CTRI/2020/06/025583 [Registered on: 03/06/2020] Trial Registered Prospectively
Last Modified On:
28/05/2020
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
A study to evaluate the blood levels of Dolutegravir Dispersible Tablet 10mg (test) compared to the Reference 02 tablets of Dolutegravir Dispersible Tablet 5mg in healthy subjects (fasting)
Scientific Title of Study
Single dose Fasting In-Vivo Bioequivalence study of Dolutegravir Sodium Dispersible Tablet 10 mg
(Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir 5mg dispersible tablets
manufactured by GlaxoSmithKline, UK on behalf of ViiV Healthcare, UK in healthy, adult, human male
subjects.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
BEQ-2602-DOLU-2019, V-02, Dated - 11/03/2020
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Channabasayya Hiremath
Designation
Principal Investigator
Affiliation
Macleods Pharmaceuticals Ltd.
Address
Bioequivalence Department, R & D: II, Plot no. 95, Road no. 16, Opp.Suncity Hotel,MIDC, Andheri (East)
Mumbai (Suburban) MAHARASHTRA 400093 India
Phone
91-22-67258412
Fax
Email
drchannabasayyah@macleodspharma.com
Details of Contact Person Scientific Query
Name
Dr Channabasayya Hiremath
Designation
Principal Investigator
Affiliation
Macleods Pharmaceuticals Ltd.
Address
Bioequivalence Department, R & D: II, Plot no. 95, Road no. 16, Opp.Suncity Hotel,MIDC, Andheri (East)
MAHARASHTRA 400093 India
Phone
91-22-67258412
Fax
Email
drchannabasayyah@macleodspharma.com
Details of Contact Person Public Query
Name
Dr Channabasayya Hiremath
Designation
Principal Investigator
Affiliation
Macleods Pharmaceuticals Ltd.
Address
Bioequivalence Department, R & D: II, Plot no. 95, Road no. 16, Opp.Suncity Hotel,MIDC, Andheri (East)
Bioequivalence Department, R & D: II, Plot no. 95,Road no. 16, Opp. Suncity Hotel,MIDC, Andheri - (East) Mumbai (Suburban) MAHARASHTRA
91-22-67258412
drchannabasayyah@macleodspharma.com
Details of Ethics Committee
No of Ethics Committees= 1
Name of Committee
Approval Status
Human Care Independent Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Healthy Human Volunteers
Fasting
Intervention / Comparator Agent
Type
Name
Details
Intervention
Dolutegravir sodium Dispersible Tablet 10mg
To determine bioequivalence.
Dose - 01 dispersible tablet Frequency - single dose (01 tablet) in Period I / II
Route of administration - Oral
Comparator Agent
Dolutegravir sodium Dispersible Tablet 5mg
To determine Bioequivalence
Dose - 02 dispersible tablets. Frequency - Single dose (02 tablets) in period I / II. Route of Administration - Oral
Inclusion Criteria
Age From
18.00 Year(s)
Age To
45.00 Year(s)
Gender
Male
Details
1. Healthy human male volunteers within the age range of 18 to 45 years.
2. Presently non-tobacco users (smokers and chewers).
3. Willingness to provide written informed consent to participate in the study.
4. Body-mass index (BMI) between 18.50 kg/m2 and 29.99 kg/m2 (both inclusive) with body weight not
less than 50 kg.
5. Absence of significant disease or abnormal laboratory values or laboratory evaluation, medical
history or physical examination during the screening.
6. Have a normal 12-lead ECG or one with abnormality considered to be clinically insignificant.
7. Have a normal chest X-ray PA view or one with abnormality considered to be clinically insignificant.
8. Comprehension of the nature and purpose of the study and compliance with the requirement of the
distributed ICF.
ExclusionCriteria
Details
1. Personal history of allergy or hypersensitivity to Dolutegravir or allied drugs or excipients (D-Mannitol,Microcrystalline Cellulose, Povidone, Sodium Starch Glycolate, Silicified Microcrystalline Cellulose,Crospovidone, Calcium Sulfate Dihydrate, Sucralose, Strawberry Cream Flavour, Sodium Stearyl Fumarate, White film coat (Contains: Hypromellose, Polyethylene Glycol and Titanium Dioxide)].
