A Double-Blind, Placebo Controlled, Multicenter Study to Assess the Effect of Evolocumab on Cognitive Function in Patients with Clinically Evident Cardiovascular Disease and Receiving Statin Background Lipid Lowering Therapy: A Study for Subjects Enrolled in the FOURIER (Study 20110118) Trial

AMG 145 is a fully human monoclonal immunoglobulin (Ig) G2 that binds
specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) and
prevents the interaction of PCSK9 with the LDL receptor. AMG 145 caused a dose
related inhibition of PCSK9 binding to the LDL receptor and of the
PCSK9-mediated reduction in low-density lipoprotein (LDL) uptake in hepatic
cells. Treatment of cells with a combination of AMG 145 and statin increased
LDL receptor protein levels more than treatment with either alone. Single
administrations in humans produced decreases in mean LDL-C with subsequent
returns to baseline. Across the dose groups, the decreases were dose-related.
Overall, AMG 145 appeared to be well tolerated at the IV and SC doses
administered in this FIH study. Incidences of overall adverse events and
treatment-related adverse events did not differ notably between treatment
groups.

Statins have been shown to lower the blood levels of LDL-C (low-density
lipoproteïne-cholesterol, *bad* cholesterol). Effects of statins on memory and
cognitive function have been investigated in several studies, but the overall
evidence available today is inconclusive. There are a number of meta analyses
(studies that combine data from many individual studies) that suggest that
statins have either no effect or a beneficial effect on cognitive function en
next to that there are some individual reports and smaller studies that suggest
a negative impact of statins.

So far, completed Amgen studies have included a total of over 6000 study
participants and do not suggest any negative effects of evolocumab on memory or
cognitive function. This includes longer-term studies lasting 1 year or
longer. However, because this is an issue of interest to medical doctors,
patients, and regulatory authorities, the Sponsor has designed the EBBINGHAUS
study (Study 20130385).

Main objective:
To evaluate change over time in executive function, as assessed by the
Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working
Memory (SWM) strategy index of executive function, in subjects receiving statin
therapy in combination with evolocumab, compared with subjects receiving statin
therapy in combination with placebo.

Secondary objectives:
To evaluate change over time in subjects receiving statin therapy in
combination with evolocumab, compared with subjects receiving statin therapy in
combination with placebo in the following:
- Working memory, as assessed by the CANTAB Spatial Working Memory (SWM) test
between-errors score
- Memory function, as assessed by the CANTAB Paired Associated Learning (PAL)
test
- Psychomotor speed, as assessed by the CANTAB Reaction Time (RTI) test

Phase 3, multicenter, double-blind, placebo controlled, parallel group.
Lipid lowering background therapy including a statin.

Randomisation in FOURIER (1:1):
- AMG145 (Q2W or Q4W, subject is allowed to choose during the study)
- placebo (Q2W or Q4W, subject is allowed tio choose during the study)

Signed Informed Consent, after which Screening will take place, followed by
Randomisation if applicable. IP-adminstration according to FOURIER-protocol
(20110118 - see above), Follow Up (with visites for the EBBINGHAUS-study during
week 24 (+/- 6 weeks), week 48 (+/- 6 weeks), thereafter every 48 weeks (+/- 6
weeks). In addition, assessments will be completed each time a subject reports
a neurocognitive adverse event in Study 20110118.End of Study-visit will take
place during the End of Study-visit of the FOURIER-study or within 6 weeks
prior to the End of Study-visit for the FOURIER study.
Participation in the EBBINGHAUS study can be for as long as the duration of the
FOURIER study (it s expected for a period of max. 4 years).

At least approximately 2000 patients, up to 4000 patients.
De study ends in accordance with the FOURIER study (20110118).

At each visit the subject will complete the following 3 different CANTAB
(Cambridge Neuropsychological Test Automated Battery)
tests on a touch screen computer (tablet computer) at the study site.
- Spatial Working Memory (SWM)
- Paired Associates Learning (PAL)
- Reaction Time (RTI)

No investigational drugs will be administered to the subjects as part of the
participation in the EBBINGHAUS study.
Therefore, potential risks to being in the EBBINGHAUS study are only from the
procedures of the computerized cognitive (brain thinking) function tests.

The risks for participation in this study are minimal (see the answer to
question E9).