Dietary Impacts on Glucose-lowering Effects of Sitagliptin in Type 2 Diabetes
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      In a prospective, randomized case-controlled study, the investigators hope to demonstrate a
      positive correlation of plasma levels of EPA and DHA as well as fish intake with the
      HbA1c-lowering effect of sitagliptin but not with the active comparator glimepiride.
    

Detailed description: 
      <Background and Rationale>

      DPP-4 inhibitors (DPP-4i) are becoming 1st line oral anti-diabetic drugs (OAD) in the
      management of type 2 diabetes in Japan; approximately 3-million patients, one third of those
      with diagnosis of diabetes, receive DPP-4i. The widespread use of DPP-4i in Japan is partly
      due to accumulating data from clinical trials demonstrating that DPP-4 inhibitors exert
      greater HbA1c-lowering effects in Japanese type 2 diabetes patients and also in non-obese
      Asian type 2 diabetes patients when compared to diabetes patients of other ethnicities (Ann
      Pharmacother 2012;46:1453-69; Diabetologia 2013;56:696-708).

      We previously demonstrated that sources of diet such as fish can enhance the HbA1c-lowering
      effects of DPP-4i (J Diabet Investig 2012:3(5):464-467). In our retrospective studies, we
      also reported that DPP-4i treatments are more effective in type 2 diabetic patients with high
      plasma levels of EPA and DHA, polyunsaturated fatty acids that are rich in fish (J Diabet
      Investig 2012:3(5):464-467; J Diabet Investig 2012:3(6):498-502). In the course of analyzing
      the mechanism, we found that ingestion of fish prior to rice enhanced secretion of GLP-1
      (Yabe D et al. Late breaking poster presentation in ADA 2014, manuscript in preparation).
      Further investigation of the ideal dietary content for combination with DPP-4i could be
      helpful in enhancing DPP-4i efficacy for more patients.

      This prospective clinical trial studying food composition in addition to compliance of diet
      therapy in Japanese patients who received sitagliptin or active comparator glimepiride should
      provide new insights on cross-talk between diet and medicines

      <Study Procedures>

      1. Initial screening period

      IC, screening assessment, eligibility check except for inclusion criteria (visit 1-4 week).

        1. Hospital visit at fasting.

        2. Patient's informed consent The investigator will hand over the written information to
           the patients and give an explanation of the contents of the study. The patients should
           be provided with ample time and opportunity to inquire about details of the study, and
           after confirmation that the patients fully understood the contents of the study, the
           informed consent form to participation in the study should be signed. (The informed
           consent form should describe the explanatory considerations specified in Ethical
           Guidelines for Clinical Studies, Part IV: Informed consent <detailed rule>) Prior to a
           patient's participation in the study, the written informed consent form should be signed
           or placed the name/seal, and personally dated by both the investigator and the patient.
           When CRC performed a supplemental explanation, he/she should also sign or place the
           name/seal, and date the informed consent form. The investigator will distribute a copy
           of the signed informed consent form and written information to the patient.

           After acquisition of informed consent to participation in the study until the end of the
           final observation, if information becomes available that may be relevant to the
           patient's willingness to continue participation in the study, the patient will be
           informed in a timely manner to confirm as to whether the patient is still willing to
           participate in the study. This communication should be recorded in writing. At this
           time, if the investigator considers that the written information should be revised, the
           written information should be promptly revised.

           The patients may withdraw from the study at any time. If a patient has withdrawn
           consent, the investigator should record the reasons for withdrawal in CRF.

        3. Make an interim registration for a patient. A unique number (screening or baseline
           number) should be assigned for identification purposes. It should be noted that that
           under no circumstances should a patient be assigned more than one allocation number

        4. Check if a patient satisfies required eligibility. Inquire about the background of a
           patient, past medical history, a history of surgery, and prior treatment drugs, and
           perform physical exam, vital signs (incl. ECG), hematology, blood biochemistry,
           pregnancy test (for women of childbearing potential), HbA1c, and fasting plasma glucose
           (FPG) as well as plasma EPA/DHA, FFQ and metabolomics.

        5. Washout periods until Visit 2 are as shown below:

             -  Patients who are not treated with an oral anti-diabetic agent: None

             -  Patients who are on a single oral anti-diabetic agent: 4 weeks

                2. Baseline period

      Physical and laboratory checkup, randomization and initiation of treatment (visit2, 0 week).

        1. Hospital admission of patients at fasting.

        2. In accordance with the study schedule, perform physical exam, vital signs (incl. ECG)
           and pregnancy test (for women of childbearing potential) should be determined.
           Concomitant drugs should be checked.

