<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01686932</url>
  </required_header>
  <id_info>
    <org_study_id>CLAF237ADE07</org_study_id>
    <nct_id>NCT01686932</nct_id>
  </id_info>
  <brief_title>Vildagliptin vs Sitagliptin add-on to Insulin - Impact on Glycemic Profile and Correlation of Hypoglycemic Episodes and Heart Function</brief_title>
  <acronym>CGM-VISIT</acronym>
  <official_title>Multicentric Cross-over Trial to Assess the Glycemic Profiles on 8 Weeks of Vildagliptin and Sitagliptin Treatment, Each, in Type-2 Diabetic Patients With a Pre-existing Cardiovascular Disease Pre-treated With Insulin, Using a PROBE-design</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Vildagliptin and Sitagliptin both belong to the class of DPP-4 inhibitors, but differ in&#xD;
      their pharmacokinetic profile as well as in their approved application (Vildagliptin, 2x 50&#xD;
      mg daily, Sitagliptin, 1x 100 mg daily). This leads to distinct results regarding&#xD;
      postprandial blood-glucose normalization as well as protective properties regarding&#xD;
      hypoglycemic episodes - especially during the night. Additionally, in type 1 diabetic&#xD;
      patients a correlation has been described between hypoglycemia and abnormal heart function&#xD;
      (QTc-elongation), which can have severe consequences for the patients. This study aims for&#xD;
      the evaluation of the potency of both drugs to prevent and/or reduce hypoglycemic events in&#xD;
      insulin-dependent type-2 diabetics and furthermore to evaluate the correlation of&#xD;
      hypoglycemic episodes with changes in heart-function measured by Holter-ECG.&#xD;
&#xD;
      The hypothesis is tested, if vildagliptin leads to a more favourable glycemic profile than&#xD;
      sitagliptin and is more potent in protecting from nocturnal abnormalities in heart-function&#xD;
      caused by undetected hypoglycemic episodes.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">September 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 &amp; 2</measure>
    <time_frame>baseline and 0-24 hours post-dose on Days 2 to 5</time_frame>
    <description>The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC&lt;3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment.</measure>
    <time_frame>after 8 weeks period 1 and Period 2</time_frame>
    <description>Hypoglycemic events are defined as blood glucose values &lt;70 mg/dL measured by a self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) measurement regardless of any symptoms suggestive of low blood glucose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Duration of Hypoglycemic Events (Min.) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 &amp; Period 2</measure>
    <time_frame>after 8 weeks for Period 1 &amp; Period 2</time_frame>
    <description>the mean duration of hypoglycemic events is detected by continuous glucose monitoring (CGM)measurement.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Amplitudes of Hypoglycemic Events (mmol/L) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 &amp; Period 2</measure>
    <time_frame>after 8 weeks Period 1 &amp; Period 2</time_frame>
    <description>To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude over 4 days after 8 weeks of treatment in Period 1 &amp; Period 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Severe Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment After 8 Weeks of Treatment in Period 1 and Period 2</measure>
    <time_frame>after 8 weeks Period 1 &amp; Period 2</time_frame>
    <description>Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of &lt;40 mg /dL. Assessed by self-monitored blood glucose (SMBG)After 8 weeks of treatment in Period 1 and Period 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose Fluctuations During the Day Under Vildagliptin Treatment Compared to Sitagliptin Treatment on Day 2 After 8 Weeks of Treatment Period 1 &amp; Period 2</measure>
    <time_frame>Day 2 after 8 weeks of treatment Period 1 &amp; Period 2</time_frame>
    <description>Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970). on day 2 after 8 weeks of treatment Period 1 &amp; Period 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 &amp; Period 2</measure>
    <time_frame>after 8 weeks of treatment Period 1 &amp; Period 2</time_frame>
    <description>ECG abnormalities are defined as either: • Occurrence of &gt;30 ventricular extrasystoles (VES) per hour or • Occurrence of ≥2 consecutive VES (Couplets) or • Occurrence of ≥3 consecutive VES (Triplets) or • QT-time corrected for heart rate (QTc) &gt;440 ms. after 8 weeks of treatment Period 1 &amp; Period 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline of Inflammatory Biomarkers High Sensitivity C-reactive Protein (hsCRP) After 8 Weeks of Treatment in Period 1 &amp; Period 2</measure>
    <time_frame>Baseline, after 8 weeks Period 1 &amp; Period 2</time_frame>
    <description>The inflammatory biomarkers hsCRP was assessed at baseline and after 8 weeks of treatment Period 1 &amp; Period 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline of Inflammatory Biomarkers Interleukin 6 (IL-6) After 8 Weeks of Treatment in Period 1 &amp; Period 2</measure>
    <time_frame>Baseline, after 8 weeks Period 1 &amp; Period 2</time_frame>
    <description>The inflammatory biomarkers IL-6 was assessed at baseline and after 8 weeks of treatment Period 1 &amp; Period 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 &amp; Period 2</measure>
    <time_frame>Baseline, after 8 weeks Period 1 &amp; Period 2</time_frame>
    <description>Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 &amp; Period 2 Higher pro-insulin / C-peptide ratios (expressing disproportional hyperproinsulinemia) may be associated with increasing beta cell dysfunction and more inefficient pro-insulin processing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2</measure>
    <time_frame>after 8 weeks Period 1 &amp; Period 2</time_frame>
    <description>Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2. ECG data were continuously recorded and analyzed over a period of 4 days simultaneously with continuous glucose monitoring. It assessed number of any Vertical Electric(al) Sounding (VES), number of 2 consecutive VES [couplets], and number of &gt;3 consecutive VES [salves]</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">51</enrollment>
  <condition>Diabetes Mellitus Type 2</condition>
  <arm_group>
    <arm_group_label>Vildagliptin followed by Sitagliptin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sitagliptin followed by Vildagliptin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vildagliptin</intervention_name>
    <description>vildagliptin 50mg BID for 8 weeks</description>
    <arm_group_label>Sitagliptin followed by Vildagliptin</arm_group_label>
    <arm_group_label>Vildagliptin followed by Sitagliptin</arm_group_label>
    <other_name>Vildagliptin (Galvus) LAF237</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sitagliptin</intervention_name>
    <description>sitagliptin 100mg QD for 8 weeks</description>
    <arm_group_label>Sitagliptin followed by Vildagliptin</arm_group_label>
    <arm_group_label>Vildagliptin followed by Sitagliptin</arm_group_label>
    <other_name>sitagliptin, Januvia</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Written informed consent must be obtained before any assessment is performed.&#xD;
&#xD;
             2. Ability to comply with all study requirements. 3. Patients with Type 2 diabetes&#xD;
             treated with stable, once or twice daily doses (minimal dose of 0.3 unit/kg/day) of&#xD;
             basal long-acting or intermediate-acting insulin alone or in pre-mixed combination&#xD;
             with rapid-acting or short-acting insulin for at least 12 weeks prior to Visit 1.&#xD;
             Stable is defined as ±10% of the Visit 1 dose during the previous 12 weeks.&#xD;
&#xD;
             4. Patients receiving metformin must be on a stable dose of metformin (at least 1500&#xD;
             mg daily or a maximally tolerated dose) for at least 12 weeks prior to Visit 1. 5.&#xD;
             HbA1c ≥7.5 to ≤ 9,0% at Visit 1 6. Known CV disease based on a documented history of&#xD;
             one or more of pre-defined criteria 7. Age: ≥40 to ≤80 years at Visit 1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. FPG ≥ 270 mg/dL (15 mmol/L) at Visit 1. 2. Use of any of the following medications&#xD;
             as assessed at Visit 1:&#xD;
&#xD;
               1. rapid or short acting insulin except in pre-mixed formulations with intermediate&#xD;
                  or long-acting insulin; insulin administration more frequently than twice-daily,&#xD;
                  or total insulin dose &lt; 0.3 unit/kg/day for the past 12 weeks&#xD;
&#xD;
               2. use of any oral antidiabetic medication or GLP-1 analogues within the last 12&#xD;
                  weeks, except metformin&#xD;
&#xD;
               3. use of weight control products including weight-loss medications in the last 12&#xD;
                  weeks.&#xD;
&#xD;
               4. use of oral (≥7 consecutive days) or chronic parenteral or intra-articular&#xD;
                  corticosteroid treatment within the last 8 weeks. Inhaled or topical steroids&#xD;
                  without systemic effects will be allowed.&#xD;
&#xD;
               5. treatment with growth hormone within the previous 6 months.&#xD;
&#xD;
               6. treatment with any drug of known and frequent toxicity to a major organ, or that&#xD;
                  may interfere with the interpretation of the efficacy and safety data during the&#xD;
                  study.&#xD;
&#xD;
                  3. a history or evidence of any of the following at Visit 1:&#xD;
&#xD;
               1. acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar&#xD;
                  state (including precoma and coma) within the past 6 months.&#xD;
&#xD;
               2. current diagnosis of congestive heart failure (NYHA III or IV).&#xD;
&#xD;
               3. myocardial infarction within the past 6 months.&#xD;
&#xD;
               4. coronary artery bypass surgery or percutaneous coronary intervention within the&#xD;
                  past 6 months.&#xD;
&#xD;
               5. Stroke, transient ischemic attack, or reversible ischemic neurologic deficit&#xD;
                  within the past 6 months.&#xD;
&#xD;
