Trial Design
`
`Effects of eicosapentaenoic acid on cardiovascular
`events in Japanese patients with
`hypercholesterolemia: Rationale, design, and
`baseline characteristics of the Japan EPA Lipid
`Intervention Study {JELIS}
`
`Mitsuhiro Yokoyama, MD, PhD, a and Hideki Origasa, PhD,h for the JELIS Investigators Kobe and Toyama, Japan
`
`Hypothesis The principle aim of the current study is to test the hypothesis that the long-term use of highly purified
`EPA (eicosapentaenoic acid: 1800 mg/day), in addition to HMG-CoA reductase inhibitor, is effective in preventing car(cid:173)
`diovascular events in Japanese patients with hypercholesterolemia.
`Background Epidemiological and clinical evidence suggest that intake of long-chain polyunsaturated n-3 fatty ac(cid:173)
`ids (PUFAs), which are abundant in fish, might have a significant role in the prevention of coronary artery disease, as ma(cid:173)
`rine PUFAs have multiple biological functions through lipid-dependent and lipid-independent mechanisms.
`Methods The Japan EPA Lipid Intervention Study (JELIS) is a prospective, randomized, open-label, blinded end point
`trial including both primary and secondary prevention strata, with a maximum follow-up of 5 years. Its main purpose is to
`examine the clinical effectiveness of EPA oil given as an additional treatment to patients taking HMG-CoA reductase in(cid:173)
`hibitors for hypercholesterolemia. A primary end point is major coronary events: sudden cardiac death, fatal and nonfatal
`myocardial infarction, and unstable angina pectoris including hospitalization for documented ischemic episodes, and
`events of angioplasty/stenting or coronary artery bypass grafting. Secondary end points include alkause mortality,
`stroke, peripheral artery disease, and cancer. Baseline study composition comprises 15 ,000 participants (4204 men and
`10,796 women) in the primary prevention stratum and 3645 (1656 men and 1989 women) in the secondary stra-
`tum. The minimum age is 40 years for men, women are required to be postmenopausal, and all patients must be -=;75
`years of age. The mean age of participants is 61 years, and 69% are female. The schedule for plasma fatty acid compo(cid:173)
`sition measurement is as follows: at baseline, at 6 month, and yearly thereafter. The mean baseline total and low-density
`lipoprotein cholesterol levels were 275 mg/dL (7.1 mmol/L) and 180 mg/dL (4.6 mmol/L).
`Results Results are expected in 2005.
`Conclusion JELIS is a large clinical trial that will evaluate whether EPA can make an additional improvement in mor(cid:173)
`tality and morbidity of coronary artery disease beyond that of HMG-CoA reductase inhibitor treatment. (Am Heart J
`2003; 146:613-20.)
`
`Beginning with the study by Dyerberg et al on
`Greenland Eskimos in the late 1970s, 1 epidemiological
`
`From the 0 Division of Cardiovascular and Respiratory Medicine, Department of Internal
`Medicine, Kobe University Graduate School of Medicine, Kobe, and the 6Division of
`Biostatistics, Toyama Medical and Pharmaceutical University, Toyama, Japan.
`Supported by Machida Pharmaceutical Company and Dainippon Pharmaceutical Com(cid:173)
`pany, Japan.
`Submiffed May 27, 2002; accepted March 11, 2003.
`Reprint requests: Mitsuhiro Yokoyama, MD, PhD, Professor of Cardiovascular and Re(cid:173)
`spiratory Medicine, Department of Internal Medicine, Kobe University Graduate School
`of Medicine, 7-5-1 Kusunokicho, Chuo-ku, Kobe 650-0017, Japan.
`E-mail: yokoyama@med.kobe-u.ac.jp
`© 2003, Mosby, Inc. All rights reserved.