        3. Confirm that there is no abnormal finding, and randomize the patient [Randomization
           procedure] 1) The following requirements should be sent to secretariat of this study:
           Patient identification code Satisfying the eligibility criteria

           Assignments should be performed by dynamic allocation by the following factors:

           Gender Age BMI Plasma EPA

        4. When the person in charge of registration assessed the entry of a patient is
           appropriate, a study drug to be administered will be designated.

        5. Initiate a study drug at following doses (visit 2-4, 0-16 weeks):

      Sitagliptin 50mg Glimepiride 0.5mg

      3. Treatment period

      Physical and laboratory checkup (visit3, 8 week; visit4, 16 week).

        1. Hospital admission of patients at fasting.

        2. Check the treatment compliance status, and the presence or absence of adverse
           event/hypoglycemic symptoms (for the glimepiride treatment group).

        3. In accordance with the study schedule, perform physical exam, vital signs (incl. ECG)
           and pregnancy test (for women of childbearing potential) are determined. Concomitant
           drugs should be checked. HbA1c, and fasting plasma glucose (FPG) as well as plasma
           EPA/DHA, FFQ and metabolomics should be also checked.

      3-1. Study configuration (parallel, crossover, etc.), Multicenter, randomized, prospective,
      open-label, 2 arm parallel, clinical trial.

      (2 centers, see appendix) 3-2. Duration of the treatment period 16 weeks 3-3. Control group
      Glimepiride 3-4. Follow-up procedures A patient was to be withdrawn from the trial if

        1. The patient withdrew consent, without the need to justify the decision.

        2. The patient had to take any concomitant drugs interfering with the study medication.

        3. The patient is no longer able to participate in the study for other medical reasons
           (e.g., surgery, AEs, or other diseases).

        4. Occurrence of unacceptable hyperglycemia or hypoglycemia that may put patients at risk
           through continued participation.

        5. The patient is not able to comply with study protocol (according to the discretion of
           the investigator or sub-investigator).

      <Statistical Analysis and Sample Size Justification>

      To evaluate the association of changes in HbA1c levels from baseline with plasma DHA/EPA,
      linear regression analyses are carried out at week16 in each treatment group. We construct
      multivariable logistic regression models to assess whether plasma DHA/EPA is independently
      associated with HbA1c reduction. We calculate Spearman correlation coefficients between
      changes in HbA1c and the following variables: compliance with diet therapy, estimated intakes
      of various food items including fish, and the clinical characteristics of the patients (age,
      sex, body mass index, duration of diabetes, baseline HbA1c) using IBM SPSS Statistics 22 (SAS
      Institute Inc., Cary, NC, USA).

      Sample size:

      In our retrospective analysis, estimated intakes of fish or DHA/EPA (n=72) as well as serum
      levels of DHA/EPA (n=20) are significantly correlated with HbA1c reduction by DPP-4
      inhibitors in drug-naïve T2DM patients (J Diabet Investig 2012:3(5):464-7). In another
      retrospective analysis, serum levels of EPA are significantly correlated with HbA1c reduction
      by DPP-4 inhibitors in T2DM patients who received DPP-4 inhibitors as monotherapy (n=16) or
      add-on therapy (n=46) (J Diabet Investig 2012: 3(6):498-502).These studies support that the
      proposed study requires a sample size of 24 patients in each treatment group considering drop
      outs.

      <Specific Drug Supply Requirements >

      Both sitagliptin and glimepiride will be prescribed according to national health insurance.
      The patients who are eligible for this study will be randomized to treatment with sitagliptin
      or glimepiride at 0 week. Patients receiving an OAD at enrollment will be subjected to
      washout prior to randomization at 0 week. The dose for each treatment group is as follows:

      Sitagliptin: Orally, 50mg/day (q.d) throughout the treatment period Glimepiride: Orally,
      0.5mg/day (q.d) throughout the treatment period

      <Adverse Experience Reporting>

      An adverse event (AE) is any unfavourable and unintended sign (including an abnormal
      laboratory finding, for example), symptom, or disease temporally associated with the use of a
      medicinal product, whether or not considered related to the medicinal product. AEs will be
      reported to sponsor through the procedure similar to the marketed product.
    

Intervention name(s): Sitagliptin; Glimepiride
Intervention type(s): Drug; Drug
Other intervention name(s): Januvia; Amaryl
Intervention MeSH terms: Sitagliptin Phosphate; Glimepiride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: DPP-4 inhibitor; sulfonylurea