               6. unstable angina within the past 6 months.&#xD;
&#xD;
               7. sustained and clinically relevant ventricular arrhythmia (patients with premature&#xD;
                  ventricular contractions if deemed not clinically significant may be enrolled).&#xD;
&#xD;
               8. Patients with permanent atrial fibrillation or pacemaker.&#xD;
&#xD;
               9. active substance abuse, alcohol abuse and history of alcohol-related diseases&#xD;
                  within the past 2 years.&#xD;
&#xD;
              10. type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury,&#xD;
                  or secondary forms of diabetes (e.g. Cushing's syndrome or acromegaly-associated&#xD;
                  diabetes).&#xD;
&#xD;
              11. malignancy of an organ system (other than localized basal cell carcinoma of the&#xD;
                  skin) treated or untreated, within the past 5 years, regardless of whether there&#xD;
                  is evidence of local recurrence or metastases.&#xD;
&#xD;
              12. hepatic disorder defined as:&#xD;
&#xD;
                    -  acute or chronic liver disease, evidence of hepatitis, cirrhosis or portal&#xD;
                       hypertension.&#xD;
&#xD;
                    -  history of imaging abnormalities that suggest liver disease (except hepatic&#xD;
                       steatosis), such as portal hypertension, capsule scalloping, cirrhosis.&#xD;
&#xD;
              13. acute infections which may affect blood glucose control within the past 4 weeks.&#xD;
&#xD;
                  4. any of the following significant laboratory abnormalities as assessed at Visit&#xD;
                  1:&#xD;
&#xD;
               1. clinically significant increase or reduction in thyroid stimulating hormone (TSH)&#xD;
                  outside of the normal range.&#xD;
&#xD;
               2. clinically significant renal dysfunction: glomerular filtration rate (GFR) &lt;50&#xD;
                  mL/min/1.73m2 (via MDRD formula).&#xD;
&#xD;
               3. Patients on metformin with a GFR &lt;60 mL/min/1.73m2 (via MDRD formula).&#xD;
&#xD;
               4. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) &gt; 2 x&#xD;
                  upper limit of normal (ULN) at Visit 1, confirmed by repeated measurements within&#xD;
                  3 working days.&#xD;
&#xD;
               5. total bilirubin &gt; 2 x ULN and/or direct bilirubin &gt; 1 x ULN confirmed by repeated&#xD;
                  measurements within 3 working days.&#xD;
&#xD;
               6. positive Hepatitis B surface antigen (HBsAg).&#xD;
&#xD;
               7. positive Hepatitis C virus (HCV) antibody test (anti-HCV).&#xD;
&#xD;
               8. elevated fasting triglycerides (TGs) &gt; 500mg/dL (5.65mmol/L), confirmed by a&#xD;
                  repeated measurements within 3 working days.&#xD;
&#xD;
               9. clinically significant laboratory abnormalities which, in the opinion of the&#xD;
                  investigator, cause the patient to be considered inappropriate for inclusion in&#xD;
                  the study.&#xD;
&#xD;
                  5. any of the following electrocardiographic abnormalities at Visit 1:&#xD;
&#xD;
               1. second or third degree atrio-ventricular block.&#xD;
&#xD;
               2. A QTc of &gt; 440 ms.&#xD;
&#xD;
               3. clinically significant electrocardiogram (ECG) abnormalities which, in the&#xD;
                  opinion of the investigator, may cause the patient to be considered inappropriate&#xD;
                  for inclusion in the study&#xD;
&#xD;
        Other protocol-defined inclusion/exclusion criteria may apply.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Berlin</city>
        <zip>10115</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Berlin</city>
        <zip>13055</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Dortmund</city>
        <zip>44137</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Dresden</city>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Elsterwerda</city>
        <zip>04910</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Falkensee</city>
        <zip>14612</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Magdeburg</city>
        <zip>39112</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Neuss</city>
        <zip>41460</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Potsdam</city>
        <zip>14469</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sulzbach-Rosenberg</city>
        <zip>92237</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wallerfing</city>
        <zip>94574</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>September 13, 2012</study_first_submitted>
  <study_first_submitted_qc>September 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2012</study_first_posted>
  <results_first_submitted>August 31, 2015</results_first_submitted>
  <results_first_submitted_qc>August 31, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">October 2, 2015</results_first_posted>
  <last_update_submitted>February 2, 2016</last_update_submitted>
  <last_update_submitted_qc>February 2, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 2, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>vildagliptin</keyword>
