An open-label, balanced, randomized, single oral dose, two treatment, two-period, two-sequence, two way crossover, bioavailability study of Narpega oral liquid 40 ML (each 10 ml contains at least 900mg of ethyl esters of omega-3 fatty acids and quercetin 14mg) of KMS Health Center Pvt. Ltd. and LOVAZA® 4 x 1 gram capsule (each 1gm capsule contains at least 900mg of the ethyl esters of omega-3 fatty acids) of GlaxoSmithKline (Woodward Pharma) along with 1 Capsule of Quercetin capsule 56mg of KMS Health Center Pvt. Ltd., in healthy, adult, human subjects under fasting conditions.
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- To evaluate the bioavailability of Narpega oral liquid 40 ML (each 10 ml contains at least 900mg of ethyl esters of omega-3 fatty acids and quercetin 14mg) of KMS Health Center Pvt. Ltd. and LOVAZA® 4 x 1 gram capsule (each 1gm capsule contains at least 900mg of the ethyl esters of omega-3 fatty acids) of Glaxosmithkline (Woodward Pharma) along with 1 Capsule of Quercetin capsule 56mg of KMS Health Center Pvt. Ltd., in healthy, adult, human subjects under fasting conditions.
Study Overview
Brief Summary
| Study Title |
An open-label, balanced, randomized, single oral dose, two treatment, two-period, two-sequence, two way crossover, bioavailability study of NARPEGA ORAL LIQUID 40 ML (each 10 ml contains at least 900mg of ethyl esters of omega-3 fatty acids and quercetin 14mg) of KMS Health Center Pvt. Ltd. and LOVAZA® 4 x 1 GRAM CAPSULE (each 1gm capsule contains at least 900mg of the ethyl esters of omega-3 fatty acids) of GlaxoSmithKline (Woodward Pharma) along with 1 Capsule of QUERCETIN CAPSULE 56MG of KMS Health Center Pvt. Ltd., in healthy, adult, human subjects under fasting conditions
|Objective
The objectives of this study are:
1.To evaluate the bioavailability of NARPEGA ORAL LIQUID 40 ML (each 10 ml contains at least 900mg of ethyl esters of omega-3 fatty acids and quercetin 14mg) of KMS Health Center Pvt. Ltd. and LOVAZA® 4 x 1 GRAM CAPSULE (each 1gm capsule contains at least 900mg of the ethyl esters of omega-3 fatty acids) of GlaxoSmithKline (Woodward Pharma) along with 1 Capsule of QUERCETIN CAPSULE 56MG of KMS Health Center Pvt. Ltd., in healthy, adult, human subjects under fasting conditions.
2.To monitor the adverse events and ensure safety of subjects.
|Investigational Products
Test Product (T) : NARPEGA ORAL LIQUID 40 ML (each 10 mL contains at least 900mg of ethyl esters of omega-3 fatty acids and quercetin 14mg)
Manufactured by: KMS Health center Pvt. Ltd.
Reference Product (R): LOVAZA® 4 X 1 GRAM CAPSULE (each 1gm capsule contains at least 900mg of the ethyl esters of omega-3 fatty acids)
Manufactured By: GlaxoSmithKline (Woodward Pharma)
Along with
1 CAPSULE OF QUERCETIN CAPSULE 56MG
Manufactured By: KMS Health center Pvt. Ltd.
|Study Design
An open-label, balanced, randomized, single oral dose, two-treatment, two-period, two-sequence, two way crossover, bioavailability study in healthy, adult, human subjects under fasting conditions.
|Investigators
Principal Investigator : Dr. Koripalli Sudhakar Reddy, M.B.B.S.
Clinical Investigators : Dr. Madan Kartiya, M.B.B.S.
Bio-analytical Investigator : Mr. A. Nagoor Meeran, B.Sc.
PK & Statistical Investigator : Ms. Latha Kommu, M.Sc
|Study Population
12 Normal healthy, adult, human subjects will be enrolled in this study.
|Screening Procedures
Demographic data, medical history and physical examination, 12-lead ECG, hematology, biochemistry, urine analysis, Lipid profile tests, [Urine and serum beta HCG test & Hormone assay (FSH & LH- for female subjects)], serology will be done within 21 days and chest X-ray within 06 months prior to check-in.
|Housing
The subjects will be housed in the clinical facility from at least -36.00 hours pre-dose to 48.00 hours post-dose in each period.
