Efficacy and Safety of Alirocumab Versus Usual Care on Top of Maximally Tolerated Statin Therapy in Patients With Type 2 Diabetes and Mixed Dyslipidemia (ODYSSEY DM-Dyslipidemia)

Dyslipidemia Clinical Trial

Official title:

A Randomized, Open-Label, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab Versus Usual Care in Patients With Type 2 Diabetes and Mixed Dyslipidemia at High Cardiovascular Risk With Non-HDL-C Not Adequately Controlled With Maximally Tolerated Statin Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02642159
• Other study ID #: LPS14354
• Secondary ID: 2015-001934-19U1
• Status: Completed
• Phase: Phase 4
• Start date: March 15, 2016
• Est. completion date: May 15, 2017

Study information

• Verified date: March 2018
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

To demonstrate the superiority of alirocumab in comparison with usual care in the reduction of non-high-density lipoprotein cholesterol (non-HDL-C) in participants with type 2 diabetes and mixed dyslipidemia at high cardiovascular risk with non-HDL-C not adequately controlled with maximally tolerated statin therapy.

Secondary Objectives:

• To demonstrate whether alirocumab is superior in comparison with usual care in its effects on other lipid parameters (ie, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (Total -C), lipoprotein a (Lp[a]), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), triglyceride rich lipoproteins (TGRLs), apolipoprotein A-1 (Apo A-1), apolipoprotein C-III (Apo C-III), lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy (ie, LDL-C particle size and LDL, very low-density lipoprotein [VLDL], HDL, and intermediate-density lipoprotein [IDL] particle number).

• To assess changes in glycemic parameters with alirocumab vs. usual care treatment.

• To demonstrate the safety and tolerability of alirocumab.

• To evaluate treatment acceptance of alirocumab.

• To evaluate proprotein convertase subtilisin kexin type 9 (PCSK9) concentrations and antibody development.

• To demonstrate the superiority of alirocumab vs. fenofibrate on non-HDL-C and other lipid parameters (subgroup analysis).

Description:

The maximum study duration was approximately 9 months per participant, including a 6 month treatment period, a screening period of up to 3 weeks, and an 8 week safety observation period.

For the purpose of scientific communication, a first-step analysis (both efficacy and safety) was performed at the Week 24 cut-off date. A second-step analysis was performed once all participants had completed the study to include a final update of the safety analysis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 413
• Est. completion date: May 15, 2017
• Est. primary completion date: March 22, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Participants with type 2 diabetes and mixed dyslipidemia whose non-HDL-C was not adequately controlled with a stable, maximum dose/regimen of statin that was tolerated by the participant.

• 18 years of age or more.

• Documented history of atherosclerotic cardiovascular disease (ASCVD) or at least one additional cardiovascular risk factor.

• Non-HDL-C of 100 mg/dL or greater.

• Triglycerides greater than or equal to 150 mg/dL and less than 500 mg/dL.

• Stable anti-hyperglycemic agents for at least 3 months prior to the screening visit and between screening and randomization (including stable insulin dose defined as no variation more than 30% in daily insulin dose within the preceding 3 months, as judged by the Investigator).

• No change in weight of more than 5 kg within the prior 3 months.

• On stable dose of medications that are known to influence weight and/or lipids within the last 3 months.

Exclusion criteria:

• Use of any lipid modifying therapies other than statins within the last 4 weeks (eg, ezetimibe, fenofibrate, nicotinic acid, omega-3 fatty acids, etc.) or use of over the counter products/nutraceuticals known to impact lipids (eg, red yeast rice) within the last 4 weeks.

• Currently drinking more than 2 standard alcoholic drinks per day.

• Body Mass Index (BMI) >45 kg/m² or currently enrolled in a weight loss program and still in active phase of weight loss.

• Glycosylated hemoglobin (HbA1c) 9% or greater.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Related Conditions & MeSH terms

• Dyslipidemia
• Dyslipidemias

Intervention

Drug:
• Alirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.
• Statins
Statins at stable dose without other LMT as clinically indicated.
• Ezetimibe
Pharmaceutical form: tablet Route of administration: oral
• Fenofibrate
Pharmaceutical form: tablet Route of administration: oral
• Nicotinic acid
Pharmaceutical form: tablet Route of administration: oral
• Omega-3 fatty acids
Pharmaceutical form: tablet Route of administration: oral
• Antihyperglycemic Drug
Insulin (injectable or inhaled) or other antihyperglycemic drugs as clinically indicated.