  <keyword>sitagliptin</keyword>
  <keyword>continuous glucose monitoring (CGM)</keyword>
  <keyword>glycemic fluctuations</keyword>
  <keyword>MAGE</keyword>
  <keyword>impact of hypoglycemia on heart function (cardiac dysfuction measured via ECG)</keyword>
  <keyword>difference in glycemic profile of vildagliptin compared to sitagliptin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sitagliptin Phosphate</mesh_term>
    <mesh_term>Vildagliptin</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Period 1: 8 weeks treatment with vildagliptin 50mg BID or sitagliptin 100mg QD, 1-4 weeks wash-out, followed by Period 2, 8 weeks treatment with sitagliptin 100mg QD or vildagliptin 50mg BID</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Vildagliptin Followed by Sitagliptin</title>
          <description>Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks</description>
        </group>
        <group group_id="P2">
          <title>Sitagliptin Followed by Vildagliptin</title>
          <description>Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
                <participants group_id="P2" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Vildagliptin Followed by Sitagliptin</title>
          <description>Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks</description>
        </group>
        <group group_id="B2">
          <title>Sitagliptin Followed by Vildagliptin</title>
          <description>Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="25"/>
            <count group_id="B2" value="26"/>
            <count group_id="B3" value="51"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.8" spread="6.0"/>
                    <measurement group_id="B2" value="65.2" spread="8.6"/>
                    <measurement group_id="B3" value="65" spread="7.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 &amp; 2</title>
        <description>The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC&lt;3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.</description>
        <time_frame>baseline and 0-24 hours post-dose on Days 2 to 5</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 &amp; 2</title>
          <description>The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC&lt;3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>mmol/L/4d</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.2" spread="25.65"/>
                    <measurement group_id="O2" value="5.3" spread="11.70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment.</title>
        <description>Hypoglycemic events are defined as blood glucose values &lt;70 mg/dL measured by a self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) measurement regardless of any symptoms suggestive of low blood glucose.</description>
        <time_frame>after 8 weeks period 1 and Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment.</title>
          <description>Hypoglycemic events are defined as blood glucose values &lt;70 mg/dL measured by a self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) measurement regardless of any symptoms suggestive of low blood glucose.</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>number of hypoglycemic events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>continuous glucose monitoring (CGM)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69"/>
                    <measurement group_id="O2" value="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>self-monitored blood glucose (SMBG)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29"/>
                    <measurement group_id="O2" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Duration of Hypoglycemic Events (Min.) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 &amp; Period 2</title>
        <description>the mean duration of hypoglycemic events is detected by continuous glucose monitoring (CGM)measurement.</description>
        <time_frame>after 8 weeks for Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Duration of Hypoglycemic Events (Min.) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 &amp; Period 2</title>
          <description>the mean duration of hypoglycemic events is detected by continuous glucose monitoring (CGM)measurement.</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.1" spread="44.71"/>
                    <measurement group_id="O2" value="28.0" spread="51.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Amplitudes of Hypoglycemic Events (mmol/L) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 &amp; Period 2</title>
        <description>To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude over 4 days after 8 weeks of treatment in Period 1 &amp; Period 2</description>
        <time_frame>after 8 weeks Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Amplitudes of Hypoglycemic Events (mmol/L) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 &amp; Period 2</title>
          <description>To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude over 4 days after 8 weeks of treatment in Period 1 &amp; Period 2</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>mmol/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2" spread="0.32"/>
