Long-term Efficacy and Safety Study of TAK-085 in Participants With Hypertriglyceridemia

A Phase 3 Long-term Study of TAK-085 in Subjects With Hypertriglyceridemia

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01350999

Enrollment

503

Registered

2011-05-10

Start date

2009-11-30

Completion date

2011-01-31

Last updated

2016-09-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertriglyceridemia

Keywords

Drug Therapy

Brief summary

The purpose of this study is to determine the safety and efficacy of TAK-085, once daily (QD) or twice daily (BID), compared to ethyl eicosapentaenoate (EPA-E), three times daily (TID) in participants with hypertriglyceridemia undergoing lifestyle modification.

Detailed description

TAK-085 is an oral capsule medicine licensed to Takeda Pharmaceutical Company Ltd. TAK-085 contains omega-3 fatty acid ethyl (mainly, ethyl eicosapentaenoate (EPA-E) and ethyl docosahexaenoic acid (DHA-E)). This is a phase 3, open-label, randomized study to evaluate the efficacy and safety of TAK-085. In addition, EPA-E is also administered for 52 weeks for reference to evaluate the safety of TAK-085 in participants with hypertriglyceridemia who are undergoing lifestyle modification. The study period is a total of 56 weeks, comprised of a 4- week screening period and 52 weeks of treatment.

Interventions

DRUGomega-3-acid ethyl esters 90 (TAK-085)

Omega-3-acid ethyl esters 90 (TAK-085) capsules. Each one gram of fatty acid in TAK-085 contains approximately 465 mg of EPA plus 375 mg of docosahexaenoic acid-ethyl as ethyl esters.

DRUGEicosapentaenoic acid-ethyl (EPA)

EPA-E capsules

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to 74 Years

Healthy volunteers

Inclusion criteria

Visit 1 (Week -4) 1. Undergoing lifestyle modification. 2. Triglyceride (TG) level (fasting state) 150 mg/dL or higher and less than 750 mg/dL at Visit 1 (Week -4). 3. Both genders, aged from 20 to less than 75 years at the time of signing informed consent. 4. Outpatient. 5. Capable of understanding and complying with protocol requirements. 6. Signed a written, informed consent form prior to the initiation of any study procedures. 7. A female with childbearing potential (premenopausal and non-sterilized) must have agreed to use routinely adequate contraception from signing of informed consent throughout the duration of the study. Visit 2 (Week -2) 8. Fasting TG level 150 mg/dL or higher and less than 750 mg/dL at Visit 2 (Week -2). 9. Difference in fasting low density lipoprotein-cholesterol (LDL-C) level between Visit 1 (Week -4) and Visit 2 (Week -2) within 25% of the higher value

Exclusion criteria

Visit 1 (Week -4) 1. Any coronary artery diseases (CAD, e.g., confirmed myocardial infarction and angina pectoris) within 6 months prior to Visit 1 (Week -4) or a history of revascularization. 2. Received aortic aneurysmectomy or had had aortic aneurysm within 6 months prior to Visit 1 (Week -4). 3. History or complication of a clinically significant hemorrhagic disease (e.g., hemophilia, capillary fragility illness, digestive tract ulcer, urinary tract haemorrhage, hemoptysis, vitreous haemorrhage) within 6 months prior to Visit 1 (Week -4). 4. Diagnosed with pancreatitis. 5. Diagnosed with lipoprotein lipase (LPL) deficiency, apolipoprotein C-II deficiency or type III familial hyperlipidemia. 6. Cushing's syndrome, uremia, systemic lupus erythematosus (SLE) or serum dysproteinemia. 7. Type 1 diabetes mellitus or with uncontrolled type 2 diabetes mellitus defined by glycosylated hemoglobin (HbA1C) level of 8.0% or higher at Visit 1 (Week -4). 8. Stage III hypertension defined by systolic blood pressure of 180 mmHg or higher or diastolic blood pressure of 110 mmHg or higher regardless of the use of antihypertensive medication. 9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level at Visit 1 (Week -4) was not less than twice the upper limit of the normal reference range. 10. If female, was pregnant or lactating. 11. Habitual drinking defined by an average daily alcohol intake of 100 mL or more , drug abuse or drug dependency, or a history of any of these conditions. 12. Started to take any antihyperlipidemic drugs within 4 weeks prior to Visit 1 (Week -4). 13. Received any investigational products (including those for post-marketing clinical study) within 12 weeks prior to Visit 1 (Week -4). 14. Received TAK-085 in a clinical study. 15. Judged as being ineligible for study participation by the investigator or subinvestigator for any other reasons. Visit 2 (Week -2) 16. ALT or AST level at Visit 2 (Week -2) was twice the upper limit of the normal reference range or higher. 17. Needed a change in the dose of antihyperlipidemic drugs or antidiabetic drugs, addition of a new drug or a change in the type of the drugs during the screening period. 18. Judged as being ineligible for study participation by the investigator or subinvestigator for any other reasons. Visit 3 (Week 0) 19. Needed a change in the dose of antihyperlipidemic drugs or antidiabetic drugs, addition of a new drug or a change in the type of the drugs during the screening period. 20. Judged as being ineligible for study participation by the investigator or subinvestigator for any other reasons

