Clinical trial NCT02476006: Safety, Tolerability, and Effect of Alirocumab in High Cardiovascular Risk Patients With Severe Hypercholesterolemia Not Adequately Controlled With Conventional Lipid-modifying Therapies (ODYSSEY APPRISE)
Official title: A Multi-country, Multicenter, Single-arm, Open-label Study to Document the Safety, Tolerability and Effect of Alirocumab on Atherogenic Lipoproteins in High Cardio-vascular Risk Patients With Severe Hypercholesterolemia Not Adequately Controlled With Conventional Lipid-modifying Therapies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2015-06-19
Enrollment: 998
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first injection of investigational medicinal product (IMP) up to 2 weeks after last dose of study drug (Week 120)
Secondary outcomes:
measure: Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 12
timeFrame: Baseline, Week 12
measure: Percentage of Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12
timeFrame: At Week 12
measure: Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 12
timeFrame: At Week 12
measure: Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) and/or >=50% Reduction From Baseline in LDL-C at Week 12
timeFrame: At Week 12
measure: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in Triglycerides at Week 12
timeFrame: Baseline, Week 12
measure: Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Feeling About Injections, Self Confidence, Satisfaction With Self-Injections
timeFrame: Baseline (Pre-SIAQ), Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96
measure: Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Self Image, Injection-Site Reactions, Ease of Use
timeFrame: Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Investigational Site Number 040001
city: Innsbruck
country: Austria
facility: Investigational Site Number 040008
city: Linz
country: Austria
facility: Investigational Site Number 040005
city: Linz
country: Austria
facility: Investigational Site Number 040006
city: Wien
country: Austria
facility: Investigational Site Number 040003
city: Wien
country: Austria
facility: Investigational Site Number 040002
city: Wien
country: Austria
facility: Investigational Site Number 040004
city: Wien
country: Austria
facility: Investigational Site Number 040007
city: Wien
country: Austria
facility: Investigational Site Number 040010
city: Aalst
country: Belgium
facility: Investigational Site Number 056005
city: Antwerpen
country: Belgium
facility: Investigational Site Number 056018
city: Arlon
country: Belgium
facility: Investigational Site Number 056008
city: Brugge
country: Belgium
facility: Investigational Site Number 056013
city: Brussel
country: Belgium
facility: Investigational Site Number 056010
city: Bruxelles
country: Belgium
facility: Investigational Site Number 056003
city: Charleroi
country: Belgium
facility: Investigational Site Number 056006
city: Edegem
country: Belgium
facility: Investigational Site Number 056007
city: Genk
country: Belgium
facility: Investigational Site Number 056019
city: Gent
country: Belgium
facility: Investigational Site Number 056001
city: Gent
country: Belgium
facility: Investigational Site Number 056017
city: Haine St Paul
country: Belgium
facility: Investigational Site Number 056002
city: Kortrijk
country: Belgium
facility: Investigational Site Number 056015
city: La Louvière
country: Belgium
facility: Investigational Site Number 056009
city: Leuven
country: Belgium
facility: Investigational Site Number 056004
city: Liège
country: Belgium
facility: Investigational Site Number 056014
city: Overpelt
country: Belgium
facility: Investigational Site Number 056011
city: Roeselare
country: Belgium
facility: Investigational Site Number 056016
city: Calgary
country: Canada
facility: Investigational Site Number 124018
city: Cambridge
country: Canada
facility: Investigational Site Number 124015
city: Chicoutimi
country: Canada
facility: Investigational Site Number 124002
city: Coquitlam
country: Canada
facility: Investigational Site Number 124027
city: Edmonton
country: Canada
facility: Investigational Site Number 124025
city: Halifax
country: Canada
facility: Investigational Site Number 124017
city: Hamilton
country: Canada
facility: Investigational Site Number 124013
city: London
country: Canada
facility: Investigational Site Number 124008
city: Maple Ridge
country: Canada
facility: Investigational Site Number 124026
city: Montreal
country: Canada
facility: Investigational Site Number 124020
