Evaluating Effect of the Study Drug Praluent (Alirocumab) on Neurocognitive Function When Compared to Placebo

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Praluent on Neurocognitive Function in Patients With Heterozygous Familial Hypercholesterolemia or With Non-Familial Hypercholesterolemia at High and Very High Cardiovascular Risk

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02957682

Enrollment

2176

Registered

2016-11-08

Start date

2016-11-02

Completion date

2020-03-05

Last updated

2021-05-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypercholesterolemia

Keywords

Hyperlipidemias, Dyslipidemias, Lipid Metabolism Disorders

Brief summary

The main purpose of this study is to evaluate the effect on mental state (known as neurocognitive function) with use of Praluent.

Interventions

DRUGPraluent (Alirocumab)

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

40 Years to 85 Years

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: * Men and women ≥ age 40 years and ≤ age 85 years * Patients with heterozygous familial hypercholesterolemia (heFH) or with non-familial hypercholesterolemia (non-FH) patients at high or very high cardiovascular risk * Patients with history of coronary heart disease (CHD) not having adequate control of their hypercholesterolemia with LDL-C ≥70 mg/dL, or all other patients with LDL-C ≥100 mg/dL and be on maximally-tolerated dose of statin (unless they are statin-intolerant) * Patients must have successfully completed the Motor Screening Task * Patients must be willing and able to comply with clinic visits and study related procedures * Patients must provide signed informed consent Key

Exclusion criteria

* Patients with known Alzheimer's disease or other dementia, schizophrenia, bipolar disorder, severe depression, cognitive impairment, or patients with a sleep disorder requiring daily pharmacological treatment * Recent (within 3 months prior to the screening visit) myocardial infarction, unstable angina leading to hospitalization, coronary artery bypass graft surgery, percutaneous coronary intervention, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease * Certain laboratory findings obtained during the screening visit as defined in the protocol * Any condition or situation, including other significant mental or neurological disorders that, in the investigator's opinion, may confound the study results, or may interfere significantly with the patient's participation in the study * Pregnant or breastfeeding women * A positive human immunodeficiency virus (HIV) test NOTE: Other protocol defined Inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Cognitive Domain Spatial Working Memory (SWM) Strategy Z-Score at Week 96	Week 96	CANTAB SWM task assessed cognitive domain of executive function. Colored boxes were shown on a screen. A token was hidden in one of the boxes (never same box twice). Instructions were to touch boxes to search for token until number of tokens found equaled number of boxes. SWM strategy index represents number of times a search began with a different box. Z-score represents standardized measure of how far an individual deviated from study cohort average at baseline. A higher Z-score reflects better performance.

