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    Summary
    EudraCT Number:2015-002824-18
    Sponsor's Protocol Code Number:8-311-3-062
    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:2021-09-10
    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 number2015-002824-18
    A.3Full title of the trial
    A PHASE II, RANDOMIZED, CROSS-OVER, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE CENTER STUDY OF THE EFFECTS OF DAPAGLIFLOZIN VS PLACEBO ON ENDOGENOUS GLUCOSE PRODUCTION IN RENAL TRANSPLANT SUBJECTS WITH OR WITHOUT TYPE 2 DIABETES AND TYPE 2 DIABETIC SUBJECTS WITH NORMAL RENAL FUNCTION
    Studio clinico di fase 2 randomizzato, cross-over, in doppio cieco, controllato con placebo su singolo centro per valutare l’effetto di Dapagliflozin sulla produzione endogena di glucosio in soggetti con trapianto di rene con o senza diabete tipo 2 in confronto con pazienti con diabete tipo 2 e normale funzione renale
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MEASUREMENTS OF THE EFFECTS OF DAPAGLIFLOZIN VS PLACEBO ON ENDOGENOUS GLUCOSE PRODUCTION IN RENAL TRANSPLANT SUBJECTS WITH OR WITHOUT TYPE 2 DIABETES AND TYPE 2 DIABETIC SUBJECTS WITH NORMAL RENAL FUNCTION
    Valutazione dell’effetto di Dapagliflozin sulla produzione endogena di glucosio in soggetti con trapianto di rene con o senza diabete tipo 2 in confronto con pazienti con diabete tipo 2 e normale funzione renale
    A.3.2Name or abbreviated title of the trial where available
    8-311-3-0062
    8-311-3-0062
    A.4.1Sponsor's protocol code number8-311-3-062
    A.5.4Other Identifiers
    Name:8-311--3-062Number:8-311--3-062
    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 SponsorAZIENDA OSPEDALIERO-UNIVERSITARIA PISANA
    B.1.3.4CountryItaly
    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 supportASTRAZENECA
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportQatar National Research Fund (QNRF)
    B.4.2CountryQatar
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationU.O. MALATTIE METABOLICHE E DIABETOLOGIA
    B.5.2Functional name of contact pointU.O. MALATTIE METABOLICHE E DIABETO
    B.5.3 Address:
    B.5.3.1Street AddressVIA PARADISA 2
    B.5.3.2Town/ cityPISA
    B.5.3.3Post code56126
    B.5.3.4CountryItaly
    B.5.4Telephone number050995103
    B.5.5Fax number050541521
    B.5.6E-mailstefano.delprato@med.unipi.it
    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 FORXIGA - 10 MG - COMPRESSE RIVESTITE CON FILM- USO ORALE - BLISTER CALENDARIZZATO (ALU/ALU) - 28 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderBRISTOL- MYERS SQUIBB/ASTRAZENECA EEIG
    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 nameFORXIGA
    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 INNDapagliflozin propanediolo monoidrato
    D.3.9.1CAS number 461432-26-8
    D.3.9.2Current sponsor codeDapagliflozin propanediolo monoidrato
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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) 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    RENAL TRANSPLANT SUBJECTS WITH OR WITHOUT TYPE 2 DIABETES AND TYPE 2 DIABETIC SUBJECTS WITH NORMAL RENAL FUNCTION
    soggetti con trapianto di rene con o senza diabete di tipo 2 e soggetti con diabete di tipo 2 e normale funzione renale
    E.1.1.1Medical condition in easily understood language
    RENAL TRANSPLANT SUBJECTS WITH OR WITHOUT DIABETES AND DIABETIC SUBJECTS WITH NORMAL RENAL FUNCTION
    soggetti con trapianto di rene con o senza diabete e soggetti con diabete e normale funzione renale
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10038533
    E.1.2Term Renal transplant
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10067585
    E.1.2Term Type 2 diabetes mellitus
    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 test the hypothesis that a single dapagliflozin (10 mg) oral administration in subjects with or without type 2 diabetes and renal transplant will stimulate EGP and increase plasma glucagon concentration as compared to placebo. The same hypothesis will be tested in patients with T2DM and normal renal function, and then the differences (Dapagliflozin vs. placebo) will be compared between the two groups.
    Valutare l’ipotesi che una singola somministrazione per os di Dapagliflozin (10 mg) in pazienti con trapianto renale con o senza diabete tipo 2 stimoli l’EGP e la secrezione di glucagone rispetto a palcebo. La stessa ipotesi verra’ valutata in soggetti con diabete tipo 2 ma normale funzione renale quindi le differenze in termini di modulazione dell’EGP verra’ confrontata tra i due gruppi.