Subjects will have to stay for 04 consecutive nights and 03 consecutive days in the facility in each period.
|Wash out period
There will be a washout period of at least 07 days between the successive dosing days
|Study duration
At least 12 days for the entire study.
| Diet, Water and Restriction
During the entire in-house stay from -36.00 hrs prior to dosing till 48.00 hrs post-dose, all subjects will be provided with standard low fat diet. Subjects will be instructed to avoid consumption of fish and fish oil from 03 weeks prior to the dosing. They will also be instructed to consume diet with limited content of fish and fish oil after check-out of till two weeks after the study completion.
During screening, wash out period and check-out till 48.00 hrs post-dose in each period subjects will be advised to consume diet with limited content of fish and fish oil.
In each period of the study, subjects will be fasted for at least 10.00 hours prior to dosing to 04.00 hours post-dose.
Standard meals will be served at around -35.00, -24.00, -20.00, -16.00,
-12.00 hrs pre-dose and at 04.00, 08.00, 12.00, 24.00, 28.00, 32.00 and 36.00 hours post-dose, in each period.
Water will be restricted to at least 01.00 hour prior to dosing until 01.00 hour post-dose (Except for water given during dosing). Free access to water will be allowed after 01.00 hour post-dose.
Subjects will be instructed to abstain from consuming caffeine and /or xanthine containing products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.), alcohol and vitamin supplements including vitamin C and ascorbic acid for at least 24 hours. Grapefruit and/or its juice and poppy containing foods at least 72.00 hours prior to check-in and throughout the study. Subjects will be instructed to avoid consumption of fish and fish oil from 03 weeks prior to the check-in.
|Postural Restrictions
Subject will remain seated upright for first 04.00 hours post-dose and only necessary movement will be allowed during this period. Thereafter subjects will be allowed to move freely during the remaining part of the study. Subject will not be allowed to lie down (except as directed by the physician secondary to adverse events) during restriction period.
| Restrictions to medicines
Subjects will be selected on the basis of abstinence from any prescription medications within 14 days prior to study check in and they will be instructed not to take prescription medications throughout the study. Subjects will be instructed not to take any over the counter medicinal products, herbal medications throughout the study and they will be selected on the basis of abstinence from over the counter medicinal products, herbal medications 07 days prior to study.
|Method of administration
In each period, after overnight fasting of at least 10.00 hours, in the morning, a single dose of either test product (T) (40 mL – oral liquid) or reference product (R) (4+1 = 5 capsules) (according to the randomization schedule) will be administered with 240 ± 2 mL of water at ambient temperature to the subjects, in sitting posture, under the supervision of investigator/medical officer and trained study personnel including Auditor(s) from the Quality Assurance department.
This activity will be followed by mouth check with the help of tongue depressor to assess compliance to dosing.
Note:
•Dosing should be done under monochromatic light or low light condition.
|Safety Assessment
. 1. Medical examination– Before check-in, before check-out (48.00 hrs) of each period and at any other time if necessary.
-
Vitals – will be recorded at the time of check-in, before check-out (48.00 hrs), -24.00, -18.00, -12.00, 00.00 hours prior to dosing and at 01.00, 04.00, 08.00, 12.00, 24.00, 36.00 and 48.00 hours post dose and at any other time if necessary. Pre-dose vital sign measurement will be recorded within 75 minutes before dosing and post-dose vital sign measurements will be recorded within ± 40 minutes for in house vital signs.
-
Wellbeing questionnaire:
At the time of pre dose and post dose vital signs recording.
- Post Study and during study Assessments :
Bloodsample for post study and during study lab assessments will be collected at the time of last blood sample collection (48.00 hours post-dose of Period II) or at any time the particular subject is withdrawn or dropped-out from the study to assess for laboratory parameters of hematology, biochemistry and Lipid profile test.
-
Stress oxidative level will be studied at predose, period I & period II.
