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    Summary
    EudraCT Number:2013-002269-21
    Sponsor's Protocol Code Number:01.00240
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-06-18
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2013-002269-21
    A.3Full title of the trial
    Metformin in diastolic dysfunction of metabolic syndrome
    A metformina na disfunção diastólica da síndrome metabólica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Metformin in diastolic dysfunction of metabolic syndrome
    A metformina na disfunção diastólica da síndrome metabólica
    A.3.2Name or abbreviated title of the trial where available
    MET-DIME Trial
    Estudo MET-DIME
    A.4.1Sponsor's protocol code number01.00240
    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 SponsorDepartment of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto
    B.1.3.4CountryPortugal
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFundação para a Ciência e Tecnologia
    B.4.2CountryPortugal
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFaculty of Medice, University of Porto
    B.5.2Functional name of contact pointDepartment of Physiology
    B.5.3 Address:
    B.5.3.1Street AddressAlameda Prof. Hernâni Monteiro
    B.5.3.2Town/ cityPorto
    B.5.3.3Post code4200-319
    B.5.3.4CountryPortugal
    B.5.4Telephone number00351225513644
    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 Metformin 500mg (Glucophage)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck S.A.
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    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.3.11 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 Yes
    D.2.1.1.1Trade name Metformin (1000mg) - Risidon
    D.2.1.1.2Name of the Marketing Authorisation holderMerck, S.A.
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    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.3.11 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diastolic dysfunction in non-diabetic patients with metabolic syndrome
    Disfunção diastólica em doentes não diabéticos com síndrome metabólica
    E.1.1.1Medical condition in easily understood language
    Impaired cardiac relaxation in metabolic syndrome
    Alteração do relaxamento do coração na síndrome metabólica
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    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 if treating non-diabetic patients with metabolic syndrome (MS) and rest diastolic dysfunction (DD) with metformin, in addition to a lifestyle change intervention program, improves diastolic function and assess its impact in functional capacity and health-related quality of life.
    - Explorar se o tratamento com metformina, para além da modificação do estilo de vida, melhora a função diastólica de doentes não diabéticos com síndrome metabólica e disfunção diastólica em repouso, avaliando também o seu impacto na capacidade funcional e qualidade de vida;

    E.2.2Secondary objectives of the trial
    - To evaluate if biomarkers of cardiac remodeling, inflammation, and glucose homeostasis are predictive factors of response to metformin treatment of non-diabetic patients with MS and DD.
    - Investigar se indicadores metabólicos (resistência à insulina e adiponectina) ou biomarcadores de remodelagem e inflamação [proteína C reativa (PCR) de alta sensibilidade, fator de necrose tumoral alfa (TNFα), inibidor tecidular da metaloproteinase tipo 1 (TIMP1) e fator de diferenciação do crescimento 15 (GDF-15)] são fatores preditivos da resposta ao tratamento com metformina nestes doentes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Non-diabetic adults aged between 40 and 64 years fulfilling the AHA/NHLBI criteria for clinical diagnosis of metabolic syndrome [(at least 3 of the following: waist circumference ≥102cm in males or ≥88cm in females; fasting plasma triglycerides ≥150mg/dL or on drug treatment for elevated triglycerides; fasting HDL cholesterol ˂40mg/dL in males or ˂50mg/dL in females or on drug treatment for reduced HDL; systolic blood pressure≥130mmHg or diastolic blood pressure≥85mmHg or on antihypertensive drug treatment in a patient with history of hypertension; fasting plasma glucose≥100mg/dL)]
    AND WITH
    - Echocardiographic evidence of left ventricle diastolic dysfunction at rest, considering the mean of septal and lateral E’ as assessed by Tissue Doppler Imaging echocardiography (E’mean˂10.2 cm/s if 40-59 years old or E’mean˂7,2 cm/s if aged 60 to 65 years old).
