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Effect of Alirocumab on Postprandial Hyperlipemia in Patients With Type 2 Diabetes (EUTERPE)

Primary Purpose

Type2 Diabetes

Status

Completed

Phase

Phase 3

Locations

France

Study Type

Interventional

Intervention

Alirocumab

Placebo

About this trial

This is an interventional treatment trial for Type2 Diabetes

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Men with type 2 diabetes diagnosed since ≥ 6 months
HbA1C <9.0%
Men with primary hypercholesterolemia and/or mixed dyslipidemia
Aged 18-75 years (limits inclusive)
Patient could be treated for type 2 diabetes when diet and physical activity are not sufficient to restore glycemic control. The treatment must be stable 1 month before the inclusion and have to remain unchanged all along the study. The only authorized treatments are:
Metformin
And/or Sulphonylureas (SUs)
And/or Repaglinide
And/or DPP-4 inhibitors
And/or GLP1 receptor agonists: exenatide, liraglutide, dulaglutide
Fasting serum TG ≥ 150 mg/dl and < 500 mg/dl
BMI: 20-45 kg/m2
Use of statins or ezetimibe is allowed if treatment is stable for ≥ 1 month before the screening

Exclusion Criteria:

Any secondary causes of hypercholesterolemia or of mixed dyslipidemia (nephrotic syndrome, hypothyroidism…)
impaired liver function (AST and/or ALT ≥ 3ULN)
impaired renal function (eGFR with CKD-EPI formula < 30 ml/min)
Alcohol abuse (> 2 standard alcoholic drink per day; 1 standard alcoholic drink is the equivalent of 10g of alcohol)
History of myocardial infarction, acute coronary syndrome, unstable angina pectoris, stroke, transient ischemic attack, or cardiac revascularization within the 6 months before the screening visit.
History of PCSK9 mAb use
Known sensitivity to monoclonal antibody therapeutics or to their excipients
Lipid lowering therapies (other than statins), including fibrates, omega-3 fatty acids, bile acid sequestrants, niacin.
Insulin-treated patients
History of bariatric surgery
Inflammatory bowel diseases and gastrointestinal malabsorption diseases
Uncontrolled hypothyroidism (TSH > ULN and Free T4 < ULN) or hyperthyroidism (TSH < ULN)
Active cancer: progressive cancer or remission ≤ 3 years, except for basal or squamous cell carcinoma of the skin that has been successfully treated
Known history of positive test for HIV, hepatitis C or chronic hepatitis B
Corticosteroids therapy
Minors
Adults under guardianship or trusteeship

Sites / Locations

University Hospital of Nantes

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Alirocumab

Placebo

Arm Description

Alirocumab 75 mg for subcutaneous injection via a pre-filled pen. One injection every 2 weeks during a 10-weeks period (5 injections in total)

Placebo matching alirocumab is prepared in the same formulation as alirocumab, without the addition of protein, for subcutaneous injection via a pre-filled pen. One injection every 2 weeks during a 10-weeks period (5 injections in total)

Outcomes

Primary Outcome Measures

Total area under the post-prandial triglycerides concentration-time curve from meal-time until 8h (AUC0-8h) after standardized high fat meal.

Fifteenth days after the fifth injection of treatment (thus 10 weeks after first injection of treatment), subjects will be reported to investigational site (after a 12 hours overnight fast). Subjects must consume the test meal within 15 min. Upon completion of the meal (T0), sequential postprandial measurements of triglycerides concentrations will be taken. Blood samples will be collected at T-15, every 30 min for the first two hours after meal consumption, thereafter in 60 min intervals from T120 until 240 min and thereafter in 120 min intervals from T240 until 480 min.

Secondary Outcome Measures

Effect of treatment with alirocumab versus placebo following a standardized high-fat meal on post-prandial lipid metabolism (plasma lipoproteins, apolipoproteins, ...)

