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

Hypercholesterolemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02476006
• Other study ID #: LPS14245
• Secondary ID: 2015-000620-28U1
• Status: Completed
• Phase: Phase 3
• Start date: June 23, 2015
• Est. completion date: April 12, 2019

Study information

• Verified date: March 2022
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 998
• Est. completion date: April 12, 2019
• Est. primary completion date: April 12, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hypercholesterolemia

Intervention

Drug:
• ALIROCUMAB SAR236553 (REGN727)
Pharmaceutical form:solution Route of administration: subcutaneous
• placebo (for injection training only)
Pharmaceutical form:solution Route of administration: subcutaneous
• ezetimibe
Pharmaceutical form:capsule Route of administration: oral
• atorvastatin
Pharmaceutical form:tablet Route of administration: oral
• rosuvastatin
Pharmaceutical form:tablet Route of administration: oral
• simvastatin
Pharmaceutical form:tablet Route of administration: oral

Locations

Country	Name	City	State
Austria	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 040002	Wien
Austria	Investigational Site Number 040003	Wien
Austria	Investigational Site Number 040004	Wien
Austria	Investigational Site Number 040007	Wien
Austria	Investigational Site Number 040010	Wien
Belgium	Investigational Site Number 056005	Aalst
Belgium	Investigational Site Number 056018	Antwerpen
Belgium	Investigational Site Number 056008	Arlon
Belgium	Investigational Site Number 056013	Brugge
Belgium	Investigational Site Number 056010	Brussel
Belgium	Investigational Site Number 056003	Bruxelles
Belgium	Investigational Site Number 056006	Charleroi
Belgium	Investigational Site Number 056007	Edegem
Belgium	Investigational Site Number 056019	Genk
Belgium	Investigational Site Number 056001	Gent
Belgium	Investigational Site Number 056017	Gent
Belgium	Investigational Site Number 056002	Haine St 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
Canada	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	Quebec
Canada	Investigational Site Number 124007	Sarnia
Canada	Investigational Site Number 124001	Sherbrooke
Canada	Investigational Site Number 124030	Smiths Falls
Canada	Investigational Site Number 124019	St-Charles Borromee
Canada	Investigational Site Number 124014	Toronto
Canada	Investigational Site Number 124023	Toronto
Canada	Investigational Site Number 124028	Trois-Rivieres
Canada	Investigational Site Number 124011	Vancouver
Canada	Investigational Site Number 124012	Victoria
Canada	Investigational Site Number 124031	Winnipeg
Canada	Investigational Site Number 124009	Woodstock
Czechia	Investigational Site Number 203004	Brno
Czechia	Investigational Site Number 203002	Hradec Kralove
Czechia	Investigational Site Number 203001	Praha
Czechia	Investigational Site Number 203005	Uherske Hradiste
Denmark	Investigational Site Number 208003	Ålborg
Denmark	Investigational Site Number 208001	Esbjerg
Denmark	Investigational Site Number 208002	Roskilde
Finland	Investigational Site Number 246003	Turku
Finland	Investigational Site Number 246001	Varkaus
France	Investigational Site Number 250027	Amiens Cedex 1
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 Cedex
France	Investigational Site Number 250049	Brest Cedex
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 cedex
France	Investigational Site Number 250033	Jossigny
France	Investigational Site Number 250035	LE CHESNAY Cedex
France	Investigational Site Number 250036	Lens
France	Investigational Site Number 250004	Lille
France	Investigational Site Number 250042	Lille
France	Investigational Site Number 250037	Limoges Cedex
France	Investigational Site Number 250057	Lyon
France	Investigational Site Number 250028	Marseille
France	Investigational Site Number 250048	Marseille Cedex 05
France	Investigational Site Number 250024	Montpellier
France	Investigational Site Number 250022	Nantes
France	Investigational Site Number 250006	Nantes cedex 01
France	Investigational Site Number 250017	Nice cedex 1
France	Investigational Site Number 250039	NIMES Cedex 9
France	Investigational Site Number 250014	Paris
France	Investigational Site Number 250026	Paris
France	Investigational Site Number 250041	Paris
France	Investigational Site Number 250044	PARIS Cedex 04
France	Investigational Site Number 250001	Paris Cedex 10
France	Investigational Site Number 250051	Pessac
France	Investigational Site Number 250031	Poitiers
France	Investigational Site Number 250011	POITIERS Cedex
France	Investigational Site Number 250010	Reims Cedex
France	Investigational Site Number 250008	Rennes
France	Investigational Site Number 250018	Rouen
France	Investigational Site Number 250023	Saint-Mandé
France	Investigational Site Number 250046	Toulouse Cedex 3
France	Investigational Site Number 250025	TOULOUSE Cedex 9
France	Investigational Site Number 250007	Tours
France	Investigational Site Number 250019	Venissieux
France	Investigational Site Number 250050	VICHY Cedex
Germany	Investigational Site Number 276001	Berlin
Germany	Investigational Site Number 276003	Magdeburg
Greece	Investigational Site Number 300003	Ampelokipoi
Greece	Investigational Site Number 300002	Ioannina
Greece	Investigational Site Number 300001	Kallithea
Hungary	Investigational Site Number 348001	Budapest
Hungary	Investigational Site Number 348002	Debrecen
Hungary	Investigational Site Number 348004	Pécs
Hungary	Investigational Site Number 348003	Szeged
Poland	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	Warszawa
Romania	Investigational Site Number 642-003	Bucuresti
Romania	Investigational Site Number 642-002	Iasi
Romania	Investigational Site Number 642-001	Timisoara
Slovakia	Investigational Site Number 703002	Bratislava
Slovakia	Investigational Site Number 703003	Bratislava
Slovakia	Investigational Site Number 703001	Kosice
Slovenia	Investigational Site Number 705001	Maribor
Spain	Investigational Site Number 724009	Alicante
Spain	Investigational Site Number 724011	Alicante
Spain	Investigational Site Number 724003	Córdoba
Spain	Investigational Site Number 724012	Donostia
Spain	Investigational Site Number 724014	Donostia
Spain	Investigational Site Number 724019	Elche
Spain	Investigational Site Number 724017	Galdakao
Spain	Investigational Site Number 724001	Hospitalet de Llobregat
Spain	Investigational Site Number 724020	Inca
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
Switzerland	Investigational Site Number 756005	Baden
Switzerland	Investigational Site Number 756002	Olten
Switzerland	Investigational Site Number 756004	Reinach
Switzerland	Investigational Site Number 756003	St. Gallen
Switzerland	Investigational Site Number 756001	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)	Adverse Event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Treatment-emergent AEs (TEAEs) were defined as AEs that that developed or worsened or became serious during the TEAE period (time from the first injection of study drug up to the day of the last injection of study drug + 14 days). A Serious Adverse Event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event.	From first injection of investigational medicinal product (IMP) up to 2 weeks after last dose of study drug (Week 120)
Secondary	Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 12	Calculated LDL-C values were obtained using the Friedewald formula. Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/5]). Baseline value was defined as the last observation before the first dose of the treatment.	Baseline, Week 12
Secondary	Percentage of Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12	LDL-Cholesterol was calculated using the Friedewald formula. Percentage of participants who reached calculated LDL-C <100 mg/dL (2.59 mmol/L) at week 12 were reported.	At Week 12
Secondary	Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 12	LDL-Cholesterol was calculated using the Friedewald formula. Percentage of participants who reached calculated LDL-C <70 mg/dL (1.81 mmol/L) at week 12 were reported.	At Week 12
Secondary	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	LDL-Cholesterol was calculated using the Friedewald formula. Percentage of participants who reached LDL-C <70 mg/dL at Week 12 and/or >=50% reduction from baseline in LDL-C at Week 12 are reported.	At Week 12
Secondary	Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12	Baseline value was defined as the last observation before the first dose of the treatment.	Baseline, Week 12
Secondary	Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12	Baseline value was defined as the last observation before the first dose of the treatment.	Baseline, Week 12
Secondary	Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12	Baseline value was defined as the last observation before the first dose of the treatment.	Baseline, Week 12
Secondary	Percent Change From Baseline in Triglycerides at Week 12	Baseline value was defined as the last observation before the first dose of the treatment.	Baseline, Week 12
Secondary	Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Feeling About Injections, Self Confidence, Satisfaction With Self-Injections	Pre-SIAQ: self-completed before first self-injection & Post-SIAQ: self-completed after self-injection. Pre-SIAQ consisted of 7 items grouped into 3 domains:feelings about injections,self-confidence & satisfaction with self-injection. Post-SIAQ consisted of 21 items grouped into 6 domains:feelings about injections,self-image,self-confidence,injection-site reactions,ease of use & satisfaction with self-injection. Participants rated each item on 5-point (or 6-point) semantic Likert-type scale, where lower numbers indicate a worse experience. Item scores were transformed to obtain a score ranging from 0 (worst experience) to 10 (best experience). Transformed scores for items contributing to a domain were then averaged into a domain score. Each domain score ranges from 0 (worst experience) to 10 (best experience), higher score=better acceptability. Domain scores common to the Pre & Post SIAQ were analyzed on participants belonging to Pre & Post-SIAQ population and are reported.	Baseline (Pre-SIAQ), Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96
Secondary	Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Self Image, Injection-Site Reactions, Ease of Use	SIAQ: contained 2 modules: Pre-SIAQ and Post-SIAQ. Post-SIAQ: self-completed after self-injection. Post-SIAQ consisted of 21 items grouped into 6 domains: feelings about injections, self-image, self-confidence, injection-site reactions, ease of use & satisfaction with self-injection. Participants rated each item on 5-point (or 6-point) semantic Likert-type scale, where lower numbers indicated a worse experience. Item scores were transformed to obtain a score ranging from 0 (worst experience) to 10 (best experience) for each item. Transformed scores for items contributing to a domain were then averaged into a domain score. Each domain score ranges from 0 (worst experience) to 10 (best experience), higher score=better acceptability. Domain scores which are not in common with Pre-SIAQ were analyzed on the Post-SIAQ population and are reported here.	Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96