The ACCELERATE Trial

The ACCELERATE Trial
Impact of the Cholesteryl Ester Transfer Protein
Inhibitor Evacetrapib on Cardiovascular Outcome
Stephen J Nicholls
for the ACCELERATE investigators
Disclosure
Research support: AstraZeneca, Amgen, Anthera, Eli Lilly, Novartis, Cerenis
The Medicines Company, Resverlogix, InfraReDx, Roche and LipoScience
Consulting and honoraria: AstraZeneca, Eli Lilly, Anthera, Merck, Takeda, Resverlogix,
Sanofi-Aventis, CSL Behring, Esperion, Boehringer Ingelheim
ACCELERATE was sponsored by Eli Lilly and Company

ACCELERATE Trial Leadership
Executive Steering Committee
Chair: Steven E. Nissen
Co-Principal Investigators
A. Michael Lincoff and Stephen J. Nicholls
Philip Barter
H. Bryan Brewer
Keith Fox
C Michael Gibson
Christopher Granger
Venu Menon
Gilles Montalescot
Daniel Rader
Alan Tall
Jeffrey Riesmeyer - Eli Lilly
Data Monitoring Committee
Paul Armstrong – Chair
Kenneth Mahaffey, Paul Ridker, Philippe Gabriel Steg, Janet Wittes

Role of Cholesteryl Ester Transfer Protein (CETP)
Liver
VLDL
FC
CE
CE
TG
TG
CE
LPL
FFA
Adipose and
other tissues
LDL
SR-BI
CETP
CETP
TG
CE
LDL receptor
Liver
LDL receptor
HDL
TG
CE
LCAT
CE
FC
Cell in
peripheral tissue

Background
• Despite widespread use of statins, many patients continue
to experience cardiovascular events.
• Considerable efforts have focused on the protective effects
of HDL as a potentially useful therapeutic approach.
• Animal and genetic studies suggest that CETP deficiency
is cardioprotective. However, prior trials demonstrated
adverse outcomes with torcetrapib and futility with dalcetrapib
• CETP inhibitors lacking the toxicity of torcetrapib have been
considered a promising approach to addressing residual risk.
• Evacetrapib is a potent CETP inhibitor with favorable effects
on HDL-C, LDL-C, Lp(a) and cholesterol efflux in phase 2.

ACCELERATE Trial Design
12,092 patients at high vascular risk, defined as:
– ACS within 30-365 days – Diabetes with coronary disease
– Peripheral arterial disease – Cerebrovascular disease
1:1 randomization
Evacetrapib 130 mg
Placebo
• Event driven - Primary endpoint in 1670 patients (CV death, MI,
stroke, coronary revascularization or hosp. for unstable angina)
• Minimum of 700 patients with hard events (CV death, MI or stroke),
minimum of 1.5 years of follow-up per patient
• 84% power to detect a 13.5% reduction in the primary endpoint

Early Termination of Trial
• On October 12, 2015 study terminated
prematurely on the recommendation of the Data
Monitoring Committee for clinical futility for the
primary composite endpoint.
• These findings represent the preliminary analyses
after 98.8% of patients completed their end of
study visit, prior to final database lock.

Baseline Clinical Characteristics
Parameter
Placebo
(n=6054)
Evacetrapib
(n=6038)
Age (years) 65 65
Males 77% 77%
Caucasian 83% 82%
Mean body mass index 30.2 30.3
History of hypertension 88% 87%
History of diabetes 68% 68%
Current smoker 16% 17%
Prior myocardial infarction 67% 67%
Prior PCI 72% 71%
Prior CABG 29% 30%

Index diagnosis
Parameter
Placebo
(n=6054)
Evacetrapib
(n=6038)
Acute coronary syndrome 31% 30%
Mean months from event 5.7 5.5
Cerebrovascular atherosclerotic disease 12% 12%
Peripheral arterial disease 14% 14%
Diabetes with coronary artery disease 64% 65%
Statin use 98% 97%
Lipid levels
Additional Baseline Characteristics
High intensity statin use 46% 46%
Mean LDL-cholesterol 81 mg/dL 82 mg/dL
Mean HDL-cholesterol 45 mg/dL 45 mg/dL

Adherence and Retention
Placebo
(n=6054)
Evacetrapib
(n=6038)
Completing end of study visit 98.7% 98.8%
End of study visit not completed 1.3% 1.2%
Study drug prematurely discontinued * 18.1% 16.4%
Average months on study drug 25 25
Average months of study participation 29 29
*p

Percent Change in HDL-C Levels During the Trial
175
Percent Change in HDL-C (%)
150
125
100
75
50
25
0
Mean HDL-C = 104 mg/dL
Mean difference = 130%
Mean HDL-C = 46 mg/dL
Evacetrapib
Placebo
-25
0 4 8 12 16 20 24 28 32
Months Following Randomization
Preliminary analysis prior to formal database lock

Percent Change in LDL-C Levels During the Trial
20
Percent Change in LDL-C (%)
10
0
-10
-20
-30
-40
Mean LDL-C = 84 mg/dL
Mean difference 37%
Mean LDL-C = 55 mg/dL
Evacetrapib
Placebo
-50
0 4 8 12 16 20 24 28 32
Months Following Randomization
Preliminary analysis prior to formal database lock

Cumulative Incidence of Primary Efficacy Endpoint
Cumulative Event Rate (%)
Evacetrapib, 774 events (12.8%)
Placebo, 768 events (12.7%)
HR = 1.01
95% CI, 0.91-1.12
P=0.85
Months Following Randomization
Preliminary analysis prior to formal database lock

Secondary Efficacy Endpoints
Placebo
(n=6054)
Evacetrapib
(n=6038)
CV death, MI, stroke 444 (7.3) 434 (7.2)
CV death 163 (2.7) 140 (2.3)
MI 255 (4.2) 256 (4.2)
Stroke 95 (1.6) 92 (1.5)
Hospitalization for unstable
angina
143 (2.4) 155 (2.6)
Coronary revascularization 482 (8.0%) 485 (8.0%)
All cause mortality 269 (4.4) 227 (3.8)
HR
(95% CI)
0.98
(0.86,1.12)
0.86
(0.68,1.08)
1.00
(0.84,1.19)
0.97
(0.73,1.29)
1.08
(0.86,1.36)
1.01
(0.89, 1.14)
0.84
(0.71-1.01)
P
Value
0.73
0.18
0.97
0.82
0.48
0.92
0.06
Preliminary analysis prior to formal database lock

Adverse Clinical and Biochemical Events
Parameter Placebo Evacetrapib P Value
Discontinuation due to adverse
events
8.7% 8.6% 0.86
ALT >3x ULN 0.7% 0.6% 0.31
Bilirubin >2x ULN 0.3% 0.1% 0.06
CK >3x ULN 3.1 % 2.3%

Systolic Blood Pressure During the Trial
134
Mean difference = 0.9 mm Hg (P

Conclusions
• Despite a 37% decrease in LDL-C and a 130% increase
in HDL-C, evacetrapib did not reduce the primary
composite endpoint of major adverse CV events.
• A borderline significant (p=0.06) reduction in all-cause
mortality was observed in the evacetrapib group.
• The failure of decreases in LDL-C to result in an overall
morbidity-mortality benefit emphasizes the limitations
of surrogate endpoints.
• The findings continue to challenge the hope that CETP
inhibition might successfully address residual CV risk.

ACCELERATE
Data Sharing Initiative
The study sponsor (Eli Lilly) and the academic leadership are
pleased to announce that the trial database will be made available to
independent investigators
• Proposals will be accepted beginning 12 months after the
publication of the primary ACCELERATE manuscript
• Review of Proposals and Governance will be coordinated by the
academic research organization at the Cleveland Clinic that led
the trial (C5Research).
• Further information on submitting research proposals for review
will be made available in the future at:
http://c5research.clevelandclinic.org/Home.aspx