2. Any major illness in the past 90 days or any clinically significant ongoing chronic medical illness e.g.Congestive Cardiac Failure, Hepatitis, Hypotensive episodes, Hyperglycemia etc.
3. Presence of any abnormal laboratory values during screening e.g. abnormality of liver function test,renal function test etc.
3.1 Alanine transaminase (ALT) >1.5x upper limit of normal (ULN)
3.2 Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
3.3 Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilberts syndrome or asymptomatic gallstones)
4. Severe cardiac, renal or liver impairment, gastro-intestinal disease or other conditions, any other organ or system impairment.
5. History of seizures, epilepsy or any kind of Neurological disorders.
6. Past history of Anaphylaxis or Angioedema.
7. Presence of disease markers of HIV or Hepatitis B or Hepatitis C virus.
8. History of chronic consumption of any kind of alcoholic beverages for more than 2 years or having consumed alcohol within 48 hours prior to dosing.
9. Consumption of products containing xanthine derivatives (chocolates, tea, coffee or cola drinks) or tobacco products within 48 hours prior to dosing.
10. Consumption of grapefruit or grapefruit containing products or any cruciferous vegetables (eg.broccoli, brussels sprouts, etc.) or char-broiled meat prior 7 days of investigational product administration.
11 . Use of any recreational drug or a history of drug addiction.
12. Participation in any clinical trial within the past 90 days.
13. History of difficulty with donating blood or difficulty in accessibility of veins in left or right arm.
14. Donation of blood (one unit or 350 ml) within 90 days prior to receiving the first dose of study
medication.
15. Consumption of any other prescription drug or over the counter (OTC) drugs (including vitamins and
medicinal products from natural origin) within two weeks prior to receiving the first dose of study
medication or repeated use of drugs within the last four weeks and throughout subjects participation in the study.
16. Consumption of products (medicines or supplements) containing Ca/Fe/Mg within 48 hours prior to dosing.
17. An unusual diet for whatever reason e.g. low sodium diet, for two weeks prior to receiving any
medication and throughout subjects participation in the study.
18. Recent history of dehydration from diarrhoea, vomiting or any other reason within a period of 48
hours prior to the study.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
An Open list of random numbers
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
To evaluate the comparative oral bioavailability
of single dose of Dolutegravir Sodium Dispersible Tablet 10 mg
(Macleods Pharmaceuticals Ltd., India) with two tablets of
Dolutegravir Dispersible Tablet 5 mg Dolutegravir 5mg dispersible
tablets manufactured by GlaxoSmithKline, UK on behalf of ViiV
Healthcare, UK in healthy, adult, human male subjects under fasting
condition.
Blood collection will be done as per sampling schedule till 72hrs. After completion of study, bioanalytical evaluation will be conducted. After completion - comparative oral bioavailability will be evaluated.
Secondary Outcome
Outcome
TimePoints
To monitor the safety and tolerability of a single oral dose
of Dolutegravir Sodium Dispersible Tablet 1 O mg and two tablets of
Dolutegravir 5mg dispersible tablets when administered in healthy,
adult, human male subjects under fasting condition.
The safety and tolerability will be monitored throughout the study period i.e. 12 days. After completion of study it will be further monitored for a period of 4 days.
Target Sample Size
Total Sample Size="24" Sample Size from India="24" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Phase of Trial
N/A
Date of First Enrollment (India)
08/06/2020
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
Date Missing
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="0" Months="1" Days="0"
Recruitment Status of Trial (Global)
Not Applicable
Recruitment Status of Trial (India)
Not Yet Recruiting
Publication Details
Publication of the results of the study, whether in whole or in part, shall be within the sole and
absolute discretion of Sponsors and Bioequivalence department of Macleods Pharmaceuticals Ltd.
shall not be entitled to publish any of the data or information arising during or out of the provision of
the services without the prior written consent of Sponsor. For the avoidance of doubt, Sponsors
reserves the unqualified right to reject any papers or articles utilizing any data generated from the
services before such paper or article is presented or submitted for publication.