Fifteenth days after the fifth injection of treatment (thus 10 weeks after first injection of treatment), subjects will be reported to investigational site (after a 12 hours overnight fast). Subjects must consume the test meal within 15 min. Upon completion of the meal (T0), sequential postprandial measurements of triglycerides concentrations will be taken. Bleed samples will be collected at T-15, every 30 min for the first two hours after meal consumption, thereafter in 60 min intervals from T120 until 240 min and thereafter in 120 min intervals from T240 until 480 min.

Effect of treatment with alirocumab versus placebo on fasting lipid metabolism following a standardized high fat meal, using the same biomarkers than those used in the post-prandial state, plus indirect markers of cholesterol absorption and synthesis

Fifteenth days after the fifth injection of treatment (thus 10 weeks after first injection of treatment), subjects will be reported to investigational site after a 12 hours overnight fast. Before ingestion of the high fat meal, blood sample will be removed to perform the analysis.

Effect of treatment with alirocumab versus placebo on fasting and post-prandial and glucose homeostasis following a standardized high-fat meal

Fasting self-monitored blood glucose test will be obtained before starting the meal and every hour during 8 hours .

Full Information

NCT ID

NCT03344692

First Posted

October 31, 2017

Last Updated

September 26, 2022

Sponsor

Nantes University Hospital

Collaborators

Regeneron Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03344692

Brief Title

Effect of Alirocumab on Postprandial Hyperlipemia in Patients With Type 2 Diabetes

Acronym

EUTERPE

Official Title

Effect of Alirocumab on Postprandial Hyperlipemia in Patients With Type 2 Diabetes : a Randomized, Double-blind, Placebo-controlled, Cross-over Trial"

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Completed

Study Start Date

February 12, 2019 (Actual)

Primary Completion Date

April 28, 2022 (Actual)

Study Completion Date

April 28, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Nantes University Hospital

Collaborators

Regeneron Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged over the past decade as a post-transcriptional regulator of the LDL receptor (LDL-R). PCSK9 acts as an endogenous natural inhibitor of the LDL-R pathway. Monoclonal antibodies (mAb) directed against PCSK9, such as Alirocumab, are the most common method of PCSK9 inhibition. The goal of the present study is to assess, in the context of type 2 diabetes, a situation associated with an increased post-prandial hyperlipemia, whether PCSK9 inhibition with Alirocumab affects postprandial intestinal lipoprotein metabolism.

Detailed Description

Recently, human monoclonal antibodies directed against PCSK9 have been shown to be effective in reducing LDL cholesterol. Besides the liver, little is known about the role of PCSK9 in the small intestine, a tissue where it is expressed at a high level. Preclinical studies in mice indicate that PCSK9 inhibition reduces post-prandial hyperlipemia. Here, the investigators will test the effect of PCSK9 inhibition with alirocumab, a PCSK9 mAb, on post-prandial hyperlipemia in 24 patients with type 2 diabetes. The investigators will perform a randomized, double-blind, placebo-controlled, cross-over trial with alirocumab 75 mg every two weeks. In the cross-over design, two periods of 10-weeks treatment (i.e. 5 injections) will be separated by a 10-week wash-out period to avoid carry-over effect. The primary endpoint will be the total area under the post-prandial triglycerides concentration-time curve from meal-time until 8h (AUC0-8h) after a standardized meal test. As secondary endpoints, the investigators will explore the effect of alirocumab on plasma lipids, markers of cholesterol absorption and synthesis, and glycemic parameters. This study will help to decipher the function of PCSK9 on intestinal lipoprotein metabolism in human and to determine whether alirocumab can reduce post-prandial hyperlipemia, which is an independent cardiovascular risk factor. From a patient perspective, this study will give some important clues for the management of cardiovascular disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type2 Diabetes

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Alirocumab

Arm Type

Experimental

Arm Description

Alirocumab 75 mg for subcutaneous injection via a pre-filled pen. One injection every 2 weeks during a 10-weeks period (5 injections in total)

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Alirocumab

Intervention Description

prefilled pen containing 75 mg of Praluent (Alirocumab) in 1 ml of solution

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

prefilled pen containing 1 ml of solution without Praluent

Primary Outcome Measure Information:

Title

Total area under the post-prandial triglycerides concentration-time curve from meal-time until 8h (AUC0-8h) after standardized high fat meal.