    -Adultos não diabéticos com idade entre os 40 e 64 anos que cumpram os critérios da AHA/NHLBI para o diagnóstico de síndrome metabólica (pelo menos 3 dos seguintes: perímetro da cintura ≥102cm nos homens ou ≥88cm nas mulheres; triglicerídeos em jejum ≥150mg/dL ou em terapêutica por hipertrigliceridemia; colesterol HDL em jejum ˂40mg/dL nos homens ou ˂50mg/dL nas mulheres ou em tratamento por níveis baixos de colesterol HDL; pressão arterial sistólica ≥130mmHg ou diastólica ≥85mmHg ou medicado com fármacos antihipertensores por diagnóstico prévio de hipertensão arterial; glicemia plasmática em jejum ≥100mg/dL)
    E COM
    -Evidência ecocardiográfica de disfunção diastólica do ventrículo esquerdo em repouso, considerando a média das velocidades protodiastólicas septal e lateral do anel mitral avaliadas por Doppler tecidular (E’médio˂10,2 cm/s se 40-59 anos ou E’médio˂7,2 cm/s se idade entre os 60 e 65 anos).
    E.4Principal exclusion criteria
    - Diagnosis of diabetes mellitus according to the ADA criteria (at least one of the following: fasting plasma glucose ≥126mg/dL; 2-hour plasma glucose ≥200mg/dL during an oral glucose tolerance test, as described the WHO; random plasma glucose ≥200mg/dL in a patient with classical symptoms of hyperglycemia or hyperglycemic crisis; hemoglobin A1C≥6.5% using a method that is NGSP certified and standardized to the DCCT assay or ≥48mmol/mol reported in IFCC units)
    - Previous diagnosis of ischemic heart disease (history of angina, acute coronary syndrome, acute myocardial infarction or coronary artery bypass graft surgery);
    - Left ventricle ejection fraction less than 50% (assessed by transthoracic echocardiography);
    - Moderate or severe cardiac valvular disease;
    - Pericardial disease;
    - Uncontrolled atrial or ventricular tachyarrhythmias;
    - History of myocarditis;
    - Renal disease or dysfunction (plasma creatinine ≥1.5mg/dL in males or ≥1.4mg/dL in females);
    - Significant liver disease (aspartate aminotransferase or alanine aminotransferase ≥2.5 times upper limit of normal);
    - Females who are pregnant, planning to become pregnant or who admit sexual activity without appropriate contraception;
    - Lactation.
    - Unable to perform cardopulmonary exercise test.
    - Recent (less than 1 month) change in anti-hypertensive or antidislipidemic medications.
    - Diabetes mellitus, de acordo com os critérios da Sociedade Americana de Diabetes(25);
    - Doença cardíaca isquémica (história de angina, síndrome coronária aguda, enfarte agudo do miocárdio ou cirurgia de revascularização miocárdica);
    - Fração de ejeção do ventrículo esquerdo inferior a 50%, avaliada por ecocardiograma transtorácico;
    - Doença cardíaca valvular moderada a severa;
    - Doença pericárdica;
    - Taquiarritmias supraventriculares ou ventriculares não controladas;
    - Disfunção renal (creatinina plasmática ≥1.5mg/dL nos homens ou ≥1.4mg/dL nas mulheres);
    - Disfunção hepática (valores de transamínases glutamo-oxaloacética ou glutamo-pirúvica ≥2,5 vezes o limite superior do normal);
    - Grávidas, mulheres a tentar engravidar ou que admitam atividade sexual sem contraceção;
    - Mulheres a amamentar;
    - Incapacidade de realizar prova de esforço cardiorrespiratória.
    - Mudança recente (com menos de 1 mês) da terapêutica anti-hipertensora ou antidislipidémica
    E.5 End points
    E.5.1Primary end point(s)
    Change in mean of septal and lateral early diastolic mitral annular velocities (E’) during the 24 month follow-up period.
