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

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ClinicalTrials.gov Identifier: NCT02476006
Recruitment Status : Completed
First Posted : June 19, 2015
Results First Posted : March 30, 2020
Last Update Posted : March 30, 2020
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE June 16, 2015
First Posted Date  ICMJE June 19, 2015
Results First Submitted Date  ICMJE March 13, 2020
Results First Posted Date  ICMJE March 30, 2020
Last Update Posted Date March 30, 2020
Actual Study Start Date  ICMJE June 23, 2015
Actual Primary Completion Date April 12, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2020)
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From first injection of investigational medicinal product (IMP) up to 2 weeks after last dose of study drug (Week 120) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 16, 2015)
  • Proportion of patients with adverse events [ Time Frame: Up to 30 months ]
  • Change from baseline in laboratory data (hematology and biochemistry) [ Time Frame: Up to 30 months ]
  • Change from baseline in vital signs [ Time Frame: Up to 30 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2020)
  • Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 [ Time Frame: Baseline, 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.
  • Percentage of Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12 [ Time Frame: 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.
  • Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 12 [ Time Frame: 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.
  • 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 [ Time Frame: 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.
  • Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12 [ Time Frame: Baseline, Week 12 ]
    Baseline value was defined as the last observation before the first dose of the treatment.
  • Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12 [ Time Frame: Baseline, Week 12 ]
    Baseline value was defined as the last observation before the first dose of the treatment.
  • Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12 [ Time Frame: Baseline, Week 12 ]
    Baseline value was defined as the last observation before the first dose of the treatment.
  • Percent Change From Baseline in Triglycerides at Week 12 [ Time Frame: Baseline, Week 12 ]
    Baseline value was defined as the last observation before the first dose of the treatment.
  • Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Feeling About Injections, Self Confidence, Satisfaction With Self-Injections [ Time Frame: Baseline (Pre-SIAQ), Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96 ]
    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.
  • Assessment of Participant's Acceptability of Self-Injection Using Self Injection Assessment Questionnaire (SIAQ): Self Image, Injection-Site Reactions, Ease of Use [ Time Frame: Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, Week 96 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2015)
  • Assessment of patient's acceptability of self-injection using Self Injection Assessment Questionnaire (SIAQ) [ Time Frame: Up to 30 months ]
  • Percent change from baseline in calculated LDL-C levels [ Time Frame: Baseline to Week 12 ]
  • Percent change from baseline in total-C levels [ Time Frame: Baseline to Week 12 ]
  • Percent change from baseline in HDL-C levels [ Time Frame: Baseline to Week 12 ]
  • Percent change from baseline in TG levels [ Time Frame: Baseline to Week 12 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hypercholesterolemia
Intervention  ICMJE
  • Drug: ALIROCUMAB SAR236553 (REGN727)
    Pharmaceutical form:solution Route of administration: subcutaneous
    Other Name: Praluent®
  • Drug: placebo (for injection training only)
    Pharmaceutical form:solution Route of administration: subcutaneous
  • Drug: ezetimibe
    Pharmaceutical form:capsule Route of administration: oral
  • Drug: atorvastatin
    Pharmaceutical form:tablet Route of administration: oral
  • Drug: rosuvastatin
    Pharmaceutical form:tablet Route of administration: oral
  • Drug: simvastatin
    Pharmaceutical form:tablet Route of administration: oral
Study Arms  ICMJE Experimental: 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.
Interventions:
  • Drug: ALIROCUMAB SAR236553 (REGN727)
  • Drug: placebo (for injection training only)
  • Drug: ezetimibe
  • Drug: atorvastatin
  • Drug: rosuvastatin
  • Drug: simvastatin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 18, 2019)
998
Original Estimated Enrollment  ICMJE
 (submitted: June 16, 2015)
1100
Actual Study Completion Date  ICMJE April 12, 2019
Actual Primary Completion Date April 12, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Canada,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hungary,   Poland,   Romania,   Slovakia,   Slovenia,   Spain,   Switzerland
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02476006
Other Study ID Numbers  ICMJE LPS14245
2015-000620-28 ( EudraCT Number )
U1111-1163-0984 ( Other Identifier: UTN )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to participant level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Participant level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP