Efficacy and Safety of Alirocumab Versus Placebo on Top of Maximally Tolerated Lipid Lowering Therapy in Patients With Hypercholesterolemia Who Have Type 1 or Type 2 Diabetes and Are Treated With Insulin (ODYSSEY DM - Insulin)

Hypercholesterolaemia Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Insulin Treated Patients With Type 1 or Type 2 Diabetes and With Hypercholesterolemia at High Cardiovascular Risk Not Adequately Controlled on Maximally Tolerated LDL-C Lowering Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02585778
• Other study ID #: LPS14355
• Secondary ID: 2015-000799-92U1
• Status: Completed
• Phase: Phase 3
• Start date: October 23, 2015
• Est. completion date: April 3, 2017

Study information

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

Clinical Trial Summary

Primary Objectives:

• To demonstrate the superiority of alirocumab in comparison with placebo in the reduction of calculated low-density lipoprotein cholesterol (LDL-C) in participants with diabetes treated with insulin and with hypercholesterolemia at high cardiovascular risk not adequately controlled on maximally tolerated LDL-C lowering therapy.

• To evaluate the safety and tolerability of alirocumab in participants with diabetes treated with insulin.

Secondary Objective:

To demonstrate that alirocumab was superior in comparison to placebo in its effects on other lipid parameters (i.e., measured LDL-C, non-high-density lipoprotein cholesterol [non-HDL-C], apolipoprotein B [Apo B], total cholesterol [TC], lipoprotein a [Lp(a)], high density lipoprotein cholesterol [HDL-C], triglyceride [TG] levels, triglyceride rich lipoproteins [TGRL], apolipoprotein A-1 [Apo A-1], apolipoprotein C-III [Apo C-III], and LDL particle number and size).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 517
• Est. completion date: April 3, 2017
• Est. primary completion date: April 3, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Participants diagnosed with Type 1 or Type 2 diabetes at least one year prior to the screening visit (Week -3).

• Signed written informed consent

• Participants with type 1 or type 2 diabetes treated with insulin whose LDL-C levels were not adequately controlled with maximally tolerated lipid-modifying therapy

• LDL-C of 70 mg/dL or greater

• 18 years of age or more

• Glycosylated hemoglobin (HbA1c) less than 10%

• History of cardiovascular disease (including coronary heart disease [CHD] and/or CHD risk equivalents) and/or at least one additional cardiovascular risk factor

Exclusion criteria:

• Not on a stable dose of statin or other lipid modifying therapy for at least 4 weeks prior to screening or from screening to randomization, unless statin intolerant

• Triglycerides >400 mg/dL

• Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m² according to the Modification of Diet in Renal Disease (MDRD) equation

• Currently received or planned to receive renal replacement therapy (for example, hemodialysis)

• Change in weight of more than 5 kilograms within the prior 2 months

• Not on a stable dose/regimen of insulin or other antidiabetic drugs for the past 3 months or planned to intensify insulin regimen during the study

• Not treated with insulin for at least 6 months

• Planned to start new lipid modifying therapy or change dose of current lipid modifying therapy during the study

• Body mass index (BMI) >45 kg/m² or planned to undergo bariatric surgery, weight loss program, or initiate weight loss drugs during the study

• History of recent decompensation of diabetes within the prior 2 months (for example, diabetic ketoacidosis)

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

• Hypercholesterolaemia
• Hypercholesterolemia

Intervention

Drug:
• Alirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.
• Placebo
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.
• Lipid-Modifying Therapy (LMT)
Statins at stable, maximally tolerated dose with or without other LMT as clinically indicated.
• Antihyperglycemic Drug
Insulin (injectable or inhaled) alone or with other antihyperglycemic drugs as clinically indicated.

