Dataset as a sensitivity analysis.
    Le analisi primarie per gli endpoint di efficacia primaria e secondaria effettuate alla Settimana 16 si baseranno sulle rilevazioni disponibili al momento o, in loro assenza, sull’ultima rilevazione post-basale prima della Settimana 16, ovvero l’ultima osservazione effettuata (LOCF). Per i soggetti che soddisfano i criteri di emergenza prestabiliti, salvo diversamente specificato, si farà riferimento all’ultima valutazione post-basale prima di iniziare il farmaco di emergenza. Tutte le analisi di efficacia saranno eseguite utilizzando il “Randomized Dataset” come definito nel Protocollo. In aggiunta, le analisi di efficacia primaria saranno effettuate utilizzando l’“Evaluable Dataset” –secondo definizione data nel Protocollo , come analisi di sensitività.
    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 No
    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 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 trial4
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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
    Canada
    India
    Israel
    Mexico
    Russian Federation
    South Africa
    Taiwan
    Turkey
    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
    Two months after last patient last visit when the locking of the database.
    Due mesi dopo l’ultima visita dell’ultimo soggetto, al momento della chiusura del database dello studio.
    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 months74
    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 months74
    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 Yes
    F.1.1Number of subjects for this age range: 465
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 19
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 446
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 97
    F.4.2.2In the whole clinical trial 465
    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)
    Subjects will be contacted 30 days after last dose to assess SAEs; this assessment may be by telephone. Study participants will be offered follow-up assessments for select parameters during a post-study observational period at least annually (see Section 5.3) for at least 5 years or for at least 2 years after reaching Tanner stage V (whichever first).
    I soggetti saranno contattati dopo 30 giorni dall’ultima dose per la valutazione dei SAE; tale valutazione potrà essere effettuata telefonicamente. Ai partecipanti allo studio saranno offerte valutazioni di follow-up per parametri selezionati durante un periodo osservazionale post-studio a intervalli di almeno un anno (vedere Sezione 5.3) per almeno 5 anni o per almeno 2 anni dopo il raggiungimento dello Stadio V di Tanner (a seconda di quale evento si verifichi per primo).
    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 Decision2012-03-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-28
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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