High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS)

This is a phase 3, double blind, placebo controlled, randomized study
evaluating the effect of evolocumab on coronary atherosclerotic plaques as
assessed by OCT at baseline and at 50 weeks of treatment in subjects with a
non-ST-segment elevation ACS (NSTE-ACS). The trial duration of approximately 1
year was chosen based on the results of several historical trials. Subjects
will be randomized 1:1 into 2 treatment groups no more than 7 days after the
signing of the informed consent: evolocumab 420 mg subcutaneously (SC) QM or
placebo QM SC. The randomization will be stratified by current statin use (> 4
weeks or * 4 weeks duration) at screening. Investigators will up titrate statin
therapy to the maximally tolerated dose, in accordance with local guidelines,
for subjects prior to randomization.

* Primary Objective: To evaluate the effect of evolocumab on fibrous cap
thickness (FCT) in subjects with non ST elevation acute coronary syndrome (NSTE
ACS) who are taking maximally tolerated statin therapy.
* Secondary Objective(s): To evaluate the effects of evolocumab on coronary
plaque morphology in subjects with NSTE-ACS who are taking maximally tolerated
statin therapy.
* Safety Objective: To evaluate the safety and tolerability of evolocumab
treatment in subjects with NSTE-ACS who are taking maximally tolerated statin
therapy.
* Exploratory Objective: To evaluate the effects of evolocumab on lipid
parameters in subjects with NSTE-ACS who are taking maximally tolerated statin
therapy. To evaluate the effects of evolocumab on features of coronary plaques
in subjects with NSTE-ACS who are taking maximally tolerated statin therapy
using different imaging techniques.

This is a phase 3, double-blind, placebo-controlled, randomized study
evaluating the effect of evolocumab on coronary atherosclerotic plaques as
assessed by OCT at baseline and at week 50 in subjects with an NSTE-ACS. The
trial duration of 1 year was chosen based on the results of several historical
trials. Subjects will be randomized 1:1 into 2 treatment groups no more than 7
days after the signing of the informed consent: evolocumab 420 mg
subcutaneously (SC) QM or placebo SC QM. The randomization will be stratified
by current statin use (> 4 weeks or * 4 weeks duration) at screening.
Investigators will up-titrate statin therapy to the maximally tolerated dose,
in accordance with local guidelines, for subjects prior to randomization On
site visits are required on Day1, 4w, 24w and 50week, phone calls at 12w and
36w End of study (EOS, 52w)phone call for all subjects will be when the safety
follow up assessment is completed. The Personal Injector will be used for IP
administration
OCT and IVUS procedures will be done during screening and on W50.

50% of the subjects will be randomized to evolocumab, 50% on placebo (1: 1
ratio).
A total of 8 visits will take place: Screening, Day 1, Week 4, Week 12 (by
telephone), Week 24, Week
36 (by telephone), Week 50, Week 52 (by telephone).

One group receives 120 mg / ml of evolocumab on day 1 and every 4 weeks for 48
weeks with a 3.5 ml injector. The other group receives an identical volume of
placebo on day 1 and every 4 weeks for 48 weeks using a 3.5 ml injector.

During the visits, physical examination is performed and vital signs are
measured (3x), complaints / side effects and medication use are discussed (8x),
blood is taken for testing in the local lab (4x, of which 3x fasting),
angiogram is done with
IVUS and OCT (during the screening and at the end of the study in week 50).
These angiograms will probably last 15 to 20 minutes longer. During the
screening, training of the injection device will take place and, if necessary,
during the planned visits.

In women of childbearing age a blood / urine sample is taken for a pregnancy
test (4x).
For an overview of all procedures / tests, see Schedule of Assessments in
section 2.2 of the protocol.

See answer to E9.