Clinical trial NCT01686932: Vildagliptin vs Sitagliptin add-on to Insulin - Impact on Glycemic Profile and Correlation of Hypoglycemic Episodes and Heart Function
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus Type 2
Keywords: vildagliptin
sitagliptin
continuous glucose monitoring (CGM)
glycemic fluctuations
MAGE
impact of hypoglycemia on heart function (cardiac dysfuction measured via ECG)
difference in glycemic profile of vildagliptin compared to sitagliptin
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-09-18
Enrollment: 51
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 1. Written informed consent must be obtained before any assessment is performed.

  2. Ability to comply with all study requirements. 3. Patients with Type 2 diabetes treated with stable, once or twice daily doses (minimal dose of 0.3 unit/kg/day) of basal long-acting or intermediate-acting insulin alone or in pre-mixed combination with rapid-acting or short-acting insulin for at least 12 weeks prior to Visit 1. Stable is defined as ±10% of the Visit 1 dose during the previous 12 weeks.

  4. Patients receiving metformin must be on a stable dose of metformin (at least 1500 mg daily or a maximally tolerated dose) for at least 12 weeks prior to Visit 1. 5. HbA1c ≥7.5 to ≤ 9,0% at Visit 1 6. Known CV disease based on a documented history of one or more of pre-defined criteria 7. Age: ≥40 to ≤80 years at Visit 1

Exclusion Criteria:

* 1. FPG ≥ 270 mg/dL (15 mmol/L) at Visit 1. 2. Use of any of the following medications as assessed at Visit 1:

  1. rapid or short acting insulin except in pre-mixed formulations with intermediate or long-acting insulin; insulin administration more frequently than twice-daily, or total insulin dose \< 0.3 unit/kg/day for the past 12 weeks
  2. use of any oral antidiabetic medication or GLP-1 analogues within the last 12 weeks, except metformin
  3. use of weight control products including weight-loss medications in the last 12 weeks.
  4. use of oral (≥7 consecutive days) or chronic parenteral or intra-articular corticosteroid treatment within the last 8 weeks. Inhaled or topical steroids without systemic effects will be allowed.
  5. treatment with growth hormone within the previous 6 months.
  6. treatment with any drug of known and frequent toxicity to a major organ, or that may interfere with the interpretation of the efficacy and safety data during the study.

     3. a history or evidence of any of the following at Visit 1:

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  1. acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar state (including precoma and coma) within the past 6 months.
  2. current diagnosis of congestive heart failure (NYHA III or IV).
  3. myocardial infarction within the past 6 months.
  4. coronary artery bypass surgery or percutaneous coronary intervention within the past 6 months.
  5. Stroke, transient ischemic attack, or reversible ischemic neurologic deficit within the past 6 months.
  6. unstable angina within the past 6 months.
  7. sustained and clinically relevant ventricular arrhythmia (patients with premature ventricular contractions if deemed not clinically significant may be enrolled).
  8. Patients with permanent atrial fibrillation or pacemaker.
  9. active substance abuse, alcohol abuse and history of alcohol-related diseases within the past 2 years.
  10. type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes (e.g. Cushing's syndrome or acromegaly-associated diabetes).
  11. malignancy of an organ system (other than localized basal cell carcinoma of the skin) treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
  12. hepatic disorder defined as:

      * acute or chronic liver disease, evidence of hepatitis, cirrhosis or portal hypertension.
      * history of imaging abnormalities that suggest liver disease (except hepatic steatosis), such as portal hypertension, capsule scalloping, cirrhosis.
  13. acute infections which may affect blood glucose control within the past 4 weeks.

      4. any of the following significant laboratory abnormalities as assessed at Visit 1:

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  1. clinically significant increase or reduction in thyroid stimulating hormone (TSH) outside of the normal range.
  2. clinically significant renal dysfunction: glomerular filtration rate (GFR) \<50 mL/min/1.73m2 (via MDRD formula).
  3. Patients on metformin with a GFR \<60 mL/min/1.73m2 (via MDRD formula).
  4. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 2 x upper limit of normal (ULN) at Visit 1, confirmed by repeated measurements within 3 working days.
  5. total bilirubin \> 2 x ULN and/or direct bilirubin \> 1 x ULN confirmed by repeated measurements within 3 working days.
  6. positive Hepatitis B surface antigen (HBsAg).
  7. positive Hepatitis C virus (HCV) antibody test (anti-HCV).
  8. elevated fasting triglycerides (TGs) \> 500mg/dL (5.65mmol/L), confirmed by a repeated measurements within 3 working days.
  9. clinically significant laboratory abnormalities which, in the opinion of the investigator, cause the patient to be considered inappropriate for inclusion in the study.

     5. any of the following electrocardiographic abnormalities at Visit 1:

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  1. second or third degree atrio-ventricular block.
  2. A QTc of \> 440 ms.
  3. clinically significant electrocardiogram (ECG) abnormalities which, in the opinion of the investigator, may cause the patient to be considered inappropriate for inclusion in the study

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 & 2
timeFrame: baseline and 0-24 hours post-dose on Days 2 to 5
Secondary outcomes:
measure: Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment.
timeFrame: after 8 weeks period 1 and Period 2
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
timeFrame: after 8 weeks for Period 1 & Period 2
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
timeFrame: after 8 weeks 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
timeFrame: after 8 weeks Period 1 & 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
timeFrame: 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
timeFrame: 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
timeFrame: Baseline, after 8 weeks 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
timeFrame: Baseline, after 8 weeks Period 1 & Period 2
measure: Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 & Period 2
timeFrame: Baseline, after 8 weeks Period 1 & Period 2
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
timeFrame: after 8 weeks Period 1 & Period 2
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dortmund
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Elsterwerda
country: Germany
facility: Novartis Investigative Site
city: Falkensee
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Neuss
country: Germany
facility: Novartis Investigative Site
city: Potsdam
country: Germany
facility: Novartis Investigative Site
city: Sulzbach-Rosenberg
country: Germany
facility: Novartis Investigative Site
city: Wallerfing
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: