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    Summary
    EudraCT Number:2011-004622-96
    Sponsor's Protocol Code Number:0431-260
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-03
    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 ConcernedIreland - HPRA
    A.2EudraCT number2011-004622-96
    A.3Full title of the trial
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-
    Controlled Clinical Trial to Study the Safety and Insulin-Sparing
    Efficacy of the Addition of Sitagliptin in Patients With Type 2
    Diabetes Mellitus Who Have Inadequate Glycemic Control on
    Insulin Alone or in Combination With Metformin
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to test the safety, tolerability, and effectiveness of sitagliptin when compared to placebo in reducing the amount of insulin (with or without metformin) needed per day, to control blood sugar, over a 24-week period.
    A.3.2Name or abbreviated title of the trial where available
    Study to test the safety, tolerability, and effectiveness of sitagliptin when compared to placebo in
    A.4.1Sponsor's protocol code number0431-260
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (referred to as Merck)
    B.1.3.4CountryUnited States
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (referred to as Merck)
    B.5.2Functional name of contact pointThomas L. Seck
    B.5.3 Address:
    B.5.3.1Street Address126 E. LINCOLN AVENUE
    B.5.3.2Town/ cityRahway
    B.5.3.3Post code07065-0900
    B.5.3.4CountryUnited States
    B.5.4Telephone number001732594-3083
    B.5.5Fax number001732594-3560
    B.5.6E-mailthomas.seck@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name JANUVIA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameJANUVIA
    D.3.2Product code MK-0431
    D.3.4Pharmaceutical form 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 INNsitagliptin phosphate
    D.3.9.1CAS number 654671-78-0
    D.3.9.2Current sponsor codeMK-0431
    D.3.9.3Other descriptive nameSITAGLIPTIN PHOSPHATE
    D.3.9.4EV Substance CodeSUB25200
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboTablet
    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
    Type 2 Diabetes Mellitus
    E.1.1.1Medical condition in easily understood language
    Type 2 Diabetes
    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 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
    After 24 weeks, to assess the effect of sitagliptin compared with placebo on the change in insulin dose in IU per day in patients with type 2 diabetes mellitus (T2DM) with inadequate glycemic control on insulin with or without metformin, who titrate insulin glargine (Treat-to-Target). To assess the safety and tolerability of sitagliptin.
    E.2.2Secondary objectives of the trial
    In patients with T2DM with inadequate glycemic control on insulin with or without metformin, who titrate insulin glargine (Treat-to-Target):
    (1) After 24 weeks, to estimate the difference between sitagliptin and placebo on hemoglobin A1c .
    (2) After 24 weeks, to estimate the difference between sitagliptin and placebo on fasting plasma glucose.
    (3) After 24 weeks, to estimate the difference between sitagliptin and placebo on body weight.
    (4) After 24 weeks, to estimate the difference between sitagliptin and placebo in the proportion of patients who achieve the fasting glucose target of 72-100 mg/dL (4.0-5.6 mmol/L).
    (5) To estimate the difference between sitagliptin and placebo in the time to achieve the fasting glucose target of 72-100 mg/dL (4.0-5.6 mmol/L) for the first time.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    At Visit 1/Screening Visit:
    1. Patient has type 2 diabetes mellitus (T2DM).
    2. Patient meets one of the following criteria:
    A. Patient was diagnosed with diabetes after age 40 years and insulin therapy was initiated at least 3 years after the diagnosis of diabetes,
    OR -
    B.Patient does not meet the criteria in (A) above (i.e., diagnosis < age 40 years or insulin started earlier than 3 years after diagnosis), but has a fasting C-peptide of >0.7 ng/mL.
    Note: Only patients who do not meet the criteria in (A) should have a C-peptide level measured.
    3. Patient must be ≥18 and ≤80 years of age on the day of signing informed consent.
    4. Patient is on a stable insulin regimen for ≥10 weeks metformin (immediate-release or extended-release formulation) at ≥1500 mg/day for ≥10 weeks sulfonylurea for ≥10 weeks, with one of the following insulins (at a dose of at least 15 U/day and a maximum dose of 150 U/day) and has a Visit 1/Screening Visit A1C ≥7.5% and ≤11.0% (for patients not on sulfonylurea) or A1C ≥7.0% and ≤10.0% (for patients on
    sulfonylurea):
    • Pre-mixed insulin with at least 70% basal insulin (e.g., Novolog 70/30®, Novolin 70/30®, Humalog 75/25®, or Humulin 70/30®) once-daily or twice-daily.