Locations

Country	Name	City	State
Australia	Investigational Site Number 036102	Herston
Australia	Investigational Site Number 036104	Merewether
Australia	Investigational Site Number 036101	St Leonards
Brazil	Investigational Site Number 076103	Campinas
Brazil	Investigational Site Number 076104	Fortaleza
Brazil	Investigational Site Number 076101	Sao Paulo
Brazil	Investigational Site Number 076102	SãO Paulo
Brazil	Investigational Site Number 076105	São paulo
Brazil	Investigational Site Number 076106	São Paulo
Finland	Investigational Site Number 246101	Oulu
Finland	Investigational Site Number 246102	Oulu
Finland	Investigational Site Number 246104	Tampere
Germany	Investigational Site Number 276109	Berlin
Germany	Investigational Site Number 276112	Berlin
Germany	Investigational Site Number 276104	Dippoldiswalde
Germany	Investigational Site Number 276101	Dresden
Germany	Investigational Site Number 276108	Essen
Germany	Investigational Site Number 276110	Essen
Germany	Investigational Site Number 276111	Goch
Germany	Investigational Site Number 276107	Karlsruhe
Germany	Investigational Site Number 276103	Künzing
Germany	Investigational Site Number 276102	Oldenburg in Holstein
Israel	Investigational Site Number 376101	Beer Sheva
Israel	Investigational Site Number 376103	Petach Tikva
Israel	Investigational Site Number 376104	Petach tikva
Israel	Investigational Site Number 376102	Rehovot
Israel	Investigational Site Number 376106	Tel-Aviv
Italy	Investigational Site Number 380104	Bergamo
Italy	Investigational Site Number 380107	Catanzaro
Italy	Investigational Site Number 380103	Napoli
Italy	Investigational Site Number 380108	Padova
Italy	Investigational Site Number 380106	Partinico
Italy	Investigational Site Number 380101	Pisa
Italy	Investigational Site Number 380105	Roma
Italy	Investigational Site Number 380102	Torino
Kuwait	Investigational Site Number 414101	Kuwait
Lebanon	Investigational Site Number 422101	Beirut
Lebanon	Investigational Site Number 422102	Hazmieh
Norway	Investigational Site Number 578101	Oslo
Norway	Investigational Site Number 578102	Oslo
Sweden	Investigational Site Number 752102	Göteborg
Sweden	Investigational Site Number 752101	Stockholm
Switzerland	Investigational Site Number 756101	Genève
Switzerland	Investigational Site Number 756102	Olten
Switzerland	Investigational Site Number 756103	Reinach
Turkey	Investigational Site Number 792105	Adana
Turkey	Investigational Site Number 792102	Ankara
Turkey	Investigational Site Number 792106	Ankara
Turkey	Investigational Site Number 792108	Corum
Turkey	Investigational Site Number 792109	Hatay
Turkey	Investigational Site Number 792101	Izmir
Turkey	Investigational Site Number 792104	Izmir
Turkey	Investigational Site Number 792110	Izmir
Turkey	Investigational Site Number 792107	Kayseri
Turkey	Investigational Site Number 792103	Samsun
United Arab Emirates	Investigational Site Number 784101	Dubai
United Kingdom	Investigational Site Number 826104	Exeter
United Kingdom	Investigational Site Number 826106	Manchester
United Kingdom	Investigational Site Number 826105	Middlesborough
United Kingdom	Investigational Site Number 826103	Stevenage
United Kingdom	Investigational Site Number 826101	Torquay
United Kingdom	Investigational Site Number 826102	West Bromwich
United States	Investigational Site Number 840-178	Albany	New York
United States	Investigational Site Number 840-137	Bainbridge	Georgia
United States	Investigational Site Number 840-136	Bend	Oregon
United States	Investigational Site Number 840-107	Boca Raton	Florida
United States	Investigational Site Number 840-170	Boynton Beach	Florida
United States	Investigational Site Number 840-114	Bradenton	Florida
United States	Investigational Site Number 840-147	Chattanooga	Tennessee
United States	Investigational Site Number 840-126	Chesapeake	Virginia
United States	Investigational Site Number 840-161	Chicago	Illinois
United States	Investigational Site Number 840-104	Columbus	Ohio
United States	Investigational Site Number 840-128	Columbus	Georgia
United States	Investigational Site Number 840-184	Crystal Lake	Illinois
United States	Investigational Site Number 840-153	Dallas	Texas
United States	Investigational Site Number 840-174	Evanston	Illinois
United States	Investigational Site Number 840-129	Fargo	North Dakota
United States	Investigational Site Number 840-141	Fresno	California
United States	Investigational Site Number 840-188	Greensboro	North Carolina
United States	Investigational Site Number 840-143	Houston	Texas
United States	Investigational Site Number 840-168	Houston	Texas
United States	Investigational Site Number 840-152	Huntington Beach	California