`0002-8703/2003/$30.00 + 0
`doi: I 0. I 016/50002-8703(03)00367-3
`
`studies from many countries including Finland, Italy,
`Japan, and The Netherlands have suggested that an
`increased intake of dietary fish or fish oil rich in the
`long-chain polym1saturated n-3 fatty acids (PUFAs), ei(cid:173)
`cosapentaenoic acid (EPA) and docosahexaenoic acid
`(DHA), is inversely related to the risk of atherothrom(cid:173)
`botic diseases, in particular coronary artery disease
`(CAD). 2 - 4
`Results of many prospective observational cohort
`studies have found that diets rich in marine PUFAs
`may be protective against major cardiovascular events,
`including mortality from CAD, total cardiovascular
`death, all-cause mortality, and nonfatal myocardial in(cid:173)
`farction.
`
`ICOSAPENT DFNDTS00007166
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1045, p. 1 of 8
`
`

`

`614 Yokoyama and Origasa
`
`American Heart Journal
`October 2003
`
`Thus, 2 randomized, controlled, secondary preven(cid:173)
`tion trials were performed to examine the effects of
`dietary fish on the risk of death from CAD in patients
`after myocardial infarction. The Diet and Reinfarction
`Trial (DART) reported that patients who were advised
`to increase their dietary intake of fish to at least 2 fish
`meals per week had a 29% decrease in all-cause mor(cid:173)
`tality over 2 years.~ The GISSI-Prevenzione trial
`showed that there was a 20% decrease in all death, a
`30% decrease in cardiovascular deaths, and a 45% de(cid:173)
`crease in sudden deaths associated with a daily supple(cid:173)
`ment of n-3 PUFAs (lg daily, EPA/DHA = 1:2) in pa(cid:173)
`tients with recent myocardial infarction. 6 These trial
`results are concordant with a body of epidemiological
`data. It has not yet been proved by clinical trials of
`primary prevention that marine n-3 PUFAs reduce the
`mortality and morbidity of CAD in high-risk subjects.
`Most trials have involved the use of diets supple(cid:173)
`mented by intake of fish, fish oils, or capsules contain(cid:173)
`ing fish oil extracts. These may contain a number of
`other fatty acids and different components. Thus, an
`evaluation of the specific effects of each n-3 PUFA was
`not possible. To date, only a few studies have exam(cid:173)
`ined the effects of purified n-3 PUFA preparations in
`human subjects for short observation periods.
`Although the underlying mechanisms of protective
`action of n-3 PUFAs against CAD remain to be estab(cid:173)
`lished, their multiple cardiovascular effects have re(cid:173)
`ceived much attention. The potential mechanisms are
`lower levels of serum lipids,7
`- 9 antithrombotic proper(cid:173)
`ties and relaxation in coronary arteries, 10
`14 anti-in(cid:173)
`-
`flammatory properties, 1 ~-rn anti-platelet- derived
`growth factor properties, 19 natural ligands for peroxi(cid:173)
`some proliferator activated receptors, 20
`21 and antiar(cid:173)
`·
`rhythmic properties. 22
`
`Rationale for the JELIS
`It is well established that cholesterol lowering with
`hydroxymethyl glutaryl coenzyme A (HMG-CoA) reduc(cid:173)
`tase inhibitors conveys potential for primary and sec(cid:173)
`ondary prevention of cardiovascular events in hyper(cid:173)
`26 Preliminary data on
`cholesterolemic patients. 23
`-
`pravastatin combined with fish oil have shown several
`beneficial effects on the lipid profile of patients with a
`mixed type of hyperlipidemia. 27
`29 This combination
`-
`therapy effectively reduced the concentration of low(cid:173)
`density lipoprotein as well as that of total cholesterol.
`It was also remarkably safe during short-term use and
`expected to be clinically beneficial.
`However, no clinical intervention trial data have
`been collected to determine whether the addition of
`EPA to conventional therapy with an HMG-CoA reduc(cid:173)
`tase inhibitor is effective in preventing cardiovascular
`events.
