Novo Nordisk EX1250-4080 (insulin degludec vs. insulin glargine)

Overview

Status: Recruiting
Keywords: Type 2 Diabetes , Insulin , Transient Ischemic Attack , Coronary Artery Disease
IRB Number: 00070397
Specialty: Endocrinology and Metabolism
Sub Specialties: Diabetes

Brief Summary

The primary objective of the study is:

1. Confirm the cardiovascular safety of insulin degludec compared to that of insulin glargine.

The secondary objectives are:

1. Assess the efficacy of insulin degludec on markers of glycaemic control.

2. Assess safety on other parameters in subjects with type 2 diabetes at high risk of cardiovascular events. 

Endpoints:

1. The primary endpoint is the time from randomization to first occurrence of a 3-component major adverse cardiovascualr event (MACE): cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. 

2. The secondary endpoints are: 

 a. Number of severe hypoglycemic episodes

 b. Time from randomization to all cause death

 c. Number of serious of adverse events (SAEs)

3. Change from baseline to last assessment:

 a. Glycosylated hemoglobin (HbA1c) (central laboratory)

 b. Fasting plasma glucose (FPG) (central laboratory 

The trial will be event-driven and will be continued until a pre-specified number of 633 positively adjudicated first MACEs are collected. After at least 150 positivey adjudicated events are collected, an interim analysis will be performed to assess the preliminary non-inferiority of IDeg to IGlar for the primary endpoint. 

Detailed Description

Background Type 2 diabetes is characterized by insulin resistance and relative insulin secretory deficiency and is associated with excess cardiovascular mortality. The current treatment guidelines for diabetes highlight the importance of diet and exercise modifications, followed by pharmacological treatment with various classes of drugs. Insulin remains the most effective and often final step in the management of type 2 diabetes. In recent years there has been increasing focus on evaluating cardiovascular risk of new antidiabetic therapies to treat type 2 diabetes. The US Food and Drug Administration (FDA) has issued guidelines on how to demonstrate that new antidiabetic therapy to treat type 2 diabetes is not associated with an unacceptable increase in cardiovascular risk. The investigational drug, insulin degludec, is approved for use in Europe whereas, the FDA has requested additional clinical cardiovascular data before the review of the New Drug Application can be completed. The currently available data neither confirms nor excludes any such increased cardiovascular risk. Novo Nordisk is therefore initiating this cardiovascular outcome trial to confirm the cardiovascular safety of insulin degludec. This is a trial designed to evaluate cardiovascular outcome data. The selective and targeted approach to safety data collection is in line with the FDA guidance on safety data collection in late stage premarket and post-approval clinical investigations. The purpose of this cardiovascular outcome trial is to confirm the cardiovascular safety of insulin degludec compared to that of insulin glargine in subjects with type 2 diabetes at high risk for cardiovascular events. Insulin Degludec (IDeg) Insulin degludec (IDeg) is a basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which IDeg is continuously and slowly absorbed into the circulation to provide a long and steady action profile. IDeg is developed to cover the basal insulin needs in all patients with diabetes mellitus with once daily subcutaneous injection. IDeg is developed as IDeg 100 units/mL and IDeg 200 units/mL, to accommodate the wide range of insulin dose requirements. The rationale for developing IDeg is that the ultra-long duration of action of IDeg in combination with the stable and smooth profile is expected to enable optimal glycaemic control with flexibility in time of dosing and with less hypoglycemia compared to marketed basil insulin preparations. IDeg is intended for once daily (OD) injection covering the basal insulin needs in patients with diabetes mellitus from early to late stages of the disease, either alone or in combination with prandial insulin and/or oral antidiabetic drugs (OADs). The current FDA approved long acting basal insulin analogues, Insulin Glargine and (IGlar) and Insulin Detemir (IDet), offer a number of advantages over conventional protamine-crystallized basal insulin formulations (i.e., NPH insulin), including a lower risk of hypoglycemia and more predictable glycemic control. The duration of action of these basal insulins is dose dependent, and they are administered once or twice daily to provide 24-hour coverage. The development of IDeg is performed in parallel with the development of insulin degludec/insulin aspart (IDegAsp), which is a co-formulation of ultra-long-acting IDeg and the rapid-acting insulin analogue aspart (IAsp). Similar to IDeg, IDegAsp is developed as 100U/mL (NN5401) and 200 U/mL (NN1045). The development programme of IDeg has been evaluated in a series of nonclinical and clinical studies. The clinical part of the programme was initiated in September 2009 and in September 2011 Novo Nordisk applied for marketing authorization in EU and US, followed by applications to Japan, Mexico and other countries. The FDA and Health Canada have requested additional cardiovascular data before the review of the drug applications can be reconsidered. IDeg (trade name: Tresiba) is approved for use in EU, Japan, Mexico, Switzerland, Iceland, Liechenstein, Norway and India.