    E.2.2Secondary objectives of the trial
    To test the hypothesis that a single dapagliflozin (10 mg) oral administration in subjects with or without type 2 diabetes and renal transplant will modulate plasma glucose, insulin, c-peptide, FFA and blood pressure as compared to placebo. The same hypothesis will be tested in patients with T2DM and normal renal function, and then the differences (Dapagliflozin vs. placebo) will be compared between the two groups.
    Valutare l’ipotesi che una singola somministrazione per os di Dapagliflozin (10 mg) in pazienti con trapianto renale con o senza diabete tipo 2 moduli le concentrazioni plasmatiche di glucosio, insulina, c-peptide, FFA e la pressione arteriosa rispetto a palcebo. La stessa ipotesi verra’ valutata in soggetti con diabete tipo 2 ma normale funzione renale quindi le differenze verranno confrontate tra i due gruppi.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria
    1. Males and females
    2. Age = 30-65 years
    3. BMI= 25-35 Kg/m2 and stable weight (± 3 lbs) over the preceding three months
    4. Normal Glucose Tolerance or Type 2 diabetes

    5. Renal transplant at least 3 months on a stable dose of any combination of the following immunosuppressant medications:
    - Mycofenolate Mofetil or Sodium
    - Tacrolimus or Tacrolimus Prolonged Released
    - Everolimus
    - Sirolimus
    - Prednisone (<7.5mg/day) or Metilprednisolone (<6mg/day)
    - Cyclosporine
    6. GFR <10 ml/min/1.73 m2 prior to renal transplantation
    7. Stable GFR (>60 ml/min/1.73 m2) after transplantation
    8. Drug naive for T2DM treatment or metformin and/or sulfonylurea on stable dose more than 3 months
    9. Subjects are capable of giving informed consent

    Inclusion Criteria (Control Group)
    1. Males and females
    2. Age = 30-65 years
    3. BMI= 25-35 Kg/m2 and stable weight (± 3 lbs) over the preceding three months
    4. Type 2 diabetes
    5. Stable GFR (>60 ml/min/1.73 m2)
    6. HbA1c > 6.5 % and <10.0%
    7. Drug naive for T2DM treatment or metformin and/or sulfonylurea on stable dose more than 3 months
    8. Subjects are capable of giving informed consent
    Criteri di Inclusione
    1. Uomo o Donna
    2. Eta’= 30-65 anni
    3. BMI= 25-35 Kg/m2 e peso stabile (± 1.5 Kg) nei precedenti 3 mesi
    4. Normale tolleranza glucidica o Diabete tipo 2
    5. Trapianto renale (da almeno 3 mesi) in trattamento con ogni combinazione dei seguenti immunosoppressori:
    - Mofetil Micofenolato o sodico
    - Tacrolimo o Tacrolimo a rilascio prolungato
    - Everolimo
    - Sirolimo
    - Prednisone (< 7.5 mg al dì) o Metilprednisolone ( < 6 mg al dì)
    - Ciclosporina
    6. GFR <10 ml/min/1.73 m2 prima del trapianto
    7. Stabile GFR (>60 ml/min/1.73 m2) dopo il trapianto
    8. Nessun trattamento o trattamento con metformina e/o sulfonilurea a dosaggio stabile da piu’ di 3 mesi.
    9. Soggetti in grado di dare il consenso informato


    Criteri di Inclusione (gruppo di controllo)