`
`This study is designed to test the fundamental hy(cid:173)
`pothesis that treatment with highly purified EPA ethyl
`ester together with lipid lowering with an HMG-CoA
`reductase inhibitor is more effective than treatment
`without EPA in reducing major coronary events. Such
`coronary events involve CAD deaths including sudden
`cardiac death, fatal and nonfatal myocardial infarction,
`and unstable angina pectoris. Other objectives are to
`evaluate the effect of EPA on the frequency of stroke
`and all-cause death, the long-term safety of EPA, and
`the relationship between plasma fatty acid levels and
`the onset of cardiovascular events.
`
`Methods
`Study design
`The }ELIS is a prospective, randomized, open-label, blind(cid:173)
`ed-end point clinical trial designed to examine the clinical
`efficacy of EPA oil administered as an adjuvant agent to pa(cid:173)
`tients under treatment with HMG-CoA reductase inhibitors
`for hypercholesterolemia. Participants are randomly assigned
`to either EPA adjuvant treatment or none in an open fashion
`(ie, an unblinded manner). Because all patients receive reduc(cid:173)
`tase inhibitors, we cannot assess whether the inhibitors and
`EPA work synergistically.
`The primary prevention stratum was defined as partici(cid:173)
`pants who had (1) no history of myocardial infarction (MI) or
`angina pectoris and with neither angioplasty/stenting nor cor(cid:173)
`onary artery bypass graft (CABG) until randomization, and (2)
`no clinical manifestations of angina pectoris or electrocardio(cid:173)
`graph (ECG) abnormalities at randomization. The secondary
`prevention stratum was defined as those who had (1) history
`of well-documented MI or angina pectoris with neither angio(cid:173)
`plasty /stenting nor CABG until randomization, and/or (2) sta(cid:173)
`ble, controlled angina pectoris at randomization.
`In the primary and secondary prevention strata, a primary
`end point is major coronary events, which include sudden
`cardiac death, fatal and nonfatal MI, unstable angina pectoris
`including hospitalization for documented ischemic episodes,
`and events of angioplasty/stenting or CABG. Secondary end
`points are all-cause mortality, mortality and morbidity of
`CAD, stroke, peripheral artery disease (arteriosclerosis oblit(cid:173)
`erans [ASO]), and cancer. Clinical end points are ascertained
`once a year by the Endpoints Adjudication Committee: ex(cid:173)
`pert cardiologists and neurologists who are blinded to the
`assigned groups. However, the assessment of the end points
`is performed without breaking a key code, by a blinded-end
`point approach. Each participant is followed-up for a maxi(cid:173)
`mum of 5 years.
`
`Random allocation
`This study used a statistical coordinating center, Toyama
`Medical and Pharmaceutical University, to manage patient
`registration, which included the confirmation of eligibility
`criteria, operation of the randomization scheme, and data
`management. We used a permuted block randomization with
`a block size of 4. Multiple blocks were assigned according to
`the number of participants enrolled at each center. Stratifica(cid:173)
`tion was based on the prevention stratum (primary or sec-
`
`ICOSAPENT DFNDTS00007167
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1045, p. 2 of 8
`
`

`

`American Heart Journal
`Volume 146, Number 4
`
`Yokoyama and Origasa 61 S
`
`Figure 1
`
`Figure 2
`
`20000
`
`18000
`
`>-
`
`16000
`
`-Total
`
`• • • • Primary prevention
`-
`- Secondary prev~
`
`" iii
`= O"
`14000
`~ 12000
`" >
`10000
`+'
`~ 8000
`= E =
`
`u_
`
`'-'
`
`6000
`
`4000
`
`2000
`
`0 h-"19'=;=;:::;:~...,..,r-rr-i'o.;=.;::.;::.:;::.;::.;::.:;::,_~~~~~~~~
`96/Nov 97
`98
`99
`99/Nov
`
`Monthly chart of the recruitment process.
`
`ondary). The results of the randomization scheme were con(cid:173)
`cealed to the investigators and participants.
`
`Patient population
`Between November 1996 and November 1999, we en(cid:173)
`rolled a total of 19,466 participants with hypercholesterol(cid:173)
`emia from all regions of Japan; a total of 821 cases were ex(cid:173)
`cluded as ineligible.
`The intention-to-treat data set currently involves 18,645
`participants, with 15,000 (80%) for primary and 3645 (20%)
`for secondary prevention who were randomly assigned to
`EPA plus HMG-CoA reductase inhibitors or HMG-CoA reduc(cid:173)
`tase inhibitors only.
`The monthly increase of the enrollment is shown in Figure
`1, and Figure 2 illustrates the trial profile.
`The study patients were recruited by local physicians par(cid:173)
`ticipating in this study with the help of regional organizing
`committees. Eligible participants had a total cholesterol level
`of ""=250 mg/dL (6.5 mmol/L), which corresponds to an LDL
`cholesterol level of 170 mg/dL (4.4 mmol/L), at baseline. The
`minimum age was 40 years for men; women were required
`to be postmenopausal. Maximum patient age was 75 years
`(due to the 5-years follow-up). Informed written consent was
`obtained from each patient. All participants are Japanese for
`the simple reason that highly purified EPA is allowed as treat(cid:173)
`ment for hyperlipidemia in Japan. Inclusion and exclusion
`criteria are listed in Table I.
`Local physicians monitor dietary and medication compli(cid:173)
`ance at every clinical visit.
`The schedule of observations is shown in Table II.
`
`Baseline data
`Patients were divided into the EPA group (n = 9326) or
`control group (n = 9319).
`The baseline demographic and clinical characteristics of
`JELIS are shown in Table III.
`In the primary prevention stratum (n = 15,000), the mean
`age was 56 years for men (28%) and 62 years for women
`(72%). Prevalence of smoking and drinking were 17% and
`24%, respectively. Concomitant diseases were prevalent in
`
`Qualifying to receive dietary advice 4-week wash-out
`period for prior antihyperl1pidem1c drug use
`
`Qualifying serum total Cholesterol (;.;250mg/dl) at
`each regional clinical center
`
`Verifying comp! iance with inclusion/exclusion
`criteria at the stat!stical coordinating center
`
`Primary prevention
`
`Secondary prevent ion
`
`(No clinical evidence of
`atherosclerot!c coronary artery
`disease)
`n=15,000
`
`(Involving clinical evidence of
`atherosclerotic cOronary artery
`n =3, 645
`disease )
`
`Trial profile.
`
`approximately 47% of the participants in the order of hyper(cid:173)
`tension, diabetes, stroke, hepatic disease, and renal disease.
`ECG abnormalities were present in 17%. The mean total cho(cid:173)
`lesterol level was 277 mg/dL at baseline with the standard
`deviation of 28 mg/dL. Mean LDL and high-density lipopro(cid:173)
`tein (HDL) cholesterol levels were 181 mg/dL and 59 mg/dL,
`respectively. There was no evidence of high blood pressure
`on average.
`In the secondary prevention stratum (n=3645), the mean
`age was 62 years for men (45%) and 65 years for women
`(55%). Prevalence of smoking and drinking were 25% and
`30%, respectively. Prior myocardial infarction was present in
`28% and stable angina was reported in 79%. Concomitant
`diseases were found in approximately 58% of the partici(cid:173)
`pants, in the order of hypertension, diabetes, stroke, hepatic
`disease, and renal disease. ECG abnormalities were present in
`58%. Mean total cholesterol level was 270 mg/dL at baseline
`with a standard deviation of 28 mg/dL. Mean LDL and HDL
`cholesterol were 177 mg/dL and 55 mg/dL, respectively.
`Figure 3 shows the plasma fatty acids composition at base(cid:173)
`line. C18:2 omega 6 (linoleic acid), C16:0 (palmitic acid) and
`C18:1 omega 9 (oleic acid) were the dominant fatty acids.
`C18:0 (stearic acid), C20:4 omega 6 (arachidonic acid), C22:6
`omega 3 (docosahexaenoic acid), and C20:5 omega 3 (eicosa(cid:173)
`pentaenoic acid) followed, but no statistically significant dif(cid:173)
`ferences were observed in the prevention stratum.
`
`Treatment/ preparations
`EPA is administered at a dose of 600 mg, three times a day
`after meals (total 1800 mg/day). We use EPADEL Capsule
`300TM (Machida Pharmaceutical Co, Ltd, Tokyo, Japan) con-
`
`ICOSAPENT DFNDTS00007168
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1045, p. 3 of 8
`
`

`

`616 Yokoyama and Origasa
`
`American Heart Journal
`October 2003
`
`Table I. Inclusion and exclusion criteria
`
`Inclusion criteria
`Hyperlipidemic patients with serum total cholesterol of 250 mg/dL or more
`(Measurement of serum total cholesterol)
`Serum total cholesterol should be measured twice at interval of 2-4 weeks. A single measurement is acceptable if the cholesterol is measured
`by blood collection at fasting under strict compliance with dietary advice after withdrawal of the antihyperlipemic drug.
`(Wash Out)
`The wash out period of 4 weeks (8 weeks for probucol) is necessary in patients under treatment with antihyperlipemic drug. However, if
`treatment with the antihyperlipemic drug was started within 6 months of the initiation of the study, the patient can participate in the study
`without the washout period.
`Men aged 40-75 years or women after menopause to 75 years
`Patients who have already received appropriate dietary advice
`Exclusion criteria
`Acute myocardial infarction occurring within last 6 months
`Unstable angina pectoris
`A history or complication of serious heart disease (severe arrhythmia, heart failure, cardiac myopathy, valvular disease, congenital disease, etc.)
`Receiving cardiovascular reconstruction within last 6 months
`Cerebrovascular disorders occurring within last 6 months
`Complication of serious hepatic disease or renal disease
`Malignant tumor
`Uncontrollable diabetes
`Hyperlipidemia arising from the following diseases:
`Nephrotic syndrome, hypothyroidism, Cushing's syndrome, secondary hyperlipidemia due to other disease
`Hyperlipidemia due to some drugs such as steroid hormone
`Hemorrage (hemophilia, capillary fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, vitreous hemorrhage, etc.)
`Hemorrhagic diathesis
`Hypersensitivity to the study drug fomulation
`Patients intending to undergo surgery
`Patients judged to be inappropriate by the physician in charge
`
`Table II. Schedule of the observations during the study period
`
`Pretreatment
`period
`
`-8
`
`-4
`
`x
`
`x
`
`x
`
`x
`
`Treatment period (months)
`
`0
`
`x
`x
`x
`x
`
`x
`x
`x
`
`2
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`42
`
`48
`
`54
`
`60
`
`x
`x
`x
`x
`
`x
`x
`x
`
`x
`
`x
`x
`x
`x
`
`x
`x
`x
`
`x
`
`x
`x
`x
`x
`
`x
`x
`x
`
`x
`x
`x
`x
`
`x
`x
`x
`
`x
`x
`x
`x
`__,.
`x
`x
`x
`
`x
`
`x
`
`x
`x
`x
`
`x
`
`Dietary advice
`Compliance check
`Smoking and drinking
`Vital signs (including ECG)
`Adverse and clinical events
`Serum lipids (at each clinical center)
`Fatty acids (central laboratory)
`Clinical visits
`
`taining 300 mg of highly (>98%) purified EPA ethyl ester
`(ethyl all-cis-5,8,11,14,17-icosapentaenoate) per capsule. EPA
`is actually purified from a long-chain polyunsaturated fatty
`acid present in fish oil (Figure 4). EPADEL Capsule 300 was
`launched in the Japanese market in 1990 for the treatment of
`ASO and hyperlipidemia. The usual adult dose is 600 mg of
`ethyl icosapentaenoate: 2 capsules administered orally 3
`times daily immediately after meals.
`
`Concomitant treatment
`Either pravastatin or simvastatin was prescribed for all par(cid:173)
`ticipants as a first-line therapy, these being the 2 HMG-CoA
`
`reductase inhibitors available in Japan at the initiation of this
`study.