Principal Investigator: Debra Simmons
Department: Endocrinology/Diabetes Researc
Co Investigator:

Contact Information

Name:Erin Vanderhoof
Phone: 801-587-8951
Email: erin.vanderhoof@hsc.utah.edu

Inclusion Criteria

Inclusion Criteria

1. Informed consent obtained before any trial-related activities. Trial related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.

2. Type 2 diabetes

3. HbA1c > 7.0% or HbA1c < 7.0% and current insulin treatment corresponding to > 20 U/day of basil insulin

4. Current treatment with one or more injectable antidiabetc agent(s)

5. Age > 50 years at screening and at least one of the below conditions:

 a. prior myocardial infarction

 b. prior stroke or prior transient ischaemic attach (TIA)

 c.  prior coronary, carotid or peripheral arterial revascularisation

 d. > 50% stenosis on angiography or other imaging of coronary, carotid r lower extremity arteries

 e. history or symptomatic coronary heart disease documented by positive exercise stress test or any       cardiac imaging, or unstable angina pectoris with ECG changes.

 f. asymptomatic cardiac ischaemia documented by positive nuclear imaging test or exercise test or dobutamine stress echo.

 g. chronic heart failure NYHA class II-III

 h. chronic kidney disease corresponding to glomerular filtration rate 30-59 mL/min/1.73m2 per CKD-Epi

OR

Age > 60 years at screening and at least one of the below risk factors:

 i. microalbuminuria or proteinuria

 j. hypertension and left ventricular hypertrophy by ECG or imaging

 k. left ventricular sytolic and diastolic dysfunction by imaging

 l. ankle/brachial index < 0.9

 

 

Exclusion Criteria

Exclusion Criteria

1. An acute coronary or cerebrovascular event in the previous 60 days

2. Planned coronary, carotid or peripheral artery revascularization

3. CHronic heart failure NYHA class IV

4. Current heamodialysis or peritoneal dialysis or eGFR < 30 mL/min/1.73 m2 per CKD-Epi

5. End stage liver disease, defined as the presence acute ir chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding. bilirubin > 2.0 mg/dL, prothrombin time > 4 seconds prolonged, international normalized ratio (INR) > 1.7 or prior liver transplant.

6. Known or suspected hypersensitivity to trial products or related products.

7. Female of child-bearing potential who is pregnant, breast-feeding or intends to become pregnant or is not using adequate contraceptive methods as required by local law or practice.

8. Expected simultaneous participation in any other clinical trial of an investigational medicinal product. Participation in a clinical trial with stent(s) is allowed.

9.Receipt of any investigational medicinal product within 30 days before randomization. Brazil: Receipt of any investigational medicinal product within one year before randomization unless there is a direct benefit to the subject at the investigator's discretion.

10. Current or past (within last 5 years) malignant neoplasms (except basal cell and squamous cell carcinoma). 

11. Any condition that in the investigator opinion would make the subject unable to adhere to the initial trial visit schedule and procedures.