city: Montreal
country: Canada
facility: Investigational Site Number 124022
city: Mount Pearl
country: Canada
facility: Investigational Site Number 124032
city: Ottawa
country: Canada
facility: Investigational Site Number 124005
city: Peterborough
country: Canada
facility: Investigational Site Number 124024
city: Quebec
country: Canada
facility: Investigational Site Number 124003
city: Sarnia
country: Canada
facility: Investigational Site Number 124007
city: Sherbrooke
country: Canada
facility: Investigational Site Number 124001
city: Smiths Falls
country: Canada
facility: Investigational Site Number 124030
city: St-Charles Borromee
country: Canada
facility: Investigational Site Number 124019
city: Toronto
country: Canada
facility: Investigational Site Number 124023
city: Toronto
country: Canada
facility: Investigational Site Number 124014
city: Trois-Rivieres
country: Canada
facility: Investigational Site Number 124028
city: Vancouver
country: Canada
facility: Investigational Site Number 124011
city: Victoria
country: Canada
facility: Investigational Site Number 124012
city: Winnipeg
country: Canada
facility: Investigational Site Number 124031
city: Woodstock
country: Canada
facility: Investigational Site Number 124009
city: Brno
country: Czechia
facility: Investigational Site Number 203004
city: Hradec Kralove
country: Czechia
facility: Investigational Site Number 203002
city: Praha
country: Czechia
facility: Investigational Site Number 203001
city: Uherske Hradiste
country: Czechia
facility: Investigational Site Number 203005
city: Esbjerg
country: Denmark
facility: Investigational Site Number 208001
city: Roskilde
country: Denmark
facility: Investigational Site Number 208002
city: Ålborg
country: Denmark
facility: Investigational Site Number 208003
city: Turku
country: Finland
facility: Investigational Site Number 246003
city: Varkaus
country: Finland
facility: Investigational Site Number 246001
city: Amiens Cedex 1
country: France
facility: Investigational Site Number 250027
city: Auxerre
country: France
facility: Investigational Site Number 250034
city: Avignon
country: France
facility: Investigational Site Number 250016
city: Bayonne
country: France
facility: Investigational Site Number 250021
city: Bobigny
country: France
facility: Investigational Site Number 250030
city: BORDEAUX Cedex
country: France
facility: Investigational Site Number 250045
city: Brest Cedex
country: France
facility: Investigational Site Number 250049
city: Bron
country: France
facility: Investigational Site Number 250054
city: Caen
country: France
facility: Investigational Site Number 250015
city: Clermont Ferrand
country: France
facility: Investigational Site Number 250047
city: Corbeil Essonnes
country: France
facility: Investigational Site Number 250013
city: Coudray
country: France
facility: Investigational Site Number 250032
city: Dijon
country: France
facility: Investigational Site Number 250002
city: Dijon
country: France
facility: Investigational Site Number 250040
city: GRENOBLE cedex
country: France
facility: Investigational Site Number 250038
city: Grenoble
country: France
facility: Investigational Site Number 250012
city: Jossigny
country: France
facility: Investigational Site Number 250033
city: LE CHESNAY Cedex
country: France
facility: Investigational Site Number 250035
city: Lens
country: France
facility: Investigational Site Number 250036
city: Lille
country: France
facility: Investigational Site Number 250042
city: Lille
country: France
facility: Investigational Site Number 250004
city: Limoges Cedex
country: France
facility: Investigational Site Number 250037
city: Lyon
country: France
facility: Investigational Site Number 250057
city: Marseille Cedex 05
country: France
facility: Investigational Site Number 250048
city: Marseille
country: France
facility: Investigational Site Number 250028
city: Montpellier
country: France
facility: Investigational Site Number 250024
city: Nantes cedex 01
country: France
facility: Investigational Site Number 250006
city: Nantes
country: France
facility: Investigational Site Number 250022
city: Nice cedex 1
country: France
facility: Investigational Site Number 250017
city: NIMES Cedex 9
country: France
facility: Investigational Site Number 250039
city: PARIS Cedex 04
country: France
facility: Investigational Site Number 250044
city: Paris Cedex 10
country: France
facility: Investigational Site Number 250001
city: Paris
country: France
facility: Investigational Site Number 250014
city: Paris
country: France
facility: Investigational Site Number 250041
city: Paris
country: France
facility: Investigational Site Number 250026
city: Pessac
country: France
facility: Investigational Site Number 250051
city: POITIERS Cedex
country: France
facility: Investigational Site Number 250011
city: Poitiers
country: France
facility: Investigational Site Number 250031
city: Reims Cedex
country: France
facility: Investigational Site Number 250010
city: Rennes
country: France
facility: Investigational Site Number 250008
city: Rouen
country: France
facility: Investigational Site Number 250018
city: Saint-Mandé
country: France
facility: Investigational Site Number 250023
city: Toulouse Cedex 3
country: France
facility: Investigational Site Number 250046
city: TOULOUSE Cedex 9
country: France
facility: Investigational Site Number 250025
city: Tours
country: France
facility: Investigational Site Number 250007
city: Venissieux
country: France
facility: Investigational Site Number 250019
city: VICHY Cedex
country: France
facility: Investigational Site Number 250050
city: Berlin
country: Germany
facility: Investigational Site Number 276001
city: Magdeburg
country: Germany
facility: Investigational Site Number 276003
city: Ampelokipoi
country: Greece
facility: Investigational Site Number 300003
city: Ioannina
country: Greece
facility: Investigational Site Number 300002
city: Kallithea
country: Greece
facility: Investigational Site Number 300001
city: Budapest
country: Hungary
facility: Investigational Site Number 348001
city: Debrecen
country: Hungary
facility: Investigational Site Number 348002
city: Pécs
country: Hungary
facility: Investigational Site Number 348004
city: Szeged
country: Hungary
facility: Investigational Site Number 348003
city: Gdansk
country: Poland
facility: Investigational Site Number 616005
city: Krakow
country: Poland
facility: Investigational Site Number 616003
city: Lodz
country: Poland
facility: Investigational Site Number 616001
city: Olsztyn
country: Poland
facility: Investigational Site Number 616004
city: Warszawa
country: Poland
facility: Investigational Site Number 616002
city: Bucuresti
country: Romania
facility: Investigational Site Number 642-003
city: Iasi
country: Romania
facility: Investigational Site Number 642-002
city: Timisoara
country: Romania
facility: Investigational Site Number 642-001
city: Bratislava
country: Slovakia
facility: Investigational Site Number 703003
city: Bratislava
country: Slovakia
facility: Investigational Site Number 703002
city: Kosice
country: Slovakia
facility: Investigational Site Number 703001
city: Maribor
country: Slovenia
facility: Investigational Site Number 705001
city: Alicante
country: Spain
facility: Investigational Site Number 724009
city: Alicante
country: Spain
facility: Investigational Site Number 724011
city: Córdoba
country: Spain
facility: Investigational Site Number 724003
city: Donostia
country: Spain
facility: Investigational Site Number 724012
city: Donostia
country: Spain
facility: Investigational Site Number 724014
city: Elche
country: Spain
facility: Investigational Site Number 724019
city: Galdakao
country: Spain
facility: Investigational Site Number 724017
city: Hospitalet de Llobregat
country: Spain
facility: Investigational Site Number 724001
city: Inca
country: Spain
facility: Investigational Site Number 724020
city: Las Palmas de Gran Canaria
country: Spain
facility: Investigational Site Number 724007
city: Madrid
country: Spain
facility: Investigational Site Number 724004
city: Madrid
country: Spain
facility: Investigational Site Number 724008
city: Madrid
country: Spain
facility: Investigational Site Number 724010
city: Málaga
country: Spain
facility: Investigational Site Number 724005
city: Santiago de Compostela
country: Spain
facility: Investigational Site Number 724002
city: Valencia
country: Spain
facility: Investigational Site Number 724006
city: Valencia
country: Spain
facility: Investigational Site Number 724016
city: Valladolid
country: Spain
facility: Investigational Site Number 724015
city: Baden
country: Switzerland
facility: Investigational Site Number 756005
city: Olten
country: Switzerland
facility: Investigational Site Number 756002
city: Reinach
country: Switzerland
facility: Investigational Site Number 756004
city: St. Gallen
country: Switzerland
facility: Investigational Site Number 756003
city: Zürich
country: Switzerland
facility: Investigational Site Number 756001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.