Saxagliptin in Combination With Dapagliflozin - Effects on Islet Cell Function
Condition: Type2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to evaluate alpha- and beta-cell function during combination
      treatment with saxagliptin in addition to dapagliflozin and metformin compared to placebo in
      addition to dapagliflozin and metformin in subjects with T2DM on stable metformin background
      therapy.
    

Detailed description: 
      List of Abbreviations AE Adverse event ALT Alanine aminotransferase ANOVA Analysis of
      variance APTT Activated partial thromboplastin time AST Aspartate aminotransferase AUCins
      Area under the serum insulin concentration time curve BMI Body mass index CRF Case report
      form CTA Clinical trial application ECG Electrocardiogram FSFV First subject first visit GCP
      Good clinical practice GIR Glucose infusion rate GIRmax Maximum glucose infusion rate HbA1C
      N-(1-deoxy)-fructosyl-haemoglobin HBsAg Hepatitis B surface antigen HIV Human
      immunodeficiency virus ICH International conference on harmonisation IEC Independent ethics
      committee INR International normalised ratio IRB Institutional review board IU International
      unit i.v. Intravenous(ly) LSFV Last subject first visit LSLV Last subject last visit MedDRA
      Medical Dictionary of Regulatory Activities OAD Oral antidiabetic drug q.d. daily SAE Serious
      adverse event SAP Statistical analysis plan s.c. Subcutaneous(ly) SMPG self-measured plasma
      glucose SOP Standard operating procedure WHO-DDE World Health Organization Drug Dictionary
      Enhanced

      Under physiological conditions blood glucose is kept within a narrow range by complex
      interactions of several signalling pathways. In this context, fine-tuning of alpha- and beta
      cell activity is fundamental to avoid excessive metabolic excursions. The pathogenesis of
      type 2 diabetes mellitus (T2DM) is driven by insulin resistance, followed by an increasing
      imbalance between alpha and beta cell activity which is characterised by relative insulin
      deficiency and increased glucagon secretion especially in the postprandial state.

      Individual arrangement of complementary antidiabetic drugs in the escalation of
      pharmacological intervention in T2DM is a major challenge. There is substantial need to
      provide a scientific rationale for the best effective combination of antidiabetic drugs with
      regard to their potency to address different aspects in the pathophysiology of T2DM.
      Therefore, studies evaluating potential synergistic and/or complementary effects of
      pharmacological interventions in T2DM deem imperative.

      This study aims to evaluate the effect of the DPP-IV inhibitor saxagliptin (as compared to
      placebo) in addition to the SGLT-2 inhibitor dapagliflozin on insulin resistance, pancreatic
      alpha and beta cell function.

      Triple therapy with metformin, SGLT-2 inhibitors, and DPP-IV inhibitors was shown to be
      efficacious and safe in several studies and has been approved for the treatment of T2DM by
      the European Medical Agency. Therefore, subjects with T2DM on a stable metformin background
      therapy will be enrolled in this trial.

      This is a single center, phase IV, prospective, placebo-controlled, exploratory,
      proof-of-mechanism study.

      This is a two-step treatment trial with a first open label and a second randomised,
      double-blinded, placebo controlled treatment phase. In treatment phase 1 (TP1, 30±4 days), 26
      subjects will receive dapagliflozin 10 mg once daily as add on to their pre-existing
      metformin monotherapy. Thereafter, in treatment phase 2 (TP2, 30±4 days), subjects will be
      randomised to additional saxagliptin 5 mg or corresponding placebo treatment in a 1:1 ratio.
      Trial subjects will subsequently undergo both treatment phases, and endpoint assessments will
      be performed at the beginning and end of each treatment phase on Visits 2, 3, and 4Assignment
      of treatment allocation will take place at the investigational site. The total study duration
      for a subject will be between 64 to 84 days.

      The use of a combined euglycaemic-hyperinsulinaemic and hyperglycaemic glucose clamp protocol
      is chosen in order to assess parameters of insulin resistance as well as alpha- and beta-cell
      function under highly standardised conditions within a small study population.

      Trained members of staff will perform all administrations of the IMP at the clinical site.
      Drug accountability will be performed from Visit 2 to Visit 4 based on subject diaries and
      returned study medication.

      Whenever a deviation is noted by the Investigator, the Sponsor and/or monitor should be
      informed and the implications of the deviation must be reviewed and discussed. The deviation
      must be documented, explaining the reason for the deviation (root cause analysis), actions
      taken and the impact of the deviation on the subject(s) and/or the trial. The safety
      laboratory will perform a first check on their values for safety parameters and flag any
      values outside the reference range. The Investigator must evaluate all results outside the
      reference range. Before the Investigator starts the trial, the laboratory reference ranges
      must be available in the Investigator's Trial File. The results provided by the safety
      laboratory will be part of the trial database. Data Management is the responsibility of
      Profil Institut für Stoffwechselforschung GmbH, Neuss Germany.