Description

Time Frame

During 8 hours at week 10 after first treatment injection

Secondary Outcome Measure Information:

Title

Effect of treatment with alirocumab versus placebo following a standardized high-fat meal on post-prandial lipid metabolism (plasma lipoproteins, apolipoproteins, ...)

Description

Fifteenth days after the fifth injection of treatment (thus 10 weeks after first injection of treatment), subjects will be reported to investigational site (after a 12 hours overnight fast). Subjects must consume the test meal within 15 min. Upon completion of the meal (T0), sequential postprandial measurements of triglycerides concentrations will be taken. Bleed samples will be collected at T-15, every 30 min for the first two hours after meal consumption, thereafter in 60 min intervals from T120 until 240 min and thereafter in 120 min intervals from T240 until 480 min.

Time Frame

During 8 hours at week 10 after first treatment injection

Title

Description

Time Frame

10 weeks after treatment first injection

Title

Effect of treatment with alirocumab versus placebo on fasting and post-prandial and glucose homeostasis following a standardized high-fat meal

Description

Fasting self-monitored blood glucose test will be obtained before starting the meal and every hour during 8 hours .

Time Frame

Before and during 8 hours after high fat meal at week 10 after first treatment injection

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Men with type 2 diabetes diagnosed since ≥ 6 months HbA1C <9.0% Men with primary hypercholesterolemia and/or mixed dyslipidemia Aged 18-75 years (limits inclusive) Patient could be treated for type 2 diabetes when diet and physical activity are not sufficient to restore glycemic control. The treatment must be stable 1 month before the inclusion and have to remain unchanged all along the study. The only authorized treatments are: Metformin And/or Sulphonylureas (SUs) And/or Repaglinide And/or DPP-4 inhibitors And/or GLP1 receptor agonists: exenatide, liraglutide, dulaglutide Fasting serum TG ≥ 150 mg/dl and < 500 mg/dl BMI: 20-45 kg/m2 Use of statins or ezetimibe is allowed if treatment is stable for ≥ 1 month before the screening Exclusion Criteria: Any secondary causes of hypercholesterolemia or of mixed dyslipidemia (nephrotic syndrome, hypothyroidism…) impaired liver function (AST and/or ALT ≥ 3ULN) impaired renal function (eGFR with CKD-EPI formula < 30 ml/min) Alcohol abuse (> 2 standard alcoholic drink per day; 1 standard alcoholic drink is the equivalent of 10g of alcohol) History of myocardial infarction, acute coronary syndrome, unstable angina pectoris, stroke, transient ischemic attack, or cardiac revascularization within the 6 months before the screening visit. History of PCSK9 mAb use Known sensitivity to monoclonal antibody therapeutics or to their excipients Lipid lowering therapies (other than statins), including fibrates, omega-3 fatty acids, bile acid sequestrants, niacin. Insulin-treated patients History of bariatric surgery Inflammatory bowel diseases and gastrointestinal malabsorption diseases Uncontrolled hypothyroidism (TSH > ULN and Free T4 < ULN) or hyperthyroidism (TSH < ULN) Active cancer: progressive cancer or remission ≤ 3 years, except for basal or squamous cell carcinoma of the skin that has been successfully treated Known history of positive test for HIV, hepatitis C or chronic hepatitis B Corticosteroids therapy Minors Adults under guardianship or trusteeship

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bertrand CARIOU

Organizational Affiliation

Nantes University Hospital

Official's Role

Study Chair

Facility Information:

Facility Name

University Hospital of Nantes

City

Nantes

ZIP/Postal Code

44093

Country

France

12. IPD Sharing Statement

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Effect of Alirocumab on Postprandial Hyperlipemia in Patients With Type 2 Diabetes

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