`Dosage, as recommended by Ministry of Health, Labour
`and Welfare (MHLW), is as follows: pravastatin 10 mg, once a
`day or simvastatin 5 mg, once a day. With serious hypercho(cid:173)
`lesterolemia, defined as a serum cholesterol level not con(cid:173)
`trolled by the recommended dosage, these can be increased
`to 20 mg and 10 mg, respectively.
`No treatment with other antihyperlipidemic agents was
`allowed during the study period. However, other kinds of
`medications were taken as needed. This regime will be fol(cid:173)
`lowed for a maximum of 5 years.
`
`ICOSAPENT DFNDTS00007169
`
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`IPR2022-00215
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`

`

`American Heart Journal
`Volume 146, Number 4
`
`Yokoyama and Origasa 617
`
`Table Ill. Baseline characteristics of primary and secondary prevention strata
`
`Primary prevention stratum
`
`Secondary prevention stratum
`
`EPA group
`(n = 7513)
`
`884 (11.8)
`2481 (33.0)
`2976 (39.6)
`1172 (15.6)
`56 ± 10
`62 ± 7
`
`2113 (28.l)
`5400 (71.9)
`1323 (17.6)
`1837 (24.5)
`24.0 ± 3.6
`1299 (17.3)
`
`Control
`group
`(n = 7487)
`
`906 (12.l)
`2549 (34.0)
`2913 (38.9)
`lll9 (14.9)
`56 ± 10
`62 ± 7
`
`2091 (27.9)
`5396 (72. l)
`1244 (16.6)
`1830 (24.4)
`23.9 ± 3.5
`1245 (16.6)
`
`1101 (14.7)
`2521 (33.6)
`370 (4.9)
`314 (4.2)
`177 (2.4)
`276.6 ± 28.0
`180.5 ± 34.5
`59.4 ± 17.7
`187.9 ± 147.8
`135.6 ± 18.7
`79.7 ± 11.0
`
`1086 (14.5)
`2451 (32.7)
`320 (4.3)
`304 (4.1)
`181 (2.4)
`276.9 ± 27.8
`181.4±33.7
`59.0 ± 18.l
`189.2 ± 159.5
`135.5 ± 18.2
`79.9±11.l
`
`EPA group
`(n = 1813)
`
`Control group
`(n= 1832)
`
`114 (6.3)
`413(22.8)
`806 (44.5)
`480 (26.5)
`62 ± 9
`65 ± 7
`
`838 (46.2)
`975 (53.8)
`485 (26.8)
`540 (29.8)
`24.0 ± 3.9
`1046 (57.7)
`
`1018 (56.2)
`389 (21.5)
`539 (29.7)
`
`363 (20.0)
`114 (6.3)
`130 (7.2)
`9 (0.5)
`22 (1.2)
`11 (0.6)
`
`400 (22.l)
`781 (43.l)
`108 (6.0)
`61 (3.4)
`59 (3.3)
`270.0 ± 27.7
`177.l ± 32.2
`55.4 ± 19.2
`189.8 ± 127.l
`137.0 ± 18.0
`78.7 ± 10.9
`
`128 (7.0)
`435 (23.7)
`777 (42.4)
`492 (26.9)
`61 ± 9
`65 ± 7
`
`818 (44.7)
`1014 (55.3)
`435 (23.7)
`542 (29.6)
`24.l ± 4.0
`1067 (58.2)
`
`1076 (58.7)
`392 (21.4)
`495 (27.0)
`
`328 (17.9)
`110 (6.0)
`120 (6.6)
`9 (0.5)
`18 (l.O)
`7 (0.4)
`
`414 (22.6)
`802 (43.8)
`131 (7.2)
`57 (3.1)
`67 (3.7)
`270.l ± 29.0
`176.3 ± 32.9
`55.5 ± 19.6
`198.6 ± 151.9
`137.l ± 18.3
`79.3 ± 11.0
`
`Age (y)
`s49 (%)
`50-59 (%)
`60-69 (%)
`270 (%)
`Male
`Female
`Sex(%)
`Male
`Female
`Smoking(%)
`Drinking (%)
`BMI (kg/m2
`)
`ECG abnormality at resting (%)
`CAD(%)
`Angina
`Effort
`Spontaneous
`Myocardial infarction
`Angioplasty
`PTCA
`Coronary bypass
`Endovascular stent
`DCA
`PTCR
`Others
`Other complications (%)
`Diabetes
`Hypertension
`Stroke
`Hepatic diseases
`Renal diseases
`Total cholesterol (mg/dL)
`LDL cholesterol (mg/ dL)
`HDL cholesterol (mg/dL)
`Triglyceride (mg/ dL)
`Systolic blood pressure (mm Hg)
`Diastolic blood pressure (mm Hg)
`
`Plus-minus values are means ± SD.