      The objectives of the monitoring procedures are to ensure that (i) the safety and rights of
      the trial subjects are respected, (ii) that accurate, valid and complete data are collected,
      and (iii) that the trial is conducted in accordance with the trial protocol, the principles
      of GCP and local legislation.

      The monitor must be given direct access to the Trial Investigator File and source documents
      (original documents, data and records). Direct access includes permission to examine,
      analyse, verify and reproduce any record(s) and report(s) that are important to evaluation of
      the clinical trial.

      Key tasks of the monitor include verifying the presence of informed consent, the adherence to
      the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety
      and efficacy variables. The monitor will also confirm the completeness of patient records,
      the adherence to the protocol and the progress in subject enrolment.

      Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany, will be responsible for the
      statistical analysis. The statistical planning and conduct of analyses of the data from this
      study will follow the principles defined in relevant ICH guidelines and the Sponsor's
      biostatistical standard operating procedures (SOPs). All statistical analyses will be
      performed using SAS® (SAS Institute Inc., Cary, North Carolina, United States of America
      [USA]), version 9.3 or later.

      For the lack of existing data for confirmatory sample size calculation, the study is designed
      as an exploratory proof-of-mechanism study with an experimental assessment set-up. All
      obtained results will be handled with equal emphasis in a strictly exploratory sense. The
      data obtained from the trial will serve for the purpose of thesis generation and the design
      of potential confirmatory studies.

      Dapagliflozin as well as Saxagliptin have been approved for treatment of T2DM in adult male
      and female patients. Because it is moreover not expected that the effects of either drug on
      the endpoint measures will differ between male and female subjects with T2DM, a specific
      gender distribution is not planned for this study.

      Based on a previous study in twelve patients with T2DM treatment with dapagliflozin, a group
      size of 12 patients in each group has a power of 80% to detect a difference at a significance
      level of 0,05 (two-tailed).

      Before data are released for statistical analysis, a blinded review of all data will take
      place to identify protocol deviations that may potentially affect the results. This review
      will be performed without revealing which trial product the subjects are assigned to. The
      blinding of the trial products will be maintained for everyone involved in allocating
      subjects to the analysis sets until data are released for statistical analysis. Furthermore,
      outliers will be identified by data review according to ICH-E9, using a fake randomisation.
      In addition, protocol deviations, which may potentially affect the results, will be
      identified and it will be evaluated if subjects and/or data should be excluded from the
      analysis.

      The subjects and observations excluded from analysis sets, and the reason for this, will be
      described in the clinical trial report.

      All available data will be included in data listings and tabulations. In general no
      imputation of values for missing data will be performed.

      In general, metric variables and derived parameters will be presented using descriptive
      summary statistics including arithmetic means, median, minimum, maximum and standard
      deviations. Categorical variables will be presented using descriptive summary statistics
      including number of patients and percentages. Percentages of patients will be based on
      non-missing values.

      In addition, for all efficacy variables as well as the derived parameters the geometric means
      and coefficients of variation will be presented as well.

      Descriptive summaries will also be presented. Unless otherwise stated, all formal tests will
      be conducted at the two-sided 5% level of significance. No alpha adjustment will be done. All
      analyses on primary and secondary efficacy endpoints will be interpreted in an exploratory
      manner.

      To investigate the dapagliflozin-corrected treatment effect, the evaluation of the change
      from Visit 3 to Visit 4 in incremental AUCGluc270-390min / AUCIns270-390min will be performed
      using analysis of covariance (ANOVA) with change in incremental AUCGluc270-390min /
      AUCIns270-390min as response, treatment as fixed effect and baseline (Visit 2) value as
      covariate. From this model, least square means of change from Visit 3 to Visit 4 and 95%
      confidence intervals for these changes will be calculated. In addition, estimate of the
      placebo-corrected treatment effect (difference of least square mean of Visit 3 to Visit 4
      changes between saxagliptin and placebo) and corresponding 95% confidence interval will be
      calculated.

      If the data are homogeneous or not normally distributed and cannot be successfully
      transformed, the analysis will be performed by non-parametric technique using Wilcoxon Signed
      Rank Test for within treatment comparisons and Wilcoxon Rank-Sum Test for between treatment
      comparisons based on a two-sided alpha level of 0.05. In addition, the estimate of Hodges and
      Lehmann and the corresponding 95% non-parametric confidence interval will be shown.

      The secondary efficacy endpoints derived from the hyperglycaemic clamp phase based on
      incremental AUCs will be calculated as described for the primary endpoint.

      All AEs that will be entered into the CRF (all AEs since first dosing) will be coded. All AEs
      will be presented by individual listings and frequency tables broken down by body system and
      preferred terms as assigned by the Medical Dictionary for Regulatory Activity, as
      appropriate. Separate tables for serious adverse events, by severity, as well as by
      relationship to trial medication, will be provided.
    

Intervention name(s): Saxagliptin; Placebo for Saxagliptin
Intervention type(s): Drug; Drug
Intervention description(s): competitive inhibitor of human dipepitdylpeptidase (DPP)-IV
Other intervention name(s): Onglyza®
Intervention MeSH terms: Saxagliptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment