Evaluation of the Safety and Efficacy of Long-term Use of Omega-3 Fatty Acid Ethyl Esters

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02153073
• Collaborator: (none)
• Enrollment: 3,084
• Locations: 2
• Actual Duration (Months): 48.1
• Patients Per Site: 1542
• Patients Per Site Per Month: 32.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of long-term use of granular capsule formulation of omega-3 fatty acid ethyl esters (Lotriga Granular Capsules) in patients with hyperlipidemia in daily medical practice

Condition or Disease	Intervention/Treatment	Phase
Hyperlipidemia	Drug: Omega-3 fatty acid ethyl esters

Detailed Description

This special drug use surveillance on long-term use of granular capsule formulation of omega-3 fatty acid ethyl esters (Lotriga Granular Capsules) was designed to investigate the frequency of adverse events in patients with hyperlipidemia The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) depending on the participant's triglyceride level.

Study Design

• Study Type: Observational
• Actual Enrollment: 3084 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Omega-3 Fatty Acid Ethyl Esters (Lotriga) Granular Capsules Special Drug Use Surveillance (Long-term Use Survey)
• Actual Study Start Date: May 29, 2013
• Actual Primary Completion Date: May 31, 2017
• Actual Study Completion Date: May 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Omega-3 fatty acid ethyl esters 2 g Omega-3 fatty acid ethyl esters 2 g, administered orally once or twice daily after meals	Drug: Omega-3 fatty acid ethyl esters; Omega-3 fatty acid ethyl esters granular capsules; Other Names: Lotriga Granular Capsules

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Had One or More Adverse Events (AE) and Serious Adverse Events (SAE) [Up to Month 12]

Secondary Outcome Measures

1. Percent Change From Baseline in Lipid Parameters - Triglycerides (TG) [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in TG values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.

2. Percent Change From Baseline in Lipid Parameters - LDL Cholesterol (LDL-C) [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in LDL-C values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.

3. Percent Change From Baseline in Lipid Parameters - VLDL Cholesterol (VLDL-C) [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in VLDL-C values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.

4. Percent Change From Baseline in Lipid Parameters - Apo-B [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in Apo-B values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.

5. Percent Change From Baseline in Lipid Parameters - Apo-CIII [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in Apo-CIII values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.

6. Percent Change From Baseline in Lipid Parameters - Lipoprotein [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in Lipoprotein values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.

7. Percent Change From Baseline in Lipid Parameters -Remnant-Like Particles-Cholesterol (RLP-C) [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in RLP-C values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.

8. Percent Change From Baseline in Lipid Parameters - Total Cholesterol (TC) [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in TC values as one of lipid parameters at final assessment point (up to Month 12) was reported.

9. Percent Change From Baseline in Lipid Parameters - Non-HDL Cholesterol (Non-HDL-C) [Baseline, up to 12 months (Final Assessment Point)]

   Percent change from baseline in Non-HDL-C values as one of lipid parameters at final assessment point (up to Month 12) was reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with hyperlipidemia

Exclusion Criteria:

1. Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage)

2. Patients with a history of hypersensitivity to ingredients in granular capsule formulation of omega-3 fatty acid ethyl esters

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Osaka		Japan
2		Tokyo		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Apr 2, 2018
• Statistical Analysis Plan - Sep 22, 2017

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02153073
• Other Study ID Numbers: 142-011; JapicCTI-142457
• First Posted: Jun 2, 2014
• Last Update Posted: Jul 18, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Pharmacological therapy
• Additional relevant MeSH terms: Hyperlipidemias

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 570 investigative sites in Japan, from 29 May 2013 to 31 May 2017.
Pre-assignment Detail	Participants with a historical diagnosis of hyperlipidemia were enrolled. Participants received interventions as part of routine medical care.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Period Title: Overall Study
STARTED	3084
COMPLETED	2786
NOT COMPLETED	298

Baseline Characteristics

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Overall Participants	2786
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	66.2 (13.27)
Sex: Female, Male (Count of Participants)
Female	1382 49.6%
Male	1404 50.4%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Number) [Number]
Japan	2786 100%
Healthcare Category (Count of Participants)
Outpatient	2765 99.2%
Inpatient	21 0.8%
BMI (Kilograms (kg)/meter (m)^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms (kg)/meter (m)^2]	24.94 (4.097)
Medical Complications (Count of Participants)
Had No Presence of Medical Complications	566 20.3%
Had Presence of Medical Complications	2220 79.7%
Drinking Habits (Count of Participants)
Yes	687 24.7%
No	1609 57.8%
Unknown	490 17.6%
Triglycerides (TG) in Fasted Condition [Milligrams (mg)/ Deciliter (dL)] (Count of Participants)
< 150 mg/dL	298 10.7%
>= 150 mg/dL and < 400 mg/dL	824 29.6%
>= 400 mg/dL and < 500mg/dL	64 2.3%
>= 500 mg/dL and < 750mg/dL	43 1.5%
>= 750mg/dL	16 0.6%
Not Measured	1541 55.3%
TG in Non-Fasted Condition (mg/dL) (Count of Participants)
< 150 mg/dL	287 10.3%
>= 150 mg/dL and < 400 mg/dL	762 27.4%
>= 400 mg/dL and < 500mg/dL	78 2.8%
>= 500 mg/dL and < 750mg/dL	82 2.9%
>= 750mg/dL	31 1.1%
Not Measured	1546 55.5%
Smoking Classification (Count of Participants)
Never Smoked	1430 51.3%
Current Smoker	307 11%
Ex-Smoker	496 17.8%
Unknown	553 19.8%
Predisposition to Hypersensitivity (Count of Participants)
Had No Predisposition to Hypersensitivity	2520 90.5%
Had Predisposition to Hypersensitivity	133 4.8%
Unknown	133 4.8%
Duration of Diagnosis of Hyperlipidemia (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	3.13 (4.755)
Surgery within One Month before Dosing (Count of Participants)
Had No Surgery within One Month before Dosing	2762 99.1%
Had Surgery within One Month before Dosing	24 0.9%
Pregnancy Status during the Administration Period (Count of Participants)
Not Pregnant	1381 49.6%
Pregnant	1 0%