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis	52 Weeks	—
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	52 Weeks	—
Number of Participants With TEAEs Associated With Abnormal Changes in Vital Signs	52 Weeks	—
Number of Participants With TEAEs Associated With Abnormal Changes in Body Weight	52 Weeks	—
Number of Participants With Clinically Significant Findings in Electrocardiogram After Study Drug Administration	52 Weeks	Participants whose results of electrocardiograms were judged as abnormal and clinically significant by investigator after study drug administration were counted in this measure.

Secondary

Measure	Time frame	Description
Percent Change From Baseline in Triglyceride Level	Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52	—
Percent Change From Baseline in Low-Density Lipoprotein - Cholesterol (LDL-C)	Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52	—
Percent Change From Baseline in Total Cholesterol	Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52	—
Percent Change From Baseline in High-Density Lipoprotein - Cholesterol (HDL-C)	Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52	—
Percent Change From Baseline in Non-High-Density Lipoprotein - Cholesterol	Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52	Non-high-density lipoprotein cholesterol was calculated by subtracting high-density lipoprotein cholesterol from total cholesterol.

Participant flow

Recruitment details

Participants took part in the study at 50 investigative sites in Japan from 11 November 2009 to 11 January 2011.

Pre-assignment details

Participants with hypertriglyceridemia were randomized to receive omega-3-acid ethyl esters 90 (TAK-085) 2 g once daily or TAK-085 2 g twice daily or EPA-E 0.6 g three-times daily.

Participants by arm

Arm	Count
TAK-085 2 g TAK-085 2 g capsule, orally, once daily for up to 52 weeks.	165
TAK-085 4 g TAK-085 2 g capsules, orally, twice daily for up to 52 weeks.	171
EPA-E 1.8 g Eicosapentaenoic acid-ethyl (EPA-E) capsule 0.6 g, orally, three-times daily for up to 52 weeks.	167
Total	503

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	4	9	10
Overall Study	Difficulty Making it to Study Visit	1	1	5
Overall Study	Voluntary withdrawal	3	4	6