-
Adverse event monitoring will be done throughout the entire study duration (clinical phase).
|Sampling
In each period, 23 blood samples per subject will be collected at scheduled sampling points. The pre-dose (-24.00, -12.00, -06.00 and
-01.00) blood sample (06 mL) will be collected prior to dosing and (00.00 hr) blood sample will be collected within 05 to 10 minutes prior to dosing (06 mL). The post-dose blood samples (05 mL each) will be collected at 00.50, 01.00, 02.00, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 06.50, 07.00, 08.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours. All the samples will be collected in pre-labeled K2EDTA – Vacutainers via an indwelling cannula placed in one of the forearm veins of the subjects. Intravenous indwelling cannula will be kept in situ as long as possible by injecting 0.5 mL of 10 IU / mL of normal saline solution to maintain the cannula patent for collection of the post-dose samples. In such cases blood samples will be collected after discarding the first 0.5 mL of normal saline mixed blood. Cannula will be removed after -06.00 hour pre-dose sample is drawn and re-cannulation will be done before at
-01.00 hours and removed after 24.00 hour sample is drawn or earlier or if blocked. If required, sample may also be collected through a direct vein puncture. The samples at 36.00 and 48.00 hours post dose in each study period will be collected only by a direct vein puncture. Vacutainers will be placed upright in a rack kept in wet ice bath until centrifugation and during separation.
Sampling schedule statistics are mentioned in the table below.
| In-House |
Ambulatory
Total (Per Period)
|23
00
23
Note:
- Sampling should be done under monochromatic light or low light condition.
|Blood Loss
Not exceeding 279 mL for each subject for the entire study.
| Sample Processing
After collection of blood samples from all the subjects at each time point, study personnel will transfer the collected samples placed in a thermo-insulated box containing wet ice to the collected samples to a sample processing room where the blood samples will be centrifuged at 4000 ± 50 RPM for 10 minutes at 02°C to 08°C to separate the plasma. Centrifugation will start within 30 minutes of the collection of samples. The resulting plasma will be equally transferred into pre-labeled polypropylene tubes into two aliquots. 1500 μL from the separated plasma will be transferred into Aliquot I and the remaining plasma will be transferred Aliquot II.
These aliquots will be stored upright in a freezer at a temperature of -30°C ± 10°C for interim storage at the clinical site until transferred to analytical site.
At the end of the study, the samples will be transferred to the bioanalytical facility in a box containing sufficient dry ice to maintain the integrity of the samples. These samples will be stored at a temperature of –70°C ± 15°C in the bioanalytical facility until analysis.
The aliquots should be used for analysis as mentioned below:
· Aliquot I will be used for estimation of Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) as total lipids.
· Aliquot II will be used for estimation of Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) as free fatty acids.
Note: All activities including blood sample processing, segregation and plasma sample storage will be done under monochromatic light or low light condition.
| Bio-analytical procedure
For this study under fasted-state conditions, the concentration of following analytes will be estimated in plasma using validated LC-MS/MS method**:**
(1) EPA total lipids in plasma
(2) Baseline-adjusted EPA total lipids in plasma
(3) DHA total lipids in plasma
(4) Baseline-adjusted DHA total lipids in plasma
(5) EPA free fatty acids in plasma
(6) Baseline-adjusted EPA free fatty acids in plasma
(7) DHA free fatty acids in plasma
(8) Baseline-adjusted DHA free fatty acids in plasma
Note: Quercetin also analysed in plasma.
Note: All activities will be done under monochromatic light or low light condition.
|Pharmacokinetics and Statistical Methods
Employing the estimated concentration vs. time profiles using WinNonlin® version 5.3 or higher version of Pharsight Corporation, USA, the following pharmacokinetic parameters will be calculated:
(1) EPA total lipids in plasma
(2) Baseline-adjusted EPA total lipids in plasma
(3) DHA total lipids in plasma
(4) Baseline-adjusted DHA total lipids in plasma
(5) EPA free fatty acids in plasma
(6) Baseline-adjusted EPA free fatty acids in plasma
(7) DHA free fatty acids in plasma
(8) Baseline-adjusted DHA free fatty acids in plasma
Note: Quercetin also analysed in plasma.
For EPA and DHA:
Primary parameters: Cmax, AUC0-t and AUC0-8.
Secondary parameters: tmax, t½, Kel, Kel_lower, Kel_Upper and AUC_%Extrap_obs.
For Quercetin:
Primary parameters: Cmax and AUC0-8.
Statistical analyses will be done using SAS® system for windows version 9.4 or above (SAS® Institute Inc., USA).
|Bioavailability Criteria
The 90% confidence interval of the geometric least square mean ratios of the test and reference products should be within 80.00% to 125.00% for Ln-transformed data to establish the bioavailability.
|Ethical Issues
The study will commence only after a written approval is obtained from the Independent Ethics Committee (Chennai Ethics Committee). The study will be conducted as per the National Ethical Guidelines for Biomedical and Health Research involving Human participants ICMR (2017), ICH (Step 5) ’Guidance on Good Clinical Practice’, New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E) dated 19 Mar 2019, ’Good Laboratory Practice’, ‘Good Clinical Practices for Clinical Research in India’ Guidelines, Good Clinical Laboratory Practice (GCLP), Declaration of Helsinki (Fortaleza, October 2013) and 21 CFR part 50, 56 and 320-USFDA guidelines for Industry and other applicable regulatory requirements.
Study Design
- Study Type
- Interventional
Eligibility Criteria
- Ages
- 18.00 Year(s) to 45.00 Year(s) (—)
- Sex
- All
Inclusion Criteria
- •1.Healthy, adult, human volunteers of age 18- 45 years with a minimum weight of 55 kg for male and 50 Kg for female with a Body Mass Index (BMI) ranges between 18.50 kg/m2 to 24.90 kg/m
- •2.Subjects with Hemoglobin ≥ 12g/dl for male and ≥ 11g/dl for female.
- •3.Given written informed consent to participate in the study.
- •4.Willing to comply with all the requirements of this study protocol.
- •5.Subjects who have no evidence of underlying disease during screening and check-in and whose screening is performed within 21 days of check in.
- •6.Subjects whose screening laboratory values are within normal limits or considered by the physician or Principal/Clinical Investigator to be of no clinical significance (laboratory tests are presented in Annexure-IV).
- •7.Generally healthy as documented by the medical history, physical examination (including but may not be limited to an evaluation of the cardiovascular, gastrointestinal, respiratory, musculoskeletal and central nervous systems) and vital sign assessments.
- •8.Generally healthy as documented by 12-lead electrocardiogram (ECG), X-Ray and clinical laboratory assessments.
- •9.Non- smokers, non-alcoholics.
- •10.Subjects with normal limits or clinically non-significant laboratory evaluation results for follicle stimulating hormone (FSH) and luteinizing hormone (LH).
- •11.Female subjects of childbearing potential who; 12.Practice an acceptable non-hormonal contraceptive method of birth control after consulting with principal investigator; and/or 13.Surgically sterile (bilateral tubal ligation).
Exclusion Criteria
- •1.Has a history or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal (GI), endocrine, immunologic, dermatologic, neurological, or psychiatric disease.
- •2.Any major illness in the last three months or any significant ongoing chronic medical illness.
- •3.Has used fish oil, other EPA and/or DHA containing supplements within 3 weeks of check-in.
- •4.Any disease or condition which might compromise the haemopoeitic, gastrointestinal, renal, hepatic, cardiovascular, Musculoskeletal, respiratory, central nervous system, diabetes, psychosis or any other body system.
- •5.History of alcohol addiction.
- •6.History of Consumption of caffeine and /or xanthine products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) and tobacco containing products for at least 24.00 hours prior to check-in and throughout the study.
- •7.History of Consumption of grapefruit and/or its juice and poppy containing foods for at least 72.00 hours prior to check-in and throughout the study.
- •8.Subject who had participated in any other study within the 90 days of check-in.
- •9.History of difficulty in swallowing.
- •10.Any blood donation / excess blood loss within 90 days of check-in.
- •11.Severe hepatic dysfunction.
- •12.Patients with hereditary disease such as galactose intolerance, lactase deficiency, glucose-galactose malabsorption 13.Female subjects demonstrating a positive pregnancy screen.
- •14.Female subjects who are currently lactating.
- •15.Use of hormone replacement therapy within 06 months prior to check-in.
- •16.Female subjects with child bearing potential using prohibited contraceptive method (oral, injectable or implantable hormonal agents).
Outcomes
Primary Outcomes
To evaluate the bioavailability of Narpega oral liquid 40 ML (each 10 ml contains at least 900mg of ethyl esters of omega-3 fatty acids and quercetin 14mg) of KMS Health Center Pvt. Ltd. and LOVAZA® 4 x 1 gram capsule (each 1gm capsule contains at least 900mg of the ethyl esters of omega-3 fatty acids) of Glaxosmithkline (Woodward Pharma) along with 1 Capsule of Quercetin capsule 56mg of KMS Health Center Pvt. Ltd., in healthy, adult, human subjects under fasting conditions.
Time Frame: The post dose blood samples 05 mL each will be collected at 00.50, 01.00, 02.00, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 06.50, 07.00, 08.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours
Secondary Outcomes
- To monitor the adverse events and ensure safety of subjects.(The post dose blood samples 05 mL each will be collected at 00.50, 01.00, 02.00, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 06.50, 07.00, 08.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours)