Text S1 Investigators, steering committee and data committee
Principal Investigators, COMBO II (National Coordinators in bold)
Canada: Christian Constance (Montreal, Quebec); Naresh Aggarwal (Brampton,
Ontario); Anil Gupta (Toronto, Ontario); Guy Tellier (Mirabel, Quebec).
Denmark: Jorgen Jeppesen (Glostup); Jens Brønnum-Schou (Copenhagen); Lars Frost
(Silkeborg); Jan Skov Jensen (Hellerup); Kim Klarlund (Køge); Soren Lind-Rasmussen
(Hvidovre); Thomas Melchior (Roskilde); Knud Skagen (Herlev); Kristian Korsgaard
Thomsen (Esbjerg).
France: Bertrand Cariou (Nantes); Eric Renard (Montpellier); Michel Rodier (Nimes);
Bruno Verges (Dijon).
Hungary: Albert Csaszar (Budapest); Akos Kalina (Budapest); Janos Kis (Budapest);
Gyorgy Paragh (Debrecen); Istvan Reiber (Szekesfehervar).
Israel: Dov Gavish (Holon); Dror Dicker (Petah Tikva); Ofer Havakuk (Tel Aviv); Osama
Hussein (Safed); Hilla Knobler (Rehovot); Michael Lishner (Kfar Saba); Maximo Maislos
(Ofakim).
Russia: Alexey Blokhin (Moscow); Olga Barbarash (Kemerovo); Svetlana Berns (Moscow);
Natalia Burova (St. Petersburg); Galina Chumakova (Barnaul); Marat Ezhov (Moscow);
Boris Goloschekin (St. Petersburg); Ivan Gordeev (Moscow); Roman Libis (Orenburg); Olga
Orlikova (Saratov); Elena Pavlikova (Moscow); Natalia Polezhaeva (St. Petersburg); Mikhail
Sandin (Moscow); Konstantin Sobolev (Moscow); Sergey Yakushin (Ryazan).
South Africa: Dirk Blom (Cape Town); Lesley Burgess (Cape Town); Eluned Delport
(Pretoria); Nyda Fourie (Bloemfontein); Shirley Middlemost (Western Cape); Mohammed
Tayob (Middelburg); Hendrik du Toit Theron (Bloemfoentein); Tjaart P Venter (Alberton).
South Korea: Myung-ho Jeong (Gwangjo); Kiyuk Chang (Seoul); Ki-Hoon Han (Seoul);
Bum-Kee Hong (Seoul); Sang-Ho Jo (Gyeonggido); Moo Hyun Kim (Busan); Sang Hyun
Kim (Seoul); Hae-Young Lee (Seoul); Jong-Min Lee (Gyeonggido); Sang-Hak Lee (Seoul);
Chang-Wook Nam (Daegu); Jeong Euy Park (Seoul); Seung-Jea Tahk (Gyeonggido);
Junghan Yoon (Gangwando).
Ukraine: Ivan Chopey (Uzhhorod); Oleksandr Karpenko (Kyiv).