Baseline characteristics

Characteristic	Total	TAK-085 2 g	TAK-085 4 g	EPA-E 1.8 g
Administration of 3-hydroxy 3-methylglutaryl coenzyme A (HMGCoA) Reductase Inhibitor No	308 participants	101 participants	105 participants	102 participants
Administration of 3-hydroxy 3-methylglutaryl coenzyme A (HMGCoA) Reductase Inhibitor Yes	195 participants	64 participants	66 participants	65 participants
Age, Continuous	55.9 years STANDARD_DEVIATION 10.11	56.0 years STANDARD_DEVIATION 10.95	55.9 years STANDARD_DEVIATION 10.12	55.8 years STANDARD_DEVIATION 9.27
Age, Customized ≥20 - <65 years	389 participants	119 participants	134 participants	136 participants
Age, Customized ≥65 - ≤74 years	114 participants	46 participants	37 participants	31 participants
Body Mass Index	26.12 kg/m^2 STANDARD_DEVIATION 3.5	25.90 kg/m^2 STANDARD_DEVIATION 3.673	26.11 kg/m^2 STANDARD_DEVIATION 3.526	26.33 kg/m^2 STANDARD_DEVIATION 3.301
Body Mass Index, Categorical ≥25.0 - <30.0 kg/m^2	228 participants	71 participants	74 participants	83 participants
Body Mass Index, Categorical <25.0 kg/m^2	209 participants	77 participants	72 participants	60 participants
Body Mass Index, Categorical ≥30.0 kg/m^2	66 participants	17 participants	25 participants	24 participants
Coronary Artery Disease (CAD) Category Category I	19 participants	7 participants	9 participants	3 participants
Coronary Artery Disease (CAD) Category Category II	197 participants	70 participants	71 participants	56 participants
Coronary Artery Disease (CAD) Category Category III	274 participants	86 participants	86 participants	102 participants
Coronary Artery Disease (CAD) Category History of CAD	13 participants	2 participants	5 participants	6 participants
Diabetes Mellitus (Including Impaired Glucose Tolerance) No	319 participants	115 participants	108 participants	96 participants
Diabetes Mellitus (Including Impaired Glucose Tolerance) Yes	184 participants	50 participants	63 participants	71 participants
Height	164.2 cm STANDARD_DEVIATION 9.23	164.2 cm STANDARD_DEVIATION 9.4	164.0 cm STANDARD_DEVIATION 8.69	164.4 cm STANDARD_DEVIATION 9.65
Height, Categorical ≥160 - <170 cm	210 participants	67 participants	77 participants	66 participants
Height, Categorical <160 cm	141 participants	48 participants	45 participants	48 participants
Height, Categorical ≥170 cm	152 participants	50 participants	49 participants	53 participants
Hypertension No	163 participants	55 participants	56 participants	52 participants
Hypertension Yes	340 participants	110 participants	115 participants	115 participants
Low Density Lipoprotein - Cholesterol (LDL-C)	130.5 mg/dL STANDARD_DEVIATION 31.06	133.2 mg/dL STANDARD_DEVIATION 29.85	129.0 mg/dL STANDARD_DEVIATION 30.26	129.3 mg/dL STANDARD_DEVIATION 33
Low Density Lipoprotein - Cholesterol (LDL-C), Categorical <140 mg/dL	319 participants	101 participants	116 participants	102 participants
Low Density Lipoprotein - Cholesterol (LDL-C), Categorical ≥140 mg/dL	184 participants	64 participants	55 participants	65 participants
Low High Density Lipoprotein - Cholesterol (HDL-C) No	377 participants	123 participants	132 participants	122 participants
Low High Density Lipoprotein - Cholesterol (HDL-C) Yes	126 participants	42 participants	39 participants	45 participants
Menopause Status No	17 participants	5 participants	7 participants	5 participants
Menopause Status Not Applicable	358 participants	118 participants	121 participants	119 participants
Menopause Status Unknown	9 participants	4 participants	1 participants	4 participants
Menopause Status Yes	119 participants	38 participants	42 participants	39 participants
Region of Enrollment Japan	503 participants	165 participants	171 participants	167 participants
Sex: Female, Male Female	145 Participants	47 Participants	50 Participants	48 Participants
Sex: Female, Male Male	358 Participants	118 Participants	121 Participants	119 Participants
Smoking Classification Current Smoker	157 participants	52 participants	47 participants	58 participants
Smoking Classification Ex-Smoker	184 participants	54 participants	68 participants	62 participants
Smoking Classification Never Smoked	162 participants	59 participants	56 participants	47 participants
Triglycerides	263.0 mg/dL STANDARD_DEVIATION 103.71	254.7 mg/dL STANDARD_DEVIATION 97.8	270.0 mg/dL STANDARD_DEVIATION 101.19	264.2 mg/dL STANDARD_DEVIATION 111.62
Triglycerides, Categorical ≥150 - <300 mg/dL	319 participants	103 participants	107 participants	109 participants
Triglycerides, Categorical <150 mg/dL	42 participants	16 participants	12 participants	14 participants
Triglycerides, Categorical ≥300 - <500 mg/dL	118 participants	38 participants	43 participants	37 participants
Triglycerides, Categorical ≥500 mg/dL	21 participants	7 participants	7 participants	7 participants
Waist Circumference	90.77 cm STANDARD_DEVIATION 9.015	90.39 cm STANDARD_DEVIATION 8.607	90.75 cm STANDARD_DEVIATION 9.169	91.16 cm STANDARD_DEVIATION 9.284
Waist Circumference, Categorical Female <90.0 cm	82 participants	26 participants	30 participants	26 participants
Waist Circumference, Categorical Female ≥90.0 cm	63 participants	21 participants	20 participants	22 participants
Waist Circumference, Categorical Male <85.0 cm	70 participants	22 participants	29 participants	19 participants
Waist Circumference, Categorical Male ≥85.0 cm	288 participants	96 participants	92 participants	100 participants
Weight	70.70 kg STANDARD_DEVIATION 12.568	70.02 kg STANDARD_DEVIATION 12.291	70.46 kg STANDARD_DEVIATION 12.097	71.61 kg STANDARD_DEVIATION 13.311
Weight, Categorical ≥60.0 - <70.0 kg	153 participants	57 participants	53 participants	43 participants
Weight, Categorical <60 kg	98 participants	32 participants	34 participants	32 participants
Weight, Categorical ≥70.0 - <80.0 kg	151 participants	44 participants	50 participants	57 participants
Weight, Categorical ≥80.0 kg	101 participants	32 participants	34 participants	35 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	96 / 165	94 / 171	104 / 167
serious Total, serious adverse events	5 / 165	10 / 171	7 / 167

Outcome results

Primary

Number of Participants With Clinically Significant Findings in Electrocardiogram After Study Drug Administration

Participants whose results of electrocardiograms were judged as abnormal and clinically significant by investigator after study drug administration were counted in this measure.

Time frame: 52 Weeks