`
`Calculations and analysis
`For the primary prevention stratum, CAD morbidity and
`mortality in the Japanese general population was estimated at
`5.3 per 1000 person years. 30 Because the JELIS population is
`restricted to those with a total cholesterol level of ""=250 mg/
`dL, we estimated a 10% higher risk for our cohort: 5.8 per
`1000 person years. For the secondary prevention stratum,
`CAD morbidity and mortality was reported at 57.6 per 1000
`person years23 from Scandinavian countries, where people
`are considered to be at an extremely high risk for CAD com(cid:173)
`pared to Japan. The incidence of CAD in the secondary pre(cid:173)
`vention stratum was estimated as 21.3 per 1000 person years.
`In fact, for primary prevention the incidence was 5.8 per
`1000 person years in Japan, 30 whereas it was 15.8 per 1000
`
`person years in Scotland. 24 Thus, the ratio of these rates, 2.7
`(15.8 divided by 5.8), was used for adjustment. We also as(cid:173)
`sumed that the proportion of participants in the primary pre(cid:173)
`vention stratum would be 65%.
`With respect to risk reduction, several megatrials and
`meta-analyses involving HMG-CoA reductase inhibitors31
`have estimated an approximate 30% reduction of CAD
`morbidity and mortality compared to none or placebo.
`Given the DART and GISSI results, we optimistically sup(cid:173)
`posed that EPA would further reduce the risk by 25%, con(cid:173)
`ditional on the use of HMG-CoA reductase inhibitors.
`Therefore, comedication of EPA with HMG-CoA reductase
`inhibitors should reduce the risk by 47.5% compared to no
`treatment.
`
`ICOSAPENT DFNDTS00007170
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1045, p. 5 of 8
`
`

`

`618 Yokoyama and Origasa
`
`Figure 3
`
`PdmaryproYMtlanstratom
`
`DEPA Group
`
`Cl Control Group
`
`Fatty acids composition at baseline.
`
`Figure 4
`
`Chemical structure of EPA ethyl ester.
`
`Assuming we perform the log-rank test with 2-sided signifi(cid:173)
`cance, 12,600 participants are required to achieve a mini(cid:173)
`mum statistical power of 80%. The accrual period is assumed
`to be 3 years with a follow-up period of 5 years at the most.
`As more participants than expected were recruited in the
`primary prevention stratum (80%), sample size projection
`correction increased the number of participants required
`from 12,600 to 18,000.
`All analyses follow an intention-to-treat approach. Analyses
`of time-to-event data are performed using the Kaplan-Meier
`method and the log-rank test is performed to test treatment
`group differences. The relative risk and its 95% CI are calcu(cid:173)
`lated from the Cox proportional hazard model. Adverse
`events are compared between groups using the Fisher exact
`test. The analysis is performed according to the stratum of
`either primary or secondary prevention. Statistical signifi(cid:173)
`cance is set at the <5% level with a 2-sided test.
`Formal interim analysis is to be performed twice during
`the trial. The first will be 2 years after the final enrollment of
`participants (ie, in early 2002). The second will be mid 2004.
`The final analysis is expected in late 2005. The interim analy(cid:173)
`sis will apply the Lan-DeMets boundary based on the number
`of cardiovascular events, supported by computing a condi(cid:173)
`tional power to demonstrate the superiority of EPA against
`the control group, toward the end of the trial.
`
`American Heart Journal
`October 2003
`
`Figure 5
`
`Steering committee
`
`Protocol committee
`
`Data and Safety Monitoring Board
`
`Endpoint adjudication committee
`
`Statistical coordinating center
`
`Regional organizing committees
`
`Organization of JELIS.
`
`Trial organizational structure
`The organizational structure of }ELIS is illustrated in Figure
`5. This study is conducted under the scientific direction of
`the Steering Committee. The External Data and Safety Moni(cid:173)
`toring Board is responsible for identifying safety issues and
`interpreting emerging study data.
`
`Discussion
`The preventive effect of n-3 PUFAs for CAD morbid(cid:173)
`ity and mortality has been reported in various epidemi(cid:173)
`ological researches and cohort studies. 32-34 JELIS is the
`first large-scale, randomized, controlled trial of highly
`purified EPA in hypercholesterolemia, including both
`primary and secondary prevention strata and using
`EPA as an adjuvant treatment with an HMG-CoA reduc(cid:173)
`tase inhibitor as the baseline drug. Study patients are
`expected to demonstrate that cardiovascular events
`can be further decreased by 25% beyond that ex(cid:173)
`pected by the use of HMG-CoA reductase inhibitors
`alone.
`Several large-scale clinical studies have evaluated the
`effects of HMG-CoA reductase inhibitors in hypercho(cid:173)
`lesterolemia.23-26 Comparing our study with 4S,23
`WOS,24 CARE, 2~ LIPID,26 and the currently ongoing
`MEGA STUDY34 in Japan, the number of participants
`enrolled for JELIS surpasses that recorded for all the
`others. Subgroup analyses by age, sex, and concomi(cid:173)
`tant disease might also produce important information
`on differences in event rates between Japan and other
`countries.
`Although the inhibitory effect of dietary n-3 PUFAs
`on cardiovascular events has been assessed in a few
`case-control studies and in 2 secondary prevention tri(cid:173)
`als, there has been no report on clinical outcomes as(cid:173)
`sessed in randomized controlled trials involving pri(cid:173)
`mary prevention cases. JELIS is the first attempt to
`collect such data.
`With respect to secondary prevention cases, random(cid:173)
`ized controlled trials such as DART~ and GISSI6
`showed an inhibitory effect of n-3 PUFAs on cardiovas-
`
`ICOSAPENT DFNDTS00007171
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1045, p. 6 of 8
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`

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`American Heart Journal
`Volume 146, Number 4
`
`Yokoyama and Origasa 619
`
`cular events. These studies, which advised consump(cid:173)
`tion of meals containing fish or EPA plus DHA prepara(cid:173)
`tions, had shorter follow-up periods than JELIS, which
`has a median duration of 2 years to date, with a range
`of 1 to 4 years.
`Further, because JELIS measured the plasma fatty
`acid fraction once a year, it is possible to study the
`relationship between changes in the composition of
`blood fatty acids, such as EPA, as well as oleic acid
`and linoleic acid, and the onset of cardiovascular
`events.
`There have been relatively recent discussions on the
`appropriateness of prescribing cholesterol-lowering
`drugs to postmenopausal women. 3 ~ Cholesterol-lower(cid:173)
`ing drngs are taken by many Japanese women. The
`subclass analysis of our study may address the useful(cid:173)
`ness of these dn1gs for women.
`As noted, we are conducting this trial on an exclu(cid:173)
`sively Japanese population mainly because EPA is an
`allowed treatment for hyperlipidemia in Japan. Should
`our fundamental hypothesis be proven, it will then
`need to be argued whether the results can be extrapo(cid:173)
`lated to non-Japanese populations and whether EPA is
`differentially effective between populations.
`
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