United States	Investigational Site Number 840-167	Idaho Falls	Idaho
United States	Investigational Site Number 840-113	Jefferson City	Missouri
United States	Investigational Site Number 840-159	Knoxville	Tennessee
United States	Investigational Site Number 840-115	La Jolla	California
United States	Investigational Site Number 840-101	Las Vegas	Nevada
United States	Investigational Site Number 840-140	Las Vegas	Nevada
United States	Investigational Site Number 840-163	Little Rock	Arkansas
United States	Investigational Site Number 840-118	Los Angeles	California
United States	Investigational Site Number 840-108	Louisville	Kentucky
United States	Investigational Site Number 840-105	Marion	Ohio
United States	Investigational Site Number 840-175	Maumee	Ohio
United States	Investigational Site Number 840-190	Metairie	Louisiana
United States	Investigational Site Number 840-131	Morehead City	North Carolina
United States	Investigational Site Number 840-158	Morganton	North Carolina
United States	Investigational Site Number 840-187	Murrells Inlet	South Carolina
United States	Investigational Site Number 840-157	New York	New York
United States	Investigational Site Number 840-181	New York	New York
United States	Investigational Site Number 840-106	Northridge	California
United States	Investigational Site Number 840-132	Ocoee	Florida
United States	Investigational Site Number 840-148	Omaha	Nebraska
United States	Investigational Site Number 840-185	Orem	Utah
United States	Investigational Site Number 840-179	Oviedo	Florida
United States	Investigational Site Number 840-183	Paducah	Kentucky
United States	Investigational Site Number 840-176	Port Hueneme	California
United States	Investigational Site Number 840-171	Richmond	Virginia
United States	Investigational Site Number 840-151	Rockville	Maryland
United States	Investigational Site Number 840-142	Round Rock	Texas
United States	Investigational Site Number 840-120	Saint Louis	Missouri
United States	Investigational Site Number 840-150	Salt Lake City	Utah
United States	Investigational Site Number 840-138	Springfield	Illinois
United States	Investigational Site Number 840-169	Stockbridge	Georgia
United States	Investigational Site Number 840-111	Summerville	South Carolina
United States	Investigational Site Number 840-123	Tampa	Florida
United States	Investigational Site Number 840-122	Tarzana	California
United States	Investigational Site Number 840-133	Tomball	Texas
United States	Investigational Site Number 840-156	Tustin	California
United States	Investigational Site Number 840-160	Van Nuys	California

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Finland,  Germany,  Israel,  Italy,  Kuwait,  Lebanon,  Norway,  Sweden,  Switzerland,  Turkey,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Non-HDL-C at Week 24: Overall Intent-to-treat (ITT) Analysis	Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis).	From Baseline to Week 24
Primary	Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis	Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis	Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum	Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis	Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum	Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Apo B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis	Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment were included in the imputation model.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall ITT Analysis	Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in HDL-C at Week 24 : Overall ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis	LDL-C particle number was calculated from lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum	LDL-C particle number was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.	From Baseline to Week 24
Secondary	Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis	Absolute change = HbA1c value at specified week minus HbA1c value at baseline.	Baseline, Week 12 and 24
Secondary	Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis	Absolute change = FPG value at specified week minus FPG value at baseline.	Baseline, Week 12 and 24
Secondary	Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis	Glucose lowering treatment was calculated for non-insulin treatments as one for each unique treatment received and for insulin treatment as one in total for all participants who have taken one or more treatments. Absolute change = number of glucose-lowering treatments at specified week minus baseline value.	Baseline, Week 12 and 24