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
Study Title: Single dose Fasting In-Vivo Bioequivalence study of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir 5mg dispersible tablets manufactured by GlaxoSmithKline, UK on behalf of ViiV Healthcare, UK in healthy, adult, human male subjects. Study Design: An open label, balanced, analyst blind, randomized, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study on 24 healthy, adult, human male subjects under fasting condition. Objective: i) Pharmacokinetic: To evaluate the comparative oral bioavailability of single dose of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg Dolutegravir 5mg dispersible tablets manufactured by GlaxoSmithKline, UK on behalf of ViiV Healthcare, UK in healthy, adult, human male subjects under fasting condition. ii) Safety: To monitor the safety and tolerability of a single oral dose of Dolutegravir Sodium Dispersible Tablet 1 O mg and two tablets of Dolutegravir 5mg dispersible tablets when administered in healthy, adult, human male subjects under fasting condition. Number of Subjects- 24 Study Duration - Total 12 days approximately for each group with 7 days washout. If period II is scheduled later the duration of study will change accordingly. Diagnosis and main Criteria for Inclusion- Healthy human male subjects within the age range of 18 to 45 years with body-mass index (BMI) between 18.50 kg/m2 and 29.99 kg/m2 (both inclusive) with body weight not less than 50 kg and having absence of significant disease, laboratory values within normal range, absence of clinically significant medical history and normal physical examination during the screening and complying with inclusion and exclusion criteria. lnvestigational Product Administration: An oral dose of Reference product (R) or Test product (T) will be administered as per the randomization schedule. Subjects will receive the alternate ’treatment’ in both the periods in such a way that each subject will receive both the treatment test and reference each, by the end of the study. Note: Test and Reference tablets will be dispersed one minute prior to dosing in 50 ml of drinking water. Allow the tablets to disintegrate and stir gently and keep ready solution for dosing. lnvestigational Products: i) Test Formulation (T) : Dolutegravir Sodium Dispersible Tablet 10 mg Batch number: N/AV Mfg. Date: N/AV Exp. Date: N/AV Manufactured by: Macleods Pharmaceuticals Ltd., India Dose: 1 Dispersible Tablet Mode of administration: The dispersible tablets will be dispersed in 50 ml of water and will be administered to the subjects, followed by rinsing of the administration device with an additional 50 ml of water and will be administered to the subjects.
ii) Reference Formulation (R) : Dolutegravir (GSK1349572) Dispersible Tablet 5 mg Lot No: N/AV Mfg. Date: N/AV Exp. Date: N/AV Manufactured for: ViiV Healthcare UK limited, 980 Great West Road , Brentford, TW8 9GS Manufactured by: GlaxoSmithKline Research & Development Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, Tel. +44 2080475000 Manufacturing site: Glaxo Operations UK Limited (trading as Glaxo Wellcome Operations), Priory Street, Ware, Hertfordshire, SG12 ODJ, Tel. +44 1920 56933 Dose: 2 Dispersible Tablets Mode of administration: The dispersible tablets will be dispersed in 50 ml of water and will be administered to the subjects, followed by rinsing of the administration device with an additional 50 ml of water and will be administered to the subjects.
Dietary Plan- The dose will be administered after an overnight fast of at least 10 hours in each period. Fasting will continue for at least four hours post-dose, then meals will be provided approximately at 4.00, 8.00 and 13.00 hours post-dose on dosing day (day 1) and at 24.50, 28.50, 32.00 and 37.00 hours post dose on day 2 of each period.