                    <measurement group_id="O2" value="0.2" spread="0.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Severe Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment After 8 Weeks of Treatment in Period 1 and Period 2</title>
        <description>Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of &lt;40 mg /dL. Assessed by self-monitored blood glucose (SMBG)After 8 weeks of treatment in Period 1 and Period 2</description>
        <time_frame>after 8 weeks Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Severe Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment After 8 Weeks of Treatment in Period 1 and Period 2</title>
          <description>Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of &lt;40 mg /dL. Assessed by self-monitored blood glucose (SMBG)After 8 weeks of treatment in Period 1 and Period 2</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>severe hypoglycemic events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Glucose Fluctuations During the Day Under Vildagliptin Treatment Compared to Sitagliptin Treatment on Day 2 After 8 Weeks of Treatment Period 1 &amp; Period 2</title>
        <description>Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970). on day 2 after 8 weeks of treatment Period 1 &amp; Period 2</description>
        <time_frame>Day 2 after 8 weeks of treatment Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Glucose Fluctuations During the Day Under Vildagliptin Treatment Compared to Sitagliptin Treatment on Day 2 After 8 Weeks of Treatment Period 1 &amp; Period 2</title>
          <description>Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970). on day 2 after 8 weeks of treatment Period 1 &amp; Period 2</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>mmol/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.7" spread="1.69"/>
                    <measurement group_id="O2" value="4.6" spread="1.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 &amp; Period 2</title>
        <description>ECG abnormalities are defined as either: • Occurrence of &gt;30 ventricular extrasystoles (VES) per hour or • Occurrence of ≥2 consecutive VES (Couplets) or • Occurrence of ≥3 consecutive VES (Triplets) or • QT-time corrected for heart rate (QTc) &gt;440 ms. after 8 weeks of treatment Period 1 &amp; Period 2</description>
        <time_frame>after 8 weeks of treatment Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 &amp; Period 2</title>
          <description>ECG abnormalities are defined as either: • Occurrence of &gt;30 ventricular extrasystoles (VES) per hour or • Occurrence of ≥2 consecutive VES (Couplets) or • Occurrence of ≥3 consecutive VES (Triplets) or • QT-time corrected for heart rate (QTc) &gt;440 ms. after 8 weeks of treatment Period 1 &amp; Period 2</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Patients with hypoglycemia (n=21,17)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Patients without hypoglycemia (n=28,32)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline of Inflammatory Biomarkers High Sensitivity C-reactive Protein (hsCRP) After 8 Weeks of Treatment in Period 1 &amp; Period 2</title>
        <description>The inflammatory biomarkers hsCRP was assessed at baseline and after 8 weeks of treatment Period 1 &amp; Period 2</description>
        <time_frame>Baseline, after 8 weeks Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline of Inflammatory Biomarkers High Sensitivity C-reactive Protein (hsCRP) After 8 Weeks of Treatment in Period 1 &amp; Period 2</title>
          <description>The inflammatory biomarkers hsCRP was assessed at baseline and after 8 weeks of treatment Period 1 &amp; Period 2</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>mg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.79" spread="4.96"/>
                    <measurement group_id="O2" value="0.60" spread="2.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline of Inflammatory Biomarkers Interleukin 6 (IL-6) After 8 Weeks of Treatment in Period 1 &amp; Period 2</title>
        <description>The inflammatory biomarkers IL-6 was assessed at baseline and after 8 weeks of treatment Period 1 &amp; Period 2</description>
        <time_frame>Baseline, after 8 weeks Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline of Inflammatory Biomarkers Interleukin 6 (IL-6) After 8 Weeks of Treatment in Period 1 &amp; Period 2</title>
          <description>The inflammatory biomarkers IL-6 was assessed at baseline and after 8 weeks of treatment Period 1 &amp; Period 2</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>pg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.40" spread="3.90"/>
                    <measurement group_id="O2" value="0.08" spread="0.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 &amp; Period 2</title>
        <description>Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 &amp; Period 2 Higher pro-insulin / C-peptide ratios (expressing disproportional hyperproinsulinemia) may be associated with increasing beta cell dysfunction and more inefficient pro-insulin processing</description>
        <time_frame>Baseline, after 8 weeks Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 &amp; Period 2</title>