    1. Uomo o Donna
    2. Eta’= 30-65 anni
    3. BMI= 25-35 Kg/m2 e peso stabile (± 1.5 Kg) nei precedenti 3 mesi
    4. Diabete tipo 2
    5. Stabile GFR (>60 ml/min/1.73 m2)
    6. HbA1c > 6.5 % e <10.0%
    7. Nessun trattamento o trattamento con metformina e/o sulfonilurea a dosaggio stabile da piu’ di 3 mesi.
    8. Soggetti in grado di dare il consenso informato
    E.4Principal exclusion criteria
    Exclusion Criteria (for both groups)
    1. Prednisone treatment at a dose = 7.5 mg per day or Metilprednisolone at a dose = 6 mg per day
    2. Beta blocker or any medication that affects sympathetic/parasympathetic activity
    3. 3. Drugs known to affect glucose metabolism (other than metformin and sulfonylurea and those listed in the inclusion criteria)
    4. Known Dapagliflozin Excipient Hypersensitivity
    5. Liver function enzymes higher more than two times the upper limit
    6. Heart Failure (NYHA III-IV)
    7. Ongoing urinary tract infection
    8. Blood pressure >140/90 mmHg
    9. Loop diuretics or thiazide diuretics therapy
    10. Hematocrit > 52%
    11. Type 1 Diabetes
    12. Diabetic Ketoacidosis
    13. GFR <60 ml/min/1.73 m2
    14. Volume depletion, hypotension or electrolytes imbalance
    15. Evidence of proliferative diabetic retinopathy, or 24-hour urinary albumin excretion > 300 mg
    16. Donation of blood to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of > 400 mL of blood during the 8 weeks prior to the enrollment visit
    17. Women of child bearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study
    18. Women who are pregnant or breastfeeding
    19. Patient with a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance which, in the opinion of the investigator or coordinator, might pose an unacceptable risk to the patient or interfere with trial procedures
    Criteri di Esclusione (per entrambi i gruppi)
    1. Trattamento con Prednisone al dosaggio = 7.5 mg al dì o Metilprednisolone al dosaggio = 6 mg al dì
    2. Trattamento con beta-bloccanti o ogni terapia che modula il sistema nervosa simpatico/parasimpatico
    3. Farmaci in grado di alterare il metabolismo del glucosio (diversi da metformina e sulfonilurea e da quelli inseriti nei criteri di inclusione)
    4. Nota ipersensibilità ad eccipienti di dapagliflozin
    5. Alterazione grave della funzione epatica (livelli di AST e ALT superiori di due volte ai limiti normali)
    6. Insufficienza cardiaca (classe NYHA III-IV)
    7. Infezione in corso delle vie urinarie
    8. Pressione arteriosa > 140/90 mmHg
    9. Terapia con diuretici dell’ansa o tiazidici
    10. Ematocrito > 25%
    11. Diabete mellito di tipo I
    12. Chetoacidosi diabetica
    13. Compromissione renale con GFR < 60 ml/min/1.73 m2
    14. Deplezione del volume, Ipotensione e/o sbilanciamento elettrolitico
    15. Evidenza di retinopatia proliferativa o escrezione di albumina urinaria (24 ore) maggiore di > 300 mg
    16. Donazione di sangue, trasfusione di sangue o partecipazione a studi clinici che hanno richiesto un prelievo di sangue maggiore di 400 ml durante 8 settimane precedenti all’arruolamento
    17. Donne potenzialmente fertili o che negano l’utilizzo di contraccezione durante il periodo dello studio per evitare una gravidanza.
    18. Donne in gravidanza o in allattamento
    19. Pazienti con storia o evidenza corrente di ogni condizione, terapia, anomalia di laboratorio o altre circostanze che a giudizio dell’investigatore la cui partecipazione allo studio comporta un rischio inaccettabile per il paziente
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the mean difference in EGP during the last hour of EGP measurement between dapagliflozin versus placebo administration in patients with or without T2DM and renal transplant versus subjects with T2DM and without renal transplant.
    L’endpoint primario e’ la differenza media di EGP durante l’ultima ora di misurazione dell’EGP tra dapagliflozin e placebo in pazienti con trapianto renale con o senza diabete tipo 2 rispetto a soggetti con diabete tipo 2 e normale funzione renale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This timepoint will be achieved in a three years study
    3 anni
    E.5.2Secondary end point(s)
    The secondary endpoints are the mean difference in plasma glucose, insulin, c-peptide, FFA and blood pressure during the last hours of the experiment between dapagliflozin versus placebo administration in patients with or without T2DM and renal transplant versus subjects with T2DM and without renal transplant
    L’endopoint secondario e’ la differenza media della concentrazione di glucosio, insulina, c-peptide, FFA e pressione arteriosa durante l’ultima ora dell’esperimento tra dapagliflozin e placebo in pazienti con trapianto renale con o senza diabete tipo 2 rispetto a soggetti con diabete tipo 2 e normale funzione renale
    E.5.2.1Timepoint(s) of evaluation of this end point
    This timepoint will be achieved in a three years study
    3 anni
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Mechanism underlying kidney-liver relationship on the control of hepatic glucose production control
    Meccanismo della relazione rene-fegato per il controllo della produzione epatica di glucosio
    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 No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    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 Information not present in EudraCT
    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 years3
    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 years3
    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: 50
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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)
    The plans for treatment or care after the subject has ended his/her participation will be not affected by this study and they will continue the standard care.
    I programmi per il trattamento o l'assistenza per i soggetti al termine della loro partecipazione allo studio non saranno influenzati dallo studio ed essi continueranno lo standard previsto dal centro.
    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 Decision2016-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
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