Study Restriction- Drinking water will be disallowed for 1.00 hour prior to dosing and until 2.00 hour post-dose except 100 ml of water at the time of dosing. Also, no food will be permitted until about 4 hours post-dose. Record should be maintained for timing, duration and amount of food and fluid consumed. Subjects will be dosed while in upright sitting posture and will be instructed to remain seated or be ambulatory (avoiding any strenuous activity and during recording of vitals) for first two hours following the investigational product administration. During this interval, under supervision, subjects will be permitted to use the washroom facilities. Thereafter the subjects will be allowed to engage only in normal activities while avoiding severe physical exertion. However should any adverse event occur at any time during housing the subjects will be placed in an appropriate posture.
Collection Schedules:Blood samples (1x 5 mL) will be collected in 5
mL blood collection tube containing K2EDTA as anticoagulant during
each period. The venous blood samples will be withdrawn pre-dose and at 0.08,
0.17, 0.33, 0.50, 0.75, 1.00, 1.33, 1.67, 2.00, 2.50, 3.00, 4.00, 6.00,
8.00, 10.00, 14.00, 18.00, 24.00, 36.00, 48.00 and 72.00 hours post dose (time points being
relative to the investigational product dosing).
Note:
During each ambulatory visit blood sample will be collected-1.00 hour to + 2.00 hours of the
scheduled time.
During
check out of period I, 6 mL blood will be collected in plain tubes for liver
function test (SGPT, SGOT and GGT).
Blood Loss:For each
subject, the total number of blood draws will be 44 (22 per period). The total
volume of blood withdrawn will not exceed 260 mL (including 13 mL for safety
assessment, 6 mL blood for liver function test (SGPT, SGOT and GGT) and 21 mL discarded
normal saline blood). Should circumstances arise, like breakage of tube after
collection, adverse event (including abnormal laboratory values) where more
blood needs to be withdrawn, additional blood samples may be taken. The consent
of the subject would be taken and the IEC would be informed and subject will be
compensated accordingly.
Handling of Blood Samples:The blood samples
collected at each time point will be centrifuged between 4 to 8 °C (short term excursion permitted up to 10°C) and at 4000 rpm for
10 minutes to separate plasma. For ambulatory samples, the samples
collected till the scheduled time of last subject will be centrifuged together
and the samples collected later will be centrifuged separately according to
their collection time. Blood samples will be
centrifuged within 30 minutes after collection of last blood sample; if there
is any delay in centrifugation then sample will be kept in cold condition. The
separated plasma will be aliquoted in duplicate in prelabelled polypropylene
tubes during each period. These tubes will be labelled with Study Number, Period Number, Subject
Number, Sample Number, Time Point (hrs) and Aliquot Number.
These
tubes will then be transferred to a deep freezer set at -75°C for storage.
Washout Period:There will be
washout period of at least 7 days from the completion of dosing between two
periods.
Safety Assessment:In each period, subject
questionnaire and vital signs (Blood pressure, Temperature and Pulse
Rate) will be done at the time of check-in, pre-dose
and at 3.00, 6.00, 10.00, 26.00, 35.00, 47.00 and 72.00 hours post-dose (Time points being relative to the investigational
product dosing).
Clinical Residency:Subject will be
admitted and housed in the facility sufficient time before to maintain 10 hours
fasting condition before the administration of dose and until 48 hours
post-dose, during each period of the study. The subjects will visit the centre
for ambulatory blood sample collection at 72.00 hours post dose.
Bioanalytical Method:Dolutegravirwill be estimated in
plasma using validated LC-MS/MS method.
Pharmacokinetic
Parameters:1) Primary parameters:
Cmax, AUC0-t and AUC0-inf.
Statistical Analysis:Summary
statistics, ANOVA, Intra subject variability, and 90% confidence interval will
be calculated using SAS® Linear & semi log graphs will be plot
using SAS®.
Criteria for Bioequivalence: The 90% confidence interval
for Cmax, AUC0-t and AUC0-inf of Dolutegravir
will
form the basis for concluding the bioequivalence ofDolutegravir Sodium in product R and T. If the
90% confidence intervals are entirely included in the range of 80.00% – 125.00%
for log-transformed Cmax, AUC0-t
and AUC0-inf then the products will be claimed to be
bioequivalent.