Vildagliptin vs Sitagliptin add-on to Insulin - Impact on Glycemic Profile and Correlation of Hypoglycemic Episodes and Heart Function (CGM-VISIT)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01686932
First received: September 13, 2012
Last updated: August 4, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus Type 2
Drug: Vildagliptin followed by Sitagliptin
Drug: Sitagliptin followed by Vildagliptin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • The hypoglycemic profile of vildagliptin compared to sitagliptin [ Time Frame: after 8 weeks of treatment for each period ] [ Designated as safety issue: No ]
    1. Outcome Measure Description: The hypoglycemic profile is defined as the area under the glucose-timeprofile obtained by continuous glucose monitoring (5 days baseline and 5 days after 8 weeks of each treatment) where the glucose levels are lower than the hypoglycemia threshold of <70 mg/dL.


Secondary Outcome Measures:
  • Number of hypoglycemic events during vildagliptin treatment compared to sitagliptin treatment. [ Time Frame: after 8 weeks of treatment for each period ] [ Designated as safety issue: No ]
    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.

  • Duration of hypoglycemic events during vildagliptin treatment compared to sitagliptin treatment [ Time Frame: after 8 weeks of treatment for each period ] [ Designated as safety issue: No ]
    the mean duration of hypoglycemic events is detected by CGM measurement.

  • grade of severity of hypoglycemia [ Time Frame: evaluation after 8 weeks of treatment for each period ] [ Designated as safety issue: No ]
    To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude

  • Number of severe hypoglycemic events during vildagliptin treatment compared to sitagliptin treatment [ Time Frame: evaluation after 8 weeks of treatment for each period ] [ Designated as safety issue: Yes ]
    Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of <40 mg /dL.

  • Glucose fluctuations during the day under vildagliptin treatment compared to sitagliptin treatment [ Time Frame: after 8 weeks of treatment for each period ] [ Designated as safety issue: No ]
    Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970).

  • Impact of hypoglycemic events on ECG abnormalities [ Time Frame: evaluation after 8 weeks of treatment for each period ] [ Designated as safety issue: Yes ]
    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.

  • Status of pro-inflammatory biomarkers under vildagliptin treatment compared to sitagliptin treatment [ Time Frame: evaluation after 8 weeks of treatment for each period ] [ Designated as safety issue: No ]
    chosen pro-inflammatory biomarkers are hsCRP and IL-6.

  • Pro-insulin/C-Peptide ratio during vildagliptin treatment compared to sitagliptin treatment. [ Time Frame: evaluation after 8 weeks of treatment for each period ] [ Designated as safety issue: No ]
    Pro-Insulin and C-Peptide will be measured after 8 weeks of each treatment


Enrollment: 50
Study Start Date: November 2012
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment Sequence 1
Vildagliptin (8 weeks) followed by Sitagliptin (8 weeks) after wash-out period (7-28 days)
Drug: Vildagliptin followed by Sitagliptin
Oral antidiabetic treatment, 50 mg tablets vildagliptin bid, 100 mg od tablets sitagliptin
Other Name: Vildagliptin (Galvus) followed by Sitagliptin (Januvia)
Experimental: Treatment Sequence 2
Sitagliptin (8 weeks) followed by Vildagliptin (8 weeks) after wash-out (7-28 days)
Drug: Sitagliptin followed by Vildagliptin
oral antidiabetic treatment, 50 mg tablets vildagliptin bid, 100 mg tablets sitagliptin od

  Eligibility

Ages Eligible for Study:   40 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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:

    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:

    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:

    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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01686932

Locations
Germany
Novartis Investigative Site
Berlin, Germany, 13055
Novartis Investigative Site
Berlin, Germany, 10115
Novartis Investigative Site
Dortmund, Germany, 44137
Novartis Investigative Site
Dresden, Germany, 01307
Novartis Investigative Site
Elsterwerda, Germany, 04910
Novartis Investigative Site
Falkensee, Germany, 14612
Novartis Investigative Site
Magdeburg, Germany, 39112
Novartis Investigative Site
Neuss, Germany, 41460
Novartis Investigative Site
Potsdam, Germany, 14469
Novartis Investigative Site
Sulzbach-Rosenberg, Germany, 92237
Novartis Investigative Site
Wallerfing, Germany, 94574
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01686932     History of Changes
Other Study ID Numbers: CLAF237ADE07
Study First Received: September 13, 2012
Last Updated: August 4, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices (BfArM)

Keywords provided by Novartis:
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

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin
Vildagliptin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014