USA: Karl Zuzarte (Fall River, MA); Mohammed Allaw (Evansville, IN); Vivek Awasty
(Marion, OH); Paramvir Bains (Marion, OH); Robert Black (Clearwater, FL); Bradley Block
(Oviedo, FL); Eric Bolster (Summerville, SC); David Butuk (Meridian, ID); David Cabrera
(Miami, FL); Louis Chaykin (Bradenton, FL); Charles Dahl (Orem, UT); Ronald DeGarmo
(Greer, SC); Hugh Durrence (Charleston, SC); Svjetlana Dziko (Lincoln, NE); Mahfouz El
Shahawy (Sarasota, FL); John Ervin (Kansas City, MO); Chris Geohas (Phoenix, AZ);
Harinder Gogia (Anaheim, CA); Terry Haas (Vista, CA); John Hoekstra (Richmond, VA);
Cynthia Huffman (Tampa, FL); Terence Isakov (Lyndhurst, OH); Vicki Kalen (Tuscon, AZ);
Norman Lepor (Beverly Hills, CA); Andrew Lewin (Los Angeles, CA); Gerald Lorch
(Renton, WA); Irving Loh (Thousand Oaks, CA); Tad Lowdermilk (Winston-Salem, NC);
Barry Lubin (Norfolk, VA); Sashi Makam (New Windsor, NY); Amir Malik (Fort Worth,
TX); Mustafa Mandviwala (Tomball, TX); Frederick Martin (Bristol, TN); Gilbert Martinez
(Chino, CA); Kelli Maw (Brooksville, FL); Barry McLean (Homewood, AL); Roger Miller
(Jacksonville, FL); Richard Montgomery (Lexington, NC); Stephen Ong (Oxon Hill, MD);
Henry Paez (Miami, FL); Richard Promin (Ocala, FL); Ronald Pruitt (Nashville, TN); Ronald
Pucillo (Sugar Land, TX); John Pullman (Butte, MT); Lance Rudolph (Albuquerque, NM);
Anthony John Scarsella (Beverly Hills, CA); Richard Schultzaberger (Greenville, NC);
Ranjan Shah (Houston, TX); Stephen Thew (Spokane, WA); Gil Vardi (St. Louis, MO);
Krishnamoorthy Vivekananthan (Houston, TX); Eric Voth (Topeka, KS); Jeffrey Wayne
(Lincoln, CA); Franklin Wefald (Smithfield, NC); Debra Weinstein (Boynton Beach, FL);
1
Matthew D. Wenker (Cincinnati, OH); Alexander White (Port Orange, FL); Daniel Williams
(Perrysburg, OH).
Committees
Steering Committee:
Chairman: Henry Ginsberg, MD (Irving Institute for Clinical and Translational Research,
Columbia University New York, NY, USA). Members: Jennifer G. Robinson, MD, MPH
(The University of Iowa, Iowa City, IA, USA); Daniel J. Rader, MD (Institute for
Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine
Philadelphia, PA, USA); Christopher P. Cannon, MD (Senior Investigator, TIMI Study
Group; Professor of Medicine, Harvard Medical School Cardiovascular Division, Brigham
and Women's Hospital, Boston, MA, USA); Helen M Colhoun, MD, MFPHM (medical
Research Institute, University of Dundee, Ninewells Hospital & Medical School, Dundee,
UK); John J.P. Kastelein, MD (Academic Medical Center University of Amsterdam,
Amsterdam, The Netherlands); Michel Farnier, MD (Le Point Médical, Département
d’Endocrinologie et de Lipidologie, Dijon, France).
Data Monitoring Committee:
Chairman: Anders Olsson, MD (Bromma, Sweden). Members: David Waters, MD
(Division of Cardiology, San Francisco General Hospital, San Francisco, CA, USA);
Dominique Larrey, MD (Hôpital Saint-Eloi Service d'hépato-gastro-entérologie, Montpellier,
France); Robert S Rosenson, MD (Director, Cardiometabolic Disorders, Mount Sinai Heart;
Professor of Medicine, Mount Sinai School of Medicine, New York, NY, USA); Peter A.
Patriarca, MD (Biologics Consulting Group, Inc., Alexandria, VA, USA); Geert
Molenberghs, Biostatistician (Center for Statistics (CenStat) Universiteit HasseltAgoralaan 1,
Diepenbeek, Belgium).
Independent physicians monitoring two consecutive LDL< 0.65 mmol/L: Karen Alexander,
and Chiara Melloni (Duke Clinical Research Institute, Durham, NC USA).
Clinical Events Committee (Reviewers), Duke Clinical Research Institute, Durham, NC
USA:
Pierluigi Tricoci, CEC Principal Investigator, Cardiology; Kenneth W Mahaffey, CEC
Director, Cardiology; Renato D Lopes, Cardiology; Bimal R Shah, Cardiology; Rajendra H
Mehta, Cardiology; Matthew T Roe, Cardiology; Zubin Eapen, Cardiology; Luciana
Armaganijan, Cardiology; Adriana Bertolami, Cardiology; Sergio Leonardi, Cardiology;
Bradley J. Kolls, Neurology; J. Dedrick Jordan, Neurology; Grégory Ducrocq, Cardiology;
Etienne Puymirat, Cardiology; Robin Mathews, Cardiology.
2
Table S1 Principal inclusion and exclusion criteria in COMBO II
Inclusion criteria
Patients with hypercholesterolaemia and established CHD or CHD risk equivalents (see
below) with LDL-C poorly controlled with a maximally tolerated daily dose of statin at stable
dose for ≥ 4 weeks before the screening visit (week –3)
Baseline entry criteria: LDL-C levels depending on history of documented CVD:
 LDL-C ≥ 1.8 mmol/L (≥ 70 mg/dL) at the screening visit with a history of documented
CVD
 LDL-C ≥ 2.6 mmol/L (≥ 100 mg/dL) at the screening visit in patients without history of
documented CVD
Signed informed consent
Document history of CHD included ≥ 1 of the following:
 Acute myocardial infarction
 Silent myocardial infarction
 Unstable angina
 Coronary revascularization procedure (percutaneous coronary intervention or coronary
artery bypass graft surgery)
 Clinically significant CHD diagnosed by invasive or non-invasive testing (such as
coronary angiography, stress test using treadmill, stress echocardiography, or nuclear
imaging)
CHD risk equivalents:
 Documented peripheral artery disease:
 Current intermittent claudication of presumed atherosclerotic origin PLUS anklebrachial index ≤ 0.90 in either leg at rest, or
 History of intermittent claudication PLUS endovascular procedure or surgical
intervention in one or both legs because of atherosclerotic disease, or
 History of critical limb ischaemia with thrombolysis, endovascular procedure, or
surgical intervention in one or both legs because of atherosclerotic disease
 Documented previous ischaemic stroke with a focal ischaemic neurological deficit that
persisted > 24 hours, considered as being of atherothrombotic origin. Computed
tomography or magnetic resonance imaging must have been performed to rule out
haemorrhage and non-ischaemic neurological disease
 Documented chronic kidney disease defined as estimated GFR (Modification of Diet
in Renal Disease1 equation) 30–< 60 mL/min/1.73 m2 for ≥ 3 months, including the
screening visit
 Known history of diabetes mellitus PLUS ≥ 2 additional risk factors:
 History of hypertension
 Documented history of ankle-brachial index ≤ 0.90
 Documented history of microalbuminuria or macroalbuminuria OR dipstick
urinalysis at screening visit (week –2) with > 2+ protein
 Documented history of preproliferative or proliferative retinopathy or laser
treatment for retinopathy
 Known family history of premature CHD (CHD in father or brother < 55 years of
age; CHD in mother or sister < 65 years of age)
Key exclusion criteria
< 18 years of age
Fasting serum triglycerides > 4.5 mmol/L during the screening period
Currently on a statin that is not simvastatin, atorvastatin, or rosuvastatin taken daily at a
registered dose
3
Use of concomitant medications:
 Ezetimibe, omega-3 fatty acid (at doses ≥ 1000 mg daily), nicotinic acid, bile acid-binding
sequestrant, or red yeast rice products in the past 4 weeks prior to screening visit (week –
3)
 Use of fibrates in the past 6 weeks prior to screening visit (week –3)
CHD, coronary heart disease; CVD, cardiovascular disease; GFR, glomerular filtration rate;
LDL-C, low-density lipoprotein cholesterol.
Reference
1.
KDIGO. CKD evaluation and management. KDIGO 2012 Clinical Practice Guideline
for the Evaluation and Management of Chronic Kidney Disease. 2012;
http://kdigo.org/home/guidelines/ckd-evaluation-management/. Accessed 27 July,
2014.