Locations

Country	Name	City	State
Austria	Investigational Site Number 040002	Innsbruck
Austria	Investigational Site Number 040005	Linz
Austria	Investigational Site Number 040003	Salzburg
Austria	Investigational Site Number 040004	Salzburg
Austria	Investigational Site Number 040001	Wien
Belgium	Investigational Site Number 056002	Edegem
Belgium	Investigational Site Number 056003	Haine-Saint-Paul
Belgium	Investigational Site Number 056001	Leuven
France	Investigational Site Number 250-008	Besancon
France	Investigational Site Number 250-005	Corbeil Essonnes
France	Investigational Site Number 250-004	La Rochelle Cedex 1
France	Investigational Site Number 250-003	Le Creusot
France	Investigational Site Number 250-009	Mulhouse
France	Investigational Site Number 250-002	Nantes cedex 01
France	Investigational Site Number 250-007	Paris
France	Investigational Site Number 250-006	Strasbourg Cedex 2
France	Investigational Site Number 250-001	TOULOUSE Cedex 9
Germany	Investigational Site Number 276015	Aschaffenburg
Germany	Investigational Site Number 276002	Berlin
Germany	Investigational Site Number 276011	Dortmund
Germany	Investigational Site Number 276009	Dresden
Germany	Investigational Site Number 276014	Dresden
Germany	Investigational Site Number 276019	Dresden
Germany	Investigational Site Number 276018	Hamburg
Germany	Investigational Site Number 276021	Hamburg
Germany	Investigational Site Number 276005	Heidelberg
Germany	Investigational Site Number 276013	Lüneburg
Germany	Investigational Site Number 276022	Magdeburg
Germany	Investigational Site Number 276008	Neumünster
Germany	Investigational Site Number 276017	Neuwied
Germany	Investigational Site Number 276004	Oldenburg
Germany	Investigational Site Number 276003	Pirna
Germany	Investigational Site Number 276006	Riesa
Germany	Investigational Site Number 276010	Saarlouis
Germany	Investigational Site Number 276016	Sulzbach-Rosenberg
Italy	Investigational Site Number 380004	Catania
Italy	Investigational Site Number 380003	Catanzaro
Italy	Investigational Site Number 380011	Como
Italy	Investigational Site Number 380006	Milano
Italy	Investigational Site Number 380007	Milano
Italy	Investigational Site Number 380005	Moncalieri
Italy	Investigational Site Number 380009	Napoli
Italy	Investigational Site Number 380008	Padova
Italy	Investigational Site Number 380002	Palermo
Italy	Investigational Site Number 380001	Pisa
Italy	Investigational Site Number 380010	Roma
Italy	Investigational Site Number 380012	Verona
Netherlands	Investigational Site Number 528002	Apeldoorn
Netherlands	Investigational Site Number 528005	Groningen
Netherlands	Investigational Site Number 528003	Hoogeveen
Netherlands	Investigational Site Number 528001	Rotterdam
Netherlands	Investigational Site Number 528004	Utrecht
Spain	Investigational Site Number 724007	Badalona
Spain	Investigational Site Number 724001	Barcelona
Spain	Investigational Site Number 724006	Ferrol
Spain	Investigational Site Number 724013	Granada
Spain	Investigational Site Number 724004	Madrid
Spain	Investigational Site Number 724005	Madrid
Spain	Investigational Site Number 724011	Majadahonda
Spain	Investigational Site Number 724008	Málaga
Spain	Investigational Site Number 724014	Oviedo
Spain	Investigational Site Number 724009	Palma de Mallorca
Spain	Investigational Site Number 724002	Pamplona
Spain	Investigational Site Number 724010	Sant Joan Despí
Spain	Investigational Site Number 724012	Segovia
Spain	Investigational Site Number 724003	Sevilla
Switzerland	Investigational Site Number 756001	Olten
Switzerland	Investigational Site Number 756003	St. Gallen
United Kingdom	Investigational Site Number 826010	Airdrie
United Kingdom	Investigational Site Number 826011	Bath
United Kingdom	Investigational Site Number 826009	Bournemouth
United Kingdom	Investigational Site Number 826005	Bradford
United Kingdom	Investigational Site Number 826004	Bristol
United Kingdom	Investigational Site Number 826001	Burton On Trent
United Kingdom	Investigational Site Number 826015	Durham
United Kingdom	Investigational Site Number 826012	High Wycombe
United Kingdom	Investigational Site Number 826007	Manchester
United Kingdom	Investigational Site Number 826006	Peterborough
United Kingdom	Investigational Site Number 826003	Southampton
United Kingdom	Investigational Site Number 826008	Truro
United Kingdom	Investigational Site Number 826002	Welwyn Garden City
United States	Investigational Site Number 840026	Atlantis	Florida
United States	Investigational Site Number 840018	Auburn	Maine
United States	Investigational Site Number 840001	Austin	Texas
United States	Investigational Site Number 840006	Bradenton	Florida
United States	Investigational Site Number 840024	Chattanooga	Tennessee
United States	Investigational Site Number 840003	Dallas	Texas
United States	Investigational Site Number 840019	Dallas	Texas
United States	Investigational Site Number 840010	Des Moines	Iowa
United States	Investigational Site Number 840020	Encino	California
United States	Investigational Site Number 840002	Fresno	California
United States	Investigational Site Number 840009	Greer	South Carolina
United States	Investigational Site Number 840025	Houston	Texas
United States	Investigational Site Number 840013	Hyattsville	Maryland
United States	Investigational Site Number 840011	Indianapolis	Indiana
United States	Investigational Site Number 840023	Jacksonville	Florida
United States	Investigational Site Number 840012	Jamaica	New York
United States	Investigational Site Number 840005	Louisville	Kentucky
United States	Investigational Site Number 840027	Loveland	Colorado
United States	Investigational Site Number 840014	Maumee	Ohio
United States	Investigational Site Number 840004	Minneapolis	Minnesota
United States	Investigational Site Number 840029	Oakland	California
United States	Investigational Site Number 840017	Ogden	Utah
United States	Investigational Site Number 840028	Palm Harbor	Florida
United States	Investigational Site Number 840022	Ponte Vedra Beach	Florida
United States	Investigational Site Number 840016	Rockville	Maryland
United States	Investigational Site Number 840021	Roswell	Georgia
United States	Investigational Site Number 840008	Salt Lake City	Utah
United States	Investigational Site Number 840007	Springfield	Illinois
United States	Investigational Site Number 840015	Valparaiso	Indiana