Outcome Measures

1. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - Triglycerides (TG)
Description	Percent change from baseline in TG values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	1018
Mean (Standard Deviation) [Percent change]	-20.54 (40.259)

2. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - LDL Cholesterol (LDL-C)
Description	Percent change from baseline in LDL-C values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	469
Mean (Standard Deviation) [Percent change]	7.73 (82.486)

3. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - VLDL Cholesterol (VLDL-C)
Description	Percent change from baseline in VLDL-C values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	22
Mean (Standard Deviation) [Percent change]	-14.15 (57.833)

4. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - Apo-B
Description	Percent change from baseline in Apo-B values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	35
Mean (Standard Deviation) [Percent change]	-7.21 (12.979)

5. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - Apo-CIII
Description	Percent change from baseline in Apo-CIII values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	31
Mean (Standard Deviation) [Percent change]	-5.49 (23.117)

6. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - Lipoprotein
Description	Percent change from baseline in Lipoprotein values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	28
Mean (Standard Deviation) [Percent change]	-2.98 (28.385)

7. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters -Remnant-Like Particles-Cholesterol (RLP-C)
Description	Percent change from baseline in RLP-C values as one of lipid parameters in fasted condition at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	39
Mean (Standard Deviation) [Percent change]	-22.42 (94.776)

8. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - Total Cholesterol (TC)
Description	Percent change from baseline in TC values as one of lipid parameters at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	1327
Mean (Standard Deviation) [Percent change]	-4.26 (17.488)

9. Secondary Outcome

Title	Percent Change From Baseline in Lipid Parameters - Non-HDL Cholesterol (Non-HDL-C)
Description	Percent change from baseline in Non-HDL-C values as one of lipid parameters at final assessment point (up to Month 12) was reported.
Time Frame	Baseline, up to 12 months (Final Assessment Point)

Outcome Measure Data

Analysis Population Description

Efficacy assessment population; The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available. The analyzed numbers were participants who were evaluable for this outcome measure at the given time point.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	51
Mean (Standard Deviation) [Percent change]	-1.42 (23.495)

10. Primary Outcome

Title	Number of Participants Who Had One or More Adverse Events (AE) and Serious Adverse Events (SAE)
Time Frame	Up to Month 12

Outcome Measure Data

Analysis Population Description

Safety Analysis Set; The safety analysis set was defined as all participants who completed the study.

Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
Measure Participants	2786
AE	130 4.7%
SAE	26 0.9%

Adverse Events

Time Frame	Up to Month12
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Omega-3 Fatty Acid Ethyl Esters 2 g
Arm/Group Description	Oral administration with granular capsule formulation of 2 g of omega-3 fatty acid ethyl esters once daily for 12 months. Participants received interventions as part of routine medical care.
All Cause Mortality
	Omega-3 Fatty Acid Ethyl Esters 2 g
	Affected / at Risk (%)	# Events
Total	10/2786 (0.4%)
Serious Adverse Events
	Omega-3 Fatty Acid Ethyl Esters 2 g
	Affected / at Risk (%)	# Events
Total	26/2786 (0.9%)
Cardiac disorders
Angina pectoris	2/2786 (0.1%)
Atrial fibrillation	2/2786 (0.1%)
Cardiac failure acute	1/2786 (0%)
Myocardial infarction	4/2786 (0.1%)
Gastrointestinal disorders
Diarrhoea	1/2786 (0%)
Rectal prolapse	1/2786 (0%)
General disorders
Asthenia	1/2786 (0%)
Death	1/2786 (0%)
Drowning	1/2786 (0%)
Hepatobiliary disorders
Liver injury	1/2786 (0%)
Infections and infestations
Sinusitis	1/2786 (0%)
Injury, poisoning and procedural complications
Road traffic accident	1/2786 (0%)
Subdural haematoma	1/2786 (0%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	1/2786 (0%)
Hypoalbuminaemia	1/2786 (0%)
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis	1/2786 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer	1/2786 (0%)
Oesophageal carcinoma	1/2786 (0%)
Lung neoplasm malignant	1/2786 (0%)
Nervous system disorders
Dementia	1/2786 (0%)
Transient ischaemic attack	1/2786 (0%)
Renal and urinary disorders
Cystitis haemorrhagic	1/2786 (0%)
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	1/2786 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/2786 (0%)
Vascular disorders
Deep vein thrombosis	1/2786 (0%)
Other (Not Including Serious) Adverse Events
	Omega-3 Fatty Acid Ethyl Esters 2 g
	Affected / at Risk (%)	# Events
Total	38/2786 (1.4%)
Gastrointestinal disorders
Diarrhoea	9/2786 (0.3%)
Nausea	9/2786 (0.3%)
Hepatobiliary disorders
Hepatic function abnormal	7/2786 (0.3%)
Infections and infestations
Bronchitis	7/2786 (0.3%)
Viral upper respiratory tract infection	6/2786 (0.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.