4
Table S2 Reasons for non-use of high-dose statins
Reason
Alirocumaba
Ezetimibeb
(n = 479)
(n = 241)
Regional practice or local labelling
85 (17.7)
34 (14.1)
Muscle symptoms and/or raised creatine
40 (8.4)
19 (7.9)
phosphokinase
Concern about cognitive adverse events
5 (1.0)
4 (1.7)
Glucose intolerance, increased blood glucose 7 (1.5)
5 (2.1)
or glycated haemoglobin
Advanced age
6 (1.3)
5 (2.1)
Liver disease or elevated liver enzymes
5 (1.0)
8 (3.3)
Concomitant medication(s)
4 (0.8)
3 (1.2)
Low body mass index
1 (0.2)
0
Other reason
9 (1.9)
4 (1.7)
LDL-C, low-density lipoprotein cholesterol; SC, subcutaneous; Q2W, every 2 weeks.
a
Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at week 12 if week 8
LDL-C was ≥ 1.8 mmol/L (≥ 70 mg/dL).
b
10 mg/day oral ezetimibe.
5
Table S3 Percent change from baseline to week 24 in LDL-C and secondary lipid
parameters (on-treatment analysis)
Alirocumaba Ezetimibeb
Alirocumab vs. ezetimibe
(n = 464)
(n = 235)
LS mean
95% CI
P value
difference
(SE) %
LDL-C
–52.4 ± 1.3
–21.8 ± 1.8
–30.6 ± 2.2
–34.9 to –26.2
< 0.0001
Apolioprotein B –42.1 ± 1.0
–19.1 ± 1.4
–23.0 ± 1.8
–26.5 to –19.6
< 0.0001
Non-HDL-C
–43.7 ± 1.1
–20.2 ± 1.6
–23.5 ± 1.9
–27.2 to –19.7
< 0.0001
Total
–30.4 ± 0.9
–15.2 ± 1.2
–15.1 ± 1.5
–18.0 to –12.2
< 0.0001
cholesterol
Lipoprotein a
–28.1 ± 1.4
–5.6 ± 1.9
–22.5 ± 2.4
–27.2 to –17.8
< 0.0001
Triglycerides
–13.5 ± 1.4
–13.3 ± 2.0
–0.2 ± 2.5
–5.1 to 4.6
0.93
(fasted)
HDL-C
9.0 ± 0.8
0.8 ± 1.1
8.2 ± 1.4
5.6 to 10.9
< 0.0001
Data are mean ± SE change from baseline unless otherwise indicated. CI, confidence interval;
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol;
LS, least squares; Q2W, every 2 weeks; SC, subcutaneous; SE, standard error.
a
Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at week 12 if week 8
LDL-C was ≥ 1.8 mmol/L (≥ 70 mg/dL).
b
10 mg/day oral ezetimibe.
6
Table S4 Percent change from baseline to week 24 in LDL-C. Pattern mixture model
sensitivity analysis in all randomized patients
All patients on
Alirocumabb
Ezetimibec
Alirocumab vs. ezetimibe
maximally tolerated
(n = 479)
(n = 241)
LS mean
95% CI P value
statin therapya
difference
(SE) %
Baseline LDL-C, mean ± 2.8 ± 0.9
2.7 ± 0.9
–
–
–
SD, mmol/L
Range
0.6–7.9
1.0–6.3
–
–
–
LS mean ± SE change
–47.8 ± 1.4
–20.1 ± 2.0
–27.7 ±
–32.5 to < 0.0001
from baseline (%)
2.5
–22.9
CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; LS, least squares; Q2W,
every 2 weeks; SC, subcutaneous; SE, standard error.
a
One patient was not on maximally tolerated statin therapy.
b
Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at week 12 if week 8
LDL-C was ≥ 1.8 mmol/L (≥ 70 mg/dL).
c
10 mg/day oral ezetimibe.
7
Table S5 Other clinical and laboratory parameters at baseline and at weeks 24 and 52
(safety population).
All patients on
Alirocumabb
Ezetimibe 10 mg dailyc
maximally
Baseline
Week 24
Week 52
Baseline
Week 24
Week 52
tolerated statin
therapya
Systolic BP
129.1±14.6 128.4±15.1 129.4±15.1
128.3±13.0
(mmHg)
130.1±13.1 127.3±13.6
Diastolic BP
77.6±9.7
77.5±9.3
77.6±9.2
77.1±8.7
(mmHg)
78.0±8.2
76.2±8.8
Heart rate
66.6±9.9
66.2±10.6 66.6±10.4 68.1±9.3
67.0±10.2 67.4±10.5
(beats/min)
HbA1c (%)
6.05±0.75 6.09±0.82 6.14±1.00 6.07±0.77 6.18±0.92 6.15±0.88
eGFR
74.5±18.3 75.2±17.9 74.4±17.4 75.0±18.9 75.7±18.4 74.8±19.5
(mL/min/1.73 m2)
ALT (ULN)
0.69±0.33 0.70±0.30 0.75±1.1
0.67±0.26 0.76±0.34 0.69±0.28
AST (ULN)
0.71±0.25 0.72±0.25 0.76±0.55 0.68±0.19 0.74±0.27 0.72±0.22
CRP (nmol/L)
34.1±74.1 30.4±53.3 33.4±87.5 34.6±51.1 29.2±74.0 25.7±47.7
Creatine kinase
0.74±0.56 0.77±0.54 0.77±0.52 0.70±0.45 0.79±0.52 0.76±0.52
(ULN)
Data given as mean±SD. ALT, alanine aminotransferase; AST, aspartate aminotransferase;
BP, blood pressure; Q2W, every 2 weeks; SC, subcutaneous.
a
One patient was not on maximally tolerated statin therapy.
b
Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at week 12 if week 8
LDL-C was ≥1.8 mmol/L (≥70 mg/dL).
c
10 mg/day oral ezetimibe.
8
Table S6 TEAEsa and laboratory parameters (safety population) at 52 weeks (including
those occurring in patients with two LDL-C values < 0.65 mmol/L on alirocumab
treatment)
All patients on maximally tolerated statin
Alirocumabc Ezetimibe Alirocumabc
b
therapy
(n = 479)
10 mg
with two
daily
consecutive
(n = 241)
LDL-C < 0.65
mmol/L
(n = 105)
Patients experiencing any TEAE
341 (71.2)
162 (67.2) 61 (58.1)
TEAEs by system organ class occurring in ≥
3% of patients in either group
Infections and infestations
130 (27.1)
61 (25.3)
26 (24.8)
Musculoskeletal and connective tissue
94 (19.6)
41 (17.0)
19 (18.1)
disorders
Nervous system disorders
77 (16.1)
40 (16.6)
12 (11.4)
Gastrointestinal disorders
72 (15.0)
33 (13.7)
15 (14.3)
Injury, poisoning, and procedural
61 (12.7)
33 (13.7)
9 (8.6)
complications
Cardiac disorders
60 (12.5)
29 (12.0)
10 (9.5)
General disorders and administration site
56 (11.7)
26 (10.8)
6 (5.7)
conditions
Respiratory, thoracic, and mediastinal
45 (9.4)
22 (9.1)
8 (7.6)
disorders
Investigations
35 (7.3)
21 (8.7)
7 (6.7)
Vascular disorders
33 (6.9)
20 (8.3)
2 (1.9)
Skin and subcutaneous tissue disorders
35 (7.3)
15 (6.2)
7 (6.7)
Metabolism and nutrition disorders
27 (5.6)
18 (7.5)
6 (5.7)
Psychiatric disorders
21 (4.4)
12 (5.0)
2 (1.9)
Renal and urinary disorders
21 (4.4)
13 (5.4)
5 (4.8)
Eye disorders
23 (4.8)
9 (3.7)
2 (1.9)
Blood and lymphatic system disorders
11 (2.3)
8 (3.3)
3 (2.9)
Neoplasms, benign, malignant and
15 (3.1)
7 (2.9)
3 (2.9)
unspecified (including cysts and polyps)
TEAEs occurring in ≥ 3% of patients in either
group or TEAEs of interest
Accidental overdosed
30 (6.3)
16 (6.6)
5 (4.8)
Upper respiratory tract infection
31 (6.5)
14 (5.8)
2 (1.9)
Dizziness
23 (4.8)
13 (5.4)
3 (2.9)
Myalgia
21 (4.4)
12 (5.0)
4 (3.8)
Headache
21 (4.4)
10 (4.1)
3 (2.9)
Arthralgia
19 (4.0)
9 (3.7)
5 (4.8)
Nasopharyngitis
18 (3.8)
9 (3.7)
5 (4.8)
Hypertension
18 (3.8)
10 (4.1)
1 (1.0)
Influenza
17 (3.5)
7 (2.9)
2 (1.9)
Angina pectoris
12 (2.5)
11 (4.6)
1 (1.0)
Sinusitis
4 (0.8)
8 (3.3)
1 (1.0)
Laboratory parameters
Blood glucose increasede
1 (0.2)
3 (1.2)
1 (1.0)
e
Haemoglobin decreased
4 (0.8)
2 (0.8)
2 (1.9)
9
LDL-C, low-density lipoprotein cholesterol; Q2W, every 2 weeks; SC, subcutaneous; TEAE,
treatment-emergent adverse event.
a
TEAEs are adverse events that developed or worsened or became serious during the TEAE
period (defined as the time from the first dose of double-blind study treatment to the last
injection plus 70 days [10 weeks], as residual effect of alirocumab was expected until 10
weeks after last injection).
b
One patient was not on maximally tolerated statin therapy.
c
Alirocumab 75 mg SC Q2W with a dose increase to 150 mg Q2W at week 12 if week 8
LDL-C was ≥ 1.8 mmol/L (≥ 70 mg/dL).
d
Accidental overdose was an event suspected by the investigator or spontaneously notified
by the patient (not based on systematic injection/capsule counts) and defined as at least twice
the intended dose within the intended therapeutic interval (i.e. ≥ 2 injections from the doubleblind treatment kit administered in < 7 calendar days or ≥ 2 capsules from the double-blind
treatment kit are administered within 1 calendar day).
e
Investigator defined.
10
Figure S1 LDL-C concentrations vs. study time point by dose-increase status (intention-totreat analysis) in the alirocumab group. LDL-C, low-density lipoprotein cholesterol; LS, least
squares; SD, standard deviation; SE, standard error.
Mean ± SD baseline LDL-C concentrations were higher in patients who had a dose increase
vs. those maintained on the same dose (3.6 ± 1.2 mmol/L [140.4 ± 47.4 mg/dL] vs. 2.6 ± 0.8
mmol/L [101.1 ± 29.7 mg/dL]). Following the dose increase (week 12), an additional mean
absolute reduction in LDL-C of 12.4% was achieved, which was maintained up to week 52.
11
Figure S2 Percent change from baseline in high-sensitivity C-reactive protein during the
treatment period (safety population). Values are given as median (quartile 1, quartile 3). HsCRP values ≥ 95.2 nmol/L were excluded from the analyses, as these are suggestive of a
concurrent acute inflammatory response. All P values (change from baseline to week 24 or
week 52 in either group, and between-group comparisons) were non-significant.
Q2W, every 2 weeks; Upt, dose increase.
70
60
hs-CRP lower than 10 Median (Q1/Q3) % change from baseline
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
Ezetimibe 10 (N=241)
Alirocumab 75 Q2W/Up150 Q2W (N=479)
-70
Baseline
Week 24
Week 52
Time point
LAST
Alirocumab
Baseline
Week 24
Ezetimibe
Week 52
Baseline
Week 24
Week 52
CRP, nmol/L 34.1±74.1 30.4±53.3 33.4±87.5 34.6±51.1 29.2±74.0 25.7±47.7
12
Figure S3 Percent change from baseline to week 24 in LDL-C: subgroup analyses (ITT
analysis). BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease;
HDL-C, high-density lipoprotein cholesterol; Lp(a), lipoprotein a; LDL-C, low-density
lipoprotein cholesterol; LS, least squares; MI, myocardial infarction; PCSK9, proprotein
convertase subtilisin/kexin 9; Q2W, every 2 weeks; SC, subcutaneous; TG, triglyceride.
a
By interactive voice response system.
13