Secondary

Measure	Time frame	Description
Percent Change From Baseline in Calculated Low-density Lipoprotein Cholesterol (LDL-C) at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in calculated LDL-C at Week 12, 24, 48, 72, and 96 was reported. LDL-C was measured using conventional units milligram per deciliter (mg/dL).
Percent Change From Baseline in Apolipoprotein (Apo) B at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in Apo B at Week 12, 24, 48, 72, and 96 was reported. Apo B was measured using conventional units mg/dL.
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in non-HDL-C at Week 12, 24, 48, 72, and 96 was reported. Non-HDL-C was measured using conventional units mg/dL.
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in calculated Total-C at Week 12, 24, 48, 72, and 96 was reported. Total-C was measured using conventional units mg/dL.
Percent Change From Baseline in Lipoprotein a [Lp(a)] at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in Lp(a) at Week 12, 24, 48, 72, and 96 was reported. Lp(a) was measured using conventional units mg/dL.
Change From Baseline in CANTAB Cognitive Domain SWM Strategy Raw Score at Week 96	Week 96	CANTAB SWM task assessed cognitive domain of executive function. Colored boxes were shown on a screen. A token was hidden in one of the boxes (never same box twice). Instructions were to touch boxes to search for token until number of tokens found equaled number of boxes. SWM strategy index represents number of times a search began with a different box. Lower change from baseline raw scores reflect better SWM performance (i.e. less impairment).
Percent Change From Baseline in Triglycerides (TG) at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in TG at Week 12, 24, 48, 72, and 96 was reported. TG was measured using conventional units mg/dL.
Percent Change From Baseline in Apolipoprotein (Apo) A-1 at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in Apo A-1 at Week 12, 24, 48, 72, and 96 was reported. Apo A-1 was measured using conventional units mg/dL.
Percentage of Participants Who Reached Low Density Lipoprotein Cholesterol (LDL-C) Level Less Than (<) 70 mg/dL (1.81 Millimoles Per Liter [mmol/L]) at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percentage of participants who reached LDL-C level \< 70 mg/dL (1.81 mmol/L) at Week 12, 24, 48, 72, and 96 were reported.
Percentage of Participants Who Reached Low Density Lipoprotein Cholesterol (LDL-C) Level Less Than (<) 50 mg/dL (1.29 mmol/L) at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percentage of participants who reached LDL-C level \< 50 mg/dL (1.29 mmol/L) at Week 12, 24, 48, 72, and 96 were reported.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Up to Week 96	An Adverse Event (AE) was any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. TEAE was defined as AEs that developed or worsened/became serious during on-treatment period (time from the first double-blind study treatment injection up to 70 days after the last double-blind study treatment injection). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-participant hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs.
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 12, 24, 48, 72, and 96	Week 12, 24, 48, 72, and 96	Percent change from baseline in HDL-C at Week 12, 24, 48, 72, and 96 was reported. HDL-C was measured using conventional units mg/dL.

Countries

Bulgaria, Chile, Estonia, Japan, Mexico, Russia, South Africa, Ukraine, United States

Participant flow

Recruitment details

A total of 2176 participants were randomized across 169 sites in Bulgaria, Chile, Estonia, Japan, Mexico, Russian Federation, South Africa, Ukraine, and the United States

Pre-assignment details

Participants who met the eligibility criteria were randomized in 1:1 ratio into 2 treatment groups: placebo and alirocumab. Randomization was stratified by age (less than \[\<\] 65 or greater than or equal to \[\>=\] 65) and by statin use (no statin, low lipophilicity of the concomitant statin, or high lipophilicity of the concomitant statin).

Participants by arm

Arm	Count
Placebo Participants received subcutaneous (SC) injections of placebo matched to alirocumab every 2 weeks (Q2W) up to 94 weeks.	1,084
Alirocumab 75 Q2W/Up150 Q2W Participants received SC injections of alirocumab at a dose of 75 milligrams (mg) Q2W and up-titrated to 150 mg Q2W at Week 12 in a blinded fashion (if LDL-C ≥ 50 mg/dL at Week 8) up to 94 weeks.	1,087
Total	2,171

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	64	67
Overall Study	Discontinued After Randomization and Prior to Any Treatment	3	2
Overall Study	Non-disclosed	16	12
Overall Study	Physician Decision	4	4
Overall Study	Poor Compliance to Protocol	30	26
Overall Study	Related to IMP Administration	3	6
Overall Study	Study Terminated by Sponsor	4	3
Overall Study	Subject Moved	10	16
Overall Study	Withdrawal by Subject	64	33

Baseline characteristics

Characteristic	Placebo	Alirocumab 75 Q2W/Up150 Q2W	Total
Age, Continuous	62.7 Years STANDARD_DEVIATION 9.02	62.6 Years STANDARD_DEVIATION 8.88	62.6 Years STANDARD_DEVIATION 8.95
CANTAB Cognitive Domain Spatial Working Memory (SWM) Strategy Raw Score	15.9 Units on a Scale STANDARD_DEVIATION 5.03	16.05 Units on a Scale STANDARD_DEVIATION 5.11	16.0 Units on a Scale STANDARD_DEVIATION 5.07
Ethnicity (NIH/OMB) Hispanic or Latino	137 Participants	142 Participants	279 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	945 Participants	943 Participants	1888 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants	2 Participants	4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	11 Participants	16 Participants	27 Participants
Race/Ethnicity, Customized Asian	19 Participants	28 Participants	47 Participants
Race/Ethnicity, Customized Black or African American	86 Participants	77 Participants	163 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Other	80 Participants	80 Participants	160 Participants
Race/Ethnicity, Customized White	888 Participants	886 Participants	1774 Participants
Sex: Female, Male Female	459 Participants	448 Participants	907 Participants
Sex: Female, Male Male	625 Participants	639 Participants	1264 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	24 / 1,084	17 / 1,087
other Total, other adverse events	387 / 1,084	366 / 1,087
serious Total, serious adverse events	216 / 1,084	189 / 1,087

