Safety, Tolerability, and Effect of Alirocumab in High Cardiovascular Risk Patients With Severe Hypercholesterolemia Not Adequately Controlled With Conventional Lipid-modifying Therapies (ODYSSEY APPRISE)

NCT ID: NCT02476006

Last Updated: 2022-03-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 998 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-23
• Study Completion Date: 2019-04-12

Brief Summary

Primary Objective:

To provide participants with severe hypercholesterolemia at risk for subsequent cardiovascular (CV) events and not adequately controlled with currently available lipid-modifying therapy (LMT) access to alirocumab ahead of commercial availability and to document the overall safety and tolerability of alirocumab in this participant population.

Secondary Objectives:

To document the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels as well as non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels after 12 weeks of treatment.

To document participant's acceptability of self-injection (Self Injection Assessment Questionnaire, SIAQ).

Detailed Description

The study duration included a screening period of up to 3 weeks, a treatment period of a minimum of 12 weeks and up to a maximum of 120 weeks (30 months), and at least 2 weeks after the last study treatment injection.

Conditions

Hypercholesterolemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Alirocumab

Participants received Alirocumab 150 milligram (mg) subcutaneously (SC) once every two weeks (Q2W) or 75 mg SC Q2W added to stable LMT up to a maximum of 120 weeks. Alirocumab dose was either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W, based on Investigator judgment and treatment response.

Group Type: EXPERIMENTAL

ALIROCUMAB SAR236553 (REGN727)

Intervention Type: DRUG

Pharmaceutical form:solution Route of administration: subcutaneous

placebo (for injection training only)

Intervention Type: DRUG

Pharmaceutical form:solution Route of administration: subcutaneous

ezetimibe

Intervention Type: DRUG

Pharmaceutical form:capsule Route of administration: oral

atorvastatin

Intervention Type: DRUG

Pharmaceutical form:tablet Route of administration: oral

rosuvastatin

Intervention Type: DRUG

Pharmaceutical form:tablet Route of administration: oral

simvastatin

Intervention Type: DRUG

Pharmaceutical form:tablet Route of administration: oral

Interventions

ALIROCUMAB SAR236553 (REGN727)

Pharmaceutical form:solution Route of administration: subcutaneous

Intervention Type: DRUG

placebo (for injection training only)

Pharmaceutical form:solution Route of administration: subcutaneous

Intervention Type: DRUG

ezetimibe

Pharmaceutical form:capsule Route of administration: oral

Intervention Type: DRUG

atorvastatin

Pharmaceutical form:tablet Route of administration: oral

Intervention Type: DRUG

rosuvastatin

Pharmaceutical form:tablet Route of administration: oral

Intervention Type: DRUG

simvastatin

Pharmaceutical form:tablet Route of administration: oral

Intervention Type: DRUG

Other Intervention Names

Praluent®

Eligibility Criteria

Inclusion Criteria

Either A, B, C, D, or E below and not adequately controlled with a maximally tolerated dose of statin with or without other LMTs, all at stable doses for at least 4 weeks prior to the screening visit (Week-3):

A. Participants suffering from heterozygous familial hypercholesterolemia (heFH) with LDL-C concentrations greater than or equal to (>=)160 mg/dL (4.14 millimoles per liter [mmol/L]) despite treatment.

B. Participants suffering from heFH with LDL-C concentrations >=130 mg/dL (3.36 mmol/L) despite treatment and two or more CV risk factors among this list:

• LDL-C greater than (>) 250 milligrams per deciliter (mg/dL) (6.46 mmol/L) at the time of the familial hypercholesterolemia (FH) diagnosis (before treatment).
• Family history of premature-onset coronary heart disease (CHD; first-degree male relative with onset before age 55 years; first-degree female relative with onset before age 65 years).
• Metabolic syndrome.
• HDL-C less than (<) 40 mg/dL (1.03 mmol/L).
• Hypertension (blood pressure >140/90 mmHg or drug treatment).
• Lipoprotein a (Lp[a]) >=50 mg/dL (1.78 µmol/L).
• Tendon xanthoma.

C. Participants suffering from heFH with LDL-C concentrations >=130 mg/dL (3.36 mmol/L) despite treatment and one of the following characteristics:

• Established CHD or other cardiovascular disease (CVD; history of acute myocardial infarction, ischemic stroke, peripheral arterial disease, coronary or peripheral arterial revascularization, stable or unstable angina, transient ischemic attack, carotid artery stenosis >=50 percent (%), or aortic abdominal aneurysm).
• Drug-treated type 2 diabetes mellitus or type 1 with target organ damage.
• Family history of first- or second-degree relative with very premature onset CHD (first- or second-degree male relative with onset before age 45; first- or second-degree female relative with onset before age 55).

D. Non-FH participants suffering from established CHD or other CVD (history of acute myocardial infarction (MI), ischemic stroke, peripheral arterial disease, coronary or peripheral arterial revascularization, stable or unstable angina, transient ischemic attack, carotid artery stenosis >=50%, or aortic abdominal aneurysm) and with LDL-C concentrations >=130 mg/dL (3.36 mmol/L).

E. Participants suffering from progressive CVD (coronary artery disease, or peripheral arterial occlusive disease or cerebrovascular disease as documented clinically or by imaging techniques, with a subsequent CV event [acute MI, ischemic stroke, ischemia-driven revascularization, unstable angina, transient ischemic attack] occurring despite stable doses of maximally tolerated LMT) with LDL-C concentrations >=100 mg/dL (2.59 mmol/L).

Exclusion Criteria

Not on a stable dose of LMT (including statin) for at least 4 weeks prior to the screening visit (Week -3) and from screening to enrollment.

Use of a fibrate other than fenofibrate within 4 weeks of the screening visit (Week-3) or between screening and enrollment.

Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for participants on simvastatin 80 mg for more than one year, who were eligible).

Use of statin other than simvastatin, atorvastatin, or rosuvastatin prior to the screening visit (Week-3) or between screening and enrollment, except when there was a documented reason for intolerance to the above mentioned potent statins (in which case the use of a different statin was allowed).

Fasting serum TG >400 mg/dL (>4.52 mmol/L) at the screening visit (Week -3). Uncontrolled hypertension (>180 mmHg systolic and/or >110 mmHg diastolic at randomization visit).

New York Heart Association Class III or IV congestive heart failure persisting despite treatment.

History of hemorrhagic stroke. Liver transaminases >3 times the upper limit of normal. Laboratory evidence of current hepatitis B or C infection. Creatine kinase >3 times the upper limit of normal. Estimated glomerular filtration rate <30 mL/min/1.73 m^2. Pregnant or breastfeeding woman or with childbearing potential without appropriate contraception.

Male participant with a female partner of childbearing potential not protected by a highly-effective method(s) of birth control.

Participants eligible for enrollment into an ongoing clinical study of alirocumab conducted at the same investigational site.

Hypersensitivity to alirocumab or any of the excipients.

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Regeneron Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Sanofi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