    • Intermediate-acting insulin (e.g., NPH/Isophane) once-daily or twicedaily.
    • Long-acting insulin (e.g., Glargine [Lantus®] and Detemir [Levemir®]) once-daily or twice-daily.
    Note: A stable insulin regimen is defined as all daily doses within 10% (or within 2 units for patient taking ≤20U/day) of the usual administered dose (e.g., if usual insulin dose is 50 U/day, then doses of 45-55 U/day would be considered stable).
    E.4Principal exclusion criteria
    At Visit 1/Screening Visit:
    1. Patient has been treated with a DPP-4 inhibitor, a thiazolidinedione (TZD), or a GLP-1 mimetic or analogue, within the prior 12 weeks.
    2. Patient is currently on treatment with daily use (one or more injections per day) of a pre-prandial short-acting or rapid-acting insulin (e.g., aspart, glulisine, lispro, regular insulin) alone or as part of a basal/bolus insulin regimen.
    Note: Patients using a pre-mixed insulin containing a short-acting insulin may participate.
    3. Patient has symptomatic hyperglycemia that, in the investigator’s opinion, requires immediate initiation, adjustment, or addition of antihyperglycemic therapy.
    4. Patient has a history of 2 or more episodes of hypoglycemia resulting in seizure, coma, or loss of consciousness, - or - patient has had recurrent (≥3 times per week) episodes of hypoglycemia over the past 8 weeks.
    5. Patient has a history of ketoacidosis.
    6. Patient is, as assessed by the investigator, not appropriate for or does not agree to target a fasting glucose of 72-100 mg/dL [4.0-5.6 mmol/L].
    7. Patient has a history of intolerance or hypersensitivity to sitagliptin, insulin, or metformin (if patient on metformin at Visit 1) or any contraindication to sitagliptin, insulin, or metformin (if patient on metformin at Visit 1) based upon the label of the country of the investigational site.
    8. Patient is pregnant or breast-feeding, or is expecting to conceive or donate eggs during the study, including 14 days following the last dose of study drug.
    9. Patient has a medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or symptomatic gallbladder disease.
    10. Patient has had new or worsening signs or symptoms of coronary heart disease or congestive heart failure within the past 3 months, or has any of the following disorders within the past 3 months:
    a. Acute coronary syndrome (e.g., MI or unstable angina)
    b. Coronary artery intervention (e.g., CABG or PTCA)
    c. Stroke or transient ischemic neurological disorder
    At Visit 4/Randomization:
    11. Patient has a site FFSG of <130 mg/dL (7.2 mmol/L) or >270 mg/dL (15.0 mmol/L).
    Note: If the patient meets this exclusion criterion AND the investigator believes that the value is not consistent with the patient’s current Self-Monitoring Blood Glucose (SMBG) values and Visit 3/Week -2 FPG value, the patient should not be excluded at this time. This visit should be changed to an Unscheduled Visit and the patient should be rescheduled for Visit 4/Day 1 within 7 days. Additional single-blind placebo run-in medication should be dispensed if needed. If the patient meets this FFSG exclusion criterion at the rescheduled Visit 4/Day1, the patient MUST be excluded
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in daily insulin dose at Week 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    E.5.2Secondary end point(s)
    Efficacy Endpoints: laboratory assessment of: A1C, FPG, and lipid panel endpoints and time when a patient meets the fasting glucose target.
    Safety endpoints: adverse events, additional hypoglycemia endpoints, percentages of patients meeting predefined limits of change (PDLC) in laboratory parameters (including blood chemistry and hematology), and change (or percent change) from baseline at Week 24 in laboratory parameters, body weight and vital signs. Serious adverse events (SAEs) consistent with vascular events (cardiovascular, cerebrovascular, and peripheral vascular events) and heart failure events, revascularization procedures, and all deaths, regardless of cause, will be subject to adjudication by an expert committee external to the SPONSOR. When an eligible event is identified, the SPONSOR will request copies of additional source documentation related to the event (e.g., hospital records) from the investigator.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24 (as defined in protocol)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA48
    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
    Australia
    Belgium
    Brazil
    Canada
    Denmark
    France
    Hungary
    India
    Ireland
    Israel
    Italy
    Korea, Democratic People's Republic of
    Lithuania
    Mexico
    New Zealand
    Norway
    Peru
    Poland
    Puerto Rico
    Russian Federation
    South Africa
    Spain
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days16
    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: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 245
    F.4.2.2In the whole clinical trial 600
    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 Decision2011-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-06-07
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