          <description>Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 &amp; Period 2 Higher pro-insulin / C-peptide ratios (expressing disproportional hyperproinsulinemia) may be associated with increasing beta cell dysfunction and more inefficient pro-insulin processing</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>Percentage Change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.34" spread="0.47"/>
                    <measurement group_id="O2" value="-0.31" spread="0.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2</title>
        <description>Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2. ECG data were continuously recorded and analyzed over a period of 4 days simultaneously with continuous glucose monitoring. It assessed number of any Vertical Electric(al) Sounding (VES), number of 2 consecutive VES [couplets], and number of &gt;3 consecutive VES [salves]</description>
        <time_frame>after 8 weeks Period 1 &amp; Period 2</time_frame>
        <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitagliptin</title>
            <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
          <group group_id="O2">
            <title>Sitagliptin</title>
            <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2</title>
          <description>Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2. ECG data were continuously recorded and analyzed over a period of 4 days simultaneously with continuous glucose monitoring. It assessed number of any Vertical Electric(al) Sounding (VES), number of 2 consecutive VES [couplets], and number of &gt;3 consecutive VES [salves]</description>
          <population>Full Analysis Set (FAS) included all patients that was treated with study medication.</population>
          <units>number of occurrence</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title># any VES Per.1 n=23, 25</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="879.7" spread="1405.2"/>
                    <measurement group_id="O2" value="2786.7" spread="6507.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title># any VES Per.2 n=25, 23</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4389.9" spread="16692"/>
                    <measurement group_id="O2" value="1060.2" spread="1812.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title># couplets VES Per.1 n=23, 25</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.8" spread="32.5"/>
                    <measurement group_id="O2" value="115.0" spread="405.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title># couplets VES Per.2 n=25, 23</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.7" spread="10.3"/>
                    <measurement group_id="O2" value="2.4" spread="3.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title># salves VES Per.1 n=23, 25</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0" spread="2.4"/>
                    <measurement group_id="O2" value="15.8" spread="52.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title># salves VES Per.2 n=25, 23</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.8" spread="1.7"/>
                    <measurement group_id="O2" value="0.9" spread="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Vildagliptin</title>
          <description>For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2</description>
        </group>
        <group group_id="E2">
          <title>Sitagliptin</title>
          <description>For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>CORONARY ARTERY DISEASE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>MYOCARDIAL INFARCTION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>PERICARDITIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>HYPOGLYCAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>LUNG NEOPLASM MALIGNANT</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>TRANSIENT ISCHAEMIC ATTACK</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>BLOOD GLUCOSE DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>HYPOGLYCAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Novartis</organization>
      <phone>862-778-8300</phone>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01686932
org study id: CLAF237ADE07
nct id: NCT01686932
lead sponsor: 
has dmc: No
Vildagliptin and Sitagliptin both belong to the class of DPP-4 inhibitors, but differ in
      their pharmacokinetic profile as well as in their approved application (Vildagliptin, 2x 50
      mg daily, Sitagliptin, 1x 100 mg daily). This leads to distinct results regarding
      postprandial blood-glucose normalization as well as protective properties regarding
      hypoglycemic episodes - especially during the night. Additionally, in type 1 diabetic
      patients a correlation has been described between hypoglycemia and abnormal heart function
      (QTc-elongation), which can have severe consequences for the patients. This study aims for
      the evaluation of the potency of both drugs to prevent and/or reduce hypoglycemic events in
      insulin-dependent type-2 diabetics and furthermore to evaluate the correlation of
      hypoglycemic episodes with changes in heart-function measured by Holter-ECG.

      The hypothesis is tested, if vildagliptin leads to a more favourable glycemic profile than
      sitagliptin and is more potent in protecting from nocturnal abnormalities in heart-function
      caused by undetected hypoglycemic episodes.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 & 2
time frame: baseline and 0-24 hours post-dose on Days 2 to 5
description: The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC<3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.
measure: Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment.
time frame: after 8 weeks period 1 and Period 2
description: Hypoglycemic events are defined as blood glucose values <70 mg/dL measured by a self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) measurement regardless of any symptoms suggestive of low blood glucose.
measure: Mean Duration of Hypoglycemic Events (Min.) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2
time frame: after 8 weeks for Period 1 & Period 2
description: the mean duration of hypoglycemic events is detected by continuous glucose monitoring (CGM)measurement.
measure: Mean Amplitudes of Hypoglycemic Events (mmol/L) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2
time frame: after 8 weeks Period 1 & Period 2
description: To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude over 4 days after 8 weeks of treatment in Period 1 & Period 2
measure: Number of Severe Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment After 8 Weeks of Treatment in Period 1 and Period 2
time frame: after 8 weeks Period 1 & Period 2
description: Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of <40 mg /dL. Assessed by self-monitored blood glucose (SMBG)After 8 weeks of treatment in Period 1 and Period 2
measure: Glucose Fluctuations During the Day Under Vildagliptin Treatment Compared to Sitagliptin Treatment on Day 2 After 8 Weeks of Treatment Period 1 & Period 2
time frame: Day 2 after 8 weeks of treatment Period 1 & Period 2
description: Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970). on day 2 after 8 weeks of treatment Period 1 & Period 2
measure: Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 & Period 2
time frame: after 8 weeks of treatment Period 1 & Period 2
description: ECG abnormalities are defined as either: • Occurrence of >30 ventricular extrasystoles (VES) per hour or • Occurrence of ≥2 consecutive VES (Couplets) or • Occurrence of ≥3 consecutive VES (Triplets) or • QT-time corrected for heart rate (QTc) >440 ms. after 8 weeks of treatment Period 1 & Period 2
measure: Change From Baseline of Inflammatory Biomarkers High Sensitivity C-reactive Protein (hsCRP) After 8 Weeks of Treatment in Period 1 & Period 2
time frame: Baseline, after 8 weeks Period 1 & Period 2
description: The inflammatory biomarkers hsCRP was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2
measure: Change From Baseline of Inflammatory Biomarkers Interleukin 6 (IL-6) After 8 Weeks of Treatment in Period 1 & Period 2
time frame: Baseline, after 8 weeks Period 1 & Period 2
description: The inflammatory biomarkers IL-6 was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2
measure: Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 & Period 2
time frame: Baseline, after 8 weeks Period 1 & Period 2
description: Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 & Period 2 Higher pro-insulin / C-peptide ratios (expressing disproportional hyperproinsulinemia) may be associated with increasing beta cell dysfunction and more inefficient pro-insulin processing
measure: Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2
time frame: after 8 weeks Period 1 & Period 2
description: Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2. ECG data were continuously recorded and analyzed over a period of 4 days simultaneously with continuous glucose monitoring. It assessed number of any Vertical Electric(al) Sounding (VES), number of 2 consecutive VES [couplets], and number of >3 consecutive VES [salves]
arm group label: Vildagliptin followed by Sitagliptin
arm group type: Experimental
description: Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks
arm group label: Sitagliptin followed by Vildagliptin
arm group type: Experimental
description: Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks
intervention type: Drug
intervention name: Vildagliptin
description: vildagliptin 50mg BID for 8 weeks
arm group label: Sitagliptin followed by Vildagliptin
arm group label: Vildagliptin followed by Sitagliptin
other name: Vildagliptin (Galvus) LAF237
intervention type: Drug
intervention name: Sitagliptin
description: sitagliptin 100mg QD for 8 weeks
arm group label: Sitagliptin followed by Vildagliptin
arm group label: Vildagliptin followed by Sitagliptin
other name: sitagliptin, Januvia
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
facility: 
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country: Germany
responsible party type: Sponsor
mesh term: Diabetes Mellitus, Type 2
mesh term: Sitagliptin Phosphate
mesh term: Vildagliptin
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 