Investigational Site Number 040001

Graz, , Austria

Investigational Site Number 040008

Innsbruck, , Austria

Investigational Site Number 040005

Linz, , Austria

Investigational Site Number 040006

Linz, , Austria

Investigational Site Number 040003

Vienna, , Austria

Investigational Site Number 040002

Vienna, , Austria

Investigational Site Number 040004

Vienna, , Austria

Investigational Site Number 040007

Vienna, , Austria

Investigational Site Number 040010

Vienna, , Austria

Investigational Site Number 056005

Aalst, , Belgium

Investigational Site Number 056018

Antwerp, , Belgium

Investigational Site Number 056008

Arlon, , Belgium

Investigational Site Number 056013

Bruges, , Belgium

Investigational Site Number 056010

Brussels, , Belgium

Investigational Site Number 056003

Brussels, , Belgium

Investigational Site Number 056006

Charleroi, , Belgium

Investigational Site Number 056007

Edegem, , Belgium

Investigational Site Number 056019

Genk, , Belgium

Investigational Site Number 056001

Ghent, , Belgium

Investigational Site Number 056017

Ghent, , Belgium

Investigational Site Number 056002

Haine-Saint-Paul, , Belgium

Investigational Site Number 056015

Kortrijk, , Belgium

Investigational Site Number 056009

La Louvière, , Belgium

Investigational Site Number 056004

Leuven, , Belgium

Investigational Site Number 056014

Liège, , Belgium

Investigational Site Number 056011

Overpelt, , Belgium

Investigational Site Number 056016

Roeselare, , Belgium

Investigational Site Number 124018

Calgary, , Canada

Investigational Site Number 124015

Cambridge, , Canada

Investigational Site Number 124002

Chicoutimi, , Canada

Investigational Site Number 124027

Coquitlam, , Canada

Investigational Site Number 124025

Edmonton, , Canada

Investigational Site Number 124017

Halifax, , Canada

Investigational Site Number 124013

Hamilton, , Canada

Investigational Site Number 124008

London, , Canada

Investigational Site Number 124026

Maple Ridge, , Canada

Investigational Site Number 124020

Montreal, , Canada

Investigational Site Number 124022

Montreal, , Canada

Investigational Site Number 124032

Mount Pearl, , Canada

Investigational Site Number 124005

Ottawa, , Canada

Investigational Site Number 124024

Peterborough, , Canada

Investigational Site Number 124003

Québec, , Canada

Investigational Site Number 124019

Saint-Charles-Borromée, , Canada

Investigational Site Number 124007

Sarnia, , Canada

Investigational Site Number 124001

Sherbrooke, , Canada

Investigational Site Number 124030

Smiths Falls, , Canada

Investigational Site Number 124023

Toronto, , Canada

Investigational Site Number 124014

Toronto, , Canada

Investigational Site Number 124028

Trois-Rivières, , Canada

Investigational Site Number 124011

Vancouver, , Canada

Investigational Site Number 124012

Victoria, , Canada

Investigational Site Number 124031

Winnipeg, , Canada

Investigational Site Number 124009

Woodstock, , Canada

Investigational Site Number 203004

Brno, , Czechia

Investigational Site Number 203002

Hradec Králové, , Czechia

Investigational Site Number 203001

Prague, , Czechia

Investigational Site Number 203005

Uherské Hradiště, , Czechia

Investigational Site Number 208003

Aalborg, , Denmark

Investigational Site Number 208001

Esbjerg, , Denmark

Investigational Site Number 208002

Roskilde, , Denmark

Investigational Site Number 246003

Turku, , Finland

Investigational Site Number 246001

Varkaus, , Finland

Investigational Site Number 250027

Amiens, , France

Investigational Site Number 250034

Auxerre, , France

Investigational Site Number 250016

Avignon, , France

Investigational Site Number 250021

Bayonne, , France

Investigational Site Number 250030

Bobigny, , France

Investigational Site Number 250045

Bordeaux, , France

Investigational Site Number 250049

Brest, , France

Investigational Site Number 250054

Bron, , France

Investigational Site Number 250015

Caen, , France

Investigational Site Number 250047

Clermont-Ferrand, , France

Investigational Site Number 250013

Corbeil-Essonnes, , France

Investigational Site Number 250032

Coudray, , France

Investigational Site Number 250002

Dijon, , France

Investigational Site Number 250040

Dijon, , France

Investigational Site Number 250012

Grenoble, , France

Investigational Site Number 250038

Grenoble, , France

Investigational Site Number 250033

Jossigny, , France

Investigational Site Number 250035

Le Chesnay, , France

Investigational Site Number 250036

Lens, , France

Investigational Site Number 250042

Lille, , France

Investigational Site Number 250004

Lille, , France

Investigational Site Number 250037

Limoges, , France

Investigational Site Number 250057

Lyon, , France

Investigational Site Number 250028

Marseille, , France

Investigational Site Number 250048

Marseille, , France

Investigational Site Number 250024

Montpellier, , France

Investigational Site Number 250006

Nantes, , France

Investigational Site Number 250022

Nantes, , France

Investigational Site Number 250017

Nice, , France

Investigational Site Number 250039

Nîmes, , France

Investigational Site Number 250014

Paris, , France

Investigational Site Number 250041

Paris, , France

Investigational Site Number 250026

Paris, , France

Investigational Site Number 250044

Paris, , France

Investigational Site Number 250001

Paris, , France

Investigational Site Number 250051

Pessac, , France

Investigational Site Number 250011

Poitiers, , France

Investigational Site Number 250031

Poitiers, , France

Investigational Site Number 250010

Reims, , France

Investigational Site Number 250008

Rennes, , France

Investigational Site Number 250018

Rouen, , France

Investigational Site Number 250023

Saint-Mandé, , France

Investigational Site Number 250025

Toulouse, , France

Investigational Site Number 250046

Toulouse, , France

Investigational Site Number 250007

Tours, , France

Investigational Site Number 250019

Vénissieux, , France

Investigational Site Number 250050

Vichy, , France

Investigational Site Number 276001

Berlin, , Germany

Investigational Site Number 276003

Magdeburg, , Germany

Investigational Site Number 300003

Ampelokipoi, , Greece

Investigational Site Number 300002

Ioannina, , Greece

Investigational Site Number 300001

Kallithea, , Greece

Investigational Site Number 348001

Budapest, , Hungary

Investigational Site Number 348002

Debrecen, , Hungary

Investigational Site Number 348004

Pécs, , Hungary

Investigational Site Number 348003

Szeged, , Hungary

Investigational Site Number 616005

Gdansk, , Poland

Investigational Site Number 616003

Krakow, , Poland

Investigational Site Number 616001

Lodz, , Poland

Investigational Site Number 616004

Olsztyn, , Poland

Investigational Site Number 616002

Warsaw, , Poland

Investigational Site Number 642-003

Bucharest, , Romania

Investigational Site Number 642-002

Iași, , Romania

Investigational Site Number 642-001

Timișoara, , Romania

Investigational Site Number 703003

Bratislava, , Slovakia

Investigational Site Number 703002

Bratislava, , Slovakia

Investigational Site Number 703001

Košice, , Slovakia

Investigational Site Number 705001

Maribor, , Slovenia

Investigational Site Number 724009

Alicante, , Spain

Investigational Site Number 724011

Alicante, , Spain

Investigational Site Number 724003

Córdoba, , Spain

Investigational Site Number 724012

Donostia / San Sebastian, , Spain

Investigational Site Number 724014

Donostia / San Sebastian, , Spain

Investigational Site Number 724019

Elche, , Spain

Investigational Site Number 724017

Galdakao, , Spain

Investigational Site Number 724020

Inca, , Spain

Investigational Site Number 724001

L'Hospitalet de Llobregat, , Spain

Investigational Site Number 724007

Las Palmas de Gran Canaria, , Spain

Investigational Site Number 724004

Madrid, , Spain

Investigational Site Number 724008

Madrid, , Spain

Investigational Site Number 724010

Madrid, , Spain

Investigational Site Number 724005

Málaga, , Spain

Investigational Site Number 724002

Santiago de Compostela, , Spain

Investigational Site Number 724006

Valencia, , Spain

Investigational Site Number 724016

Valencia, , Spain

Investigational Site Number 724015

Valladolid, , Spain

Investigational Site Number 756005

Baden, , Switzerland

Investigational Site Number 756002

Olten, , Switzerland

Investigational Site Number 756004

Reinach, , Switzerland

Investigational Site Number 756003

Sankt Gallen, , Switzerland

Investigational Site Number 756001

Zurich, , Switzerland

Countries

Austria; Belgium; Canada; Czechia; Denmark; Finland; France; Germany; Greece; Hungary; Poland; Romania; Slovakia; Slovenia; Spain; Switzerland

References

Cefalu AB, Garbelotto R, Mombelli G, Pirro M, Rubba P, Arca M, Borghi C, Bonomo K, Gonnelli S, Massaroni K, Tirone G, Averna M; ODYSSEY APPRISE Study Italian Investigators. A subgroup analysis of the ODYSSEY APPRISE study: Safety and efficacy of alirocumab in the Italian cohort. Nutr Metab Cardiovasc Dis. 2022 Nov;32(11):2638-2646. doi: 10.1016/j.numecd.2022.07.020. Epub 2022 Aug 9.

Reference Type: DERIVED

PMID: 36064689 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-000620-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1163-0984

Identifier Type: OTHER

Identifier Source: secondary_id

LPS14245

Identifier Type: -

Identifier Source: org_study_id