    Variação na média das velocidades protodiastólicas do anel mitral (E’médio) septal e lateral, avaliadas por ecocardiografia Doppler tecidular (TDI).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Serial echocardiographic measurements will be performed at baseline, month 6, month 12 and month 24 after randomization.
    Avaliação seriada aos 6, 12 e 24 meses após randomização.
    E.5.2Secondary end point(s)
    - Change in diastolic echocardiographic parameters: E/E´ratio, isovolumetric relaxation time (IVRT), E/A ratio, E wave deceleration time (DT), diastolic dysfunction grades according to the ASE/ESE consensus, strain rate during IVRT (SR-IVR) and E/SR-IVR ratio;
    - Change in metabolic parameters: insulin and glucose plasma levels, insulin resistance (HOMA – Homeostasis Model Assessment) and adiponectin levels.
    - Change in cardiovascular biomarkers: NTproBNP and high sensitivity C-reactive protein;
    - Change in remodeling and inflammation biomarkers: TNFα, TIMP1 e GDF-15;
    - Change in functional capacity during cardiopulmonary exercise test, including assessment of peak oxygen uptake, anaerobic threshold and ventilatory efficiency;
    - Change in epicardial, pericardial and abdominal adipose tissue volumes, and coronary calcium score, assessed by cardiac multidetector CT (MDCT)
    - Change in health-related quality of life, according to Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36).
    Alterações em:
    - parâmetros ecocardiográficos de avaliação da função diastólica: relação E/E´(septal e lateral), tempo de relaxamento isovolumétrico (IVRT), relação E/A, tempo de desaceleração (DT) da onda E, graus de disfunção diastólica de acordo com documento de consenso da ASE/ESE, strain rate durante o relaxamento isovolumétrico (SR-IVR) e razão E/SR-IVR;
    - indicadores metabólicos [níveis plasmáticos de insulina, glicose, índice de resistência à insulina (HOMA – Homeostasis Model Assessment) e adiponectina];
    - biomarcadores cardiovasculares: níveis plasmáticos do fragmento N-terminal do pró-peptídeo natriurético do tipo B (NT-pró-BNP) e proteína C reativa (PCR) de alta sensibilidade;
    - biomarcadores de remodelagem e inflamação: TNFα, TIMP1 e GDF-15;
    - capacidade funcional durante a prova de esforço cardiorrespiratória, incluindo pico de consumo de oxigénio, limiar anaeróbio e eficiência ventilatória;
    - quantidade de gordura pericárdica, epicárdica e abdominal;
    - quantidade de cálcio na árvore coronária (Agatston score);
    - qualidade de vida relacionada com a saúde, de acordo com a versão reduzida do questionário de qualidade de vida Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Blood sampling: baseline, months 12 and 24
    Echocardiography: baseline, months 6, 12 and 24
    Cardiac CT: baseline, month 24
    Cardiopulmonary exercise test: baseline, months 12 and 24
    SF-36: baseline, months 12 and 24
    Colheita de sangue: pré-randomização, meses 12 e 24
    Ecocardiografia: pré-randomização, meses 6, 12 e 24
    Tomografia computorizada cardíaca: pré-reandomização e mês 24
    Prova cardiorrespiratória: pré-randomização, meses 12 e 24
    Questionário SF-36: pré-randomização, meses 12 e 24
    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 No
    E.6.5Efficacy No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Programa de alteração do estilo de vida
    Lifestyle change intervention program
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    24 month follow-up visit of the last included subject.
    Visita dos 24 meses do último participante incluído.
    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 months10
    E.8.9.1In the Member State concerned 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: 54
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state54
    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)
    Expected normal treament for diastolic dysfunction and metabolic syndrome.
    Tratamento de acordo com as orientações mais recentes para disfunção diastólica e síndrome metabólica.
    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 Decision2013-08-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-06
    P. End of Trial
    P.End of Trial StatusOngoing
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