Outcome results

Primary

Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Cognitive Domain Spatial Working Memory (SWM) Strategy Z-Score at Week 96

CANTAB SWM task assessed cognitive domain of executive function. Colored boxes were shown on a screen. A token was hidden in one of the boxes (never same box twice). Instructions were to touch boxes to search for token until number of tokens found equaled number of boxes. SWM strategy index represents number of times a search began with a different box. Z-score represents standardized measure of how far an individual deviated from study cohort average at baseline. A higher Z-score reflects better performance.

Time frame: Week 96

Population: Primary safety population included participants from the safety population who had an assessment of the SWM strategy score at baseline, and at least 1 score measured during the treatment-emergent adverse event (TEAE) period. The TEAE period is defined as the first double-blind treatment dose to last dose of double-blind treatment + 70 days (10 weeks). Participants were analyzed according to the treatment actually received.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Cognitive Domain Spatial Working Memory (SWM) Strategy Z-Score at Week 96	-0.180 Z-score	Standard Error 0.027
Alirocumab 75 Q2W/Up150 Q2W	Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Cognitive Domain Spatial Working Memory (SWM) Strategy Z-Score at Week 96	-0.200 Z-score	Standard Error 0.027

Comparison: Change at Week 96p-value: 0.605595% CI: [-0.094, 0.055]Mixed-effect Model Repeated Measures

Secondary

Change From Baseline in CANTAB Cognitive Domain SWM Strategy Raw Score at Week 96

CANTAB SWM task assessed cognitive domain of executive function. Colored boxes were shown on a screen. A token was hidden in one of the boxes (never same box twice). Instructions were to touch boxes to search for token until number of tokens found equaled number of boxes. SWM strategy index represents number of times a search began with a different box. Lower change from baseline raw scores reflect better SWM performance (i.e. less impairment).

Time frame: Week 96

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in CANTAB Cognitive Domain SWM Strategy Raw Score at Week 96	-0.9 Units on a Scale	Standard Deviation 4.49
Alirocumab 75 Q2W/Up150 Q2W	Change From Baseline in CANTAB Cognitive Domain SWM Strategy Raw Score at Week 96	-1.0 Units on a Scale	Standard Deviation 4.31

Secondary

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

An Adverse Event (AE) was any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. TEAE was defined as AEs that developed or worsened/became serious during on-treatment period (time from the first double-blind study treatment injection up to 70 days after the last double-blind study treatment injection). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-participant hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs.

Time frame: Up to Week 96

Population: Safety population included all participants randomized and exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any TEAEs	857 Participants
Placebo	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any Serious TEAEs	216 Participants
Placebo	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any TEAE leading to death	17 Participants
Placebo	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any TEAE leading to permanent treatment discontinuation	59 Participants
Alirocumab 75 Q2W/Up150 Q2W	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any TEAE leading to permanent treatment discontinuation	64 Participants
Alirocumab 75 Q2W/Up150 Q2W	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any TEAEs	866 Participants
Alirocumab 75 Q2W/Up150 Q2W	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any TEAE leading to death	13 Participants
Alirocumab 75 Q2W/Up150 Q2W	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Participants with any Serious TEAEs	189 Participants

Secondary

Percentage of Participants Who Reached Low Density Lipoprotein Cholesterol (LDL-C) Level Less Than (<) 50 mg/dL (1.29 mmol/L) at Week 12, 24, 48, 72, and 96

Percentage of participants who reached LDL-C level \< 50 mg/dL (1.29 mmol/L) at Week 12, 24, 48, 72, and 96 were reported.