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  France,  Germany,  Italy,  Netherlands,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Calculated LDL-C at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis).	From Baseline to Week 24
Primary	Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)	Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'treatment-emergent period' (the time from the first dose of study drug up to the last dose of study drug +70 days).	From Baseline up to 10 weeks after last study drug administration (maximum of 32 weeks)
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
Secondary	Percent Change From Baseline in Measured LDL-C at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis	Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 4 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 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 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis	Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	Up to Week 24
Secondary	Percentage of Participants Reaching Calculated LDL-C <50 mg/dL (1.3 mmol/L) at Week 24 - On-Treatment Analysis	Adjusted percentages at Week 24 from last observation carried forward (LOCF) approach (for T1DM participants) and multiple imputation approach model (for T2DM participants) including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection). The maximum likelihood estimate did not exist as response rate was zero in a treatment group of T1DM participants.	Up to Week 24
Secondary	Percentage of Participants Reaching Calculated Non-HDL-C <100 mg/dL at Week 24 - On-Treatment Analysis	Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	Up to Week 24
Secondary	Percentage of Participants Reaching Calculated Non-HDL-C <80 mg/dL at Week 24 - On-Treatment Analysis	Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	Up to Week 24
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis	Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach for handling of missing data followed by robust regression model. All available post-baseline data from Week 4 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 HDL-C at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 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 Analysis	Adjusted means and standard errors at Week 24 from multiple imputation approach for handling of missing data followed by robust regression model including all available post-baseline data from Week 4 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 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 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Percent Change From Baseline in LDL-C Particle Size at Week 24 - ITT Analysis	LDL-C particle size was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Secondary	Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Weeks 12 and 24 - ITT Analysis	Absolute change = HbA1c value at specified weeks minus HbA1c value at baseline.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in HbA1c at Weeks 12 and 24 - On-Treatment Analysis	Absolute change = HbA1c value at specified weeks minus HbA1c value at baseline.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 12 and 24 - ITT Analysis	Absolute change = FPG value at specified weeks minus FPG value at baseline.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in FPG at Weeks 12 and 24 - On-Treatment Analysis	Absolute change = FPG value at specified weeks minus FPG value at baseline.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - ITT Analysis	Absolute change = total daily insulin dose at specified weeks minus baseline value.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - On-Treatment Analysis	Absolute change = total daily insulin dose at specified weeks minus baseline value.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - ITT Analysis	Absolute change = daily insulin dose/kg at specified weeks minus baseline value.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - On-Treatment Analysis	Absolute change = daily insulin dose/kg at specified weeks minus baseline value.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Weeks 12 and 24 - 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 weeks minus baseline value.	Baseline, Weeks 12 and 24
Secondary	Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Weeks 12 and 24 - On-Treatment 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 weeks minus baseline value.	Baseline, Weeks 12 and 24