CTRI/2021/04/033064 [Registered on: 23/04/2021] Trial Registered Prospectively
Last Modified On:
07/06/2021
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
Bioequivalence study of Abacavir, Dolutegravir and Lamivudine Tablets for Oral Suspension 60mg/5mg/30mg (1 × 5 Tablets) with comparision to the marketed product under fed conditions.
Scientific Title of Study
An open label, balanced, randomized, two-treatment, two-sequence, two-period, cross-over, single-dose, oral bioequivalence study of Abacavir, Dolutegravir and Lamivudine Tablets for Oral Suspension 60mg/5mg/30mg (1 × 5 Tablets) (Test) of Aurobindo Pharma Limited, India with Dolutegravir (GSK1349572)/Abacavir/Lamivudine Dispersible Tablets 5 mg/60 mg/30 mg (1 × 5 Tablets) (Reference) of ViiV Healthcare, UK in 14 healthy, adult, human subjects under fed conditions.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
214-20,Version 01, Dated 10Nov2020
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr M Gyaneshwar
Designation
Principal Investigator
Affiliation
Axis Clinicals Limited
Address
CU Department, First Floor, 1-121/1, Miyapur
Hyderabad TELANGANA 500049 India
Phone
9642990039
Fax
04040408060
Email
Gyaneswar.Mandugula@axisclinicals.com
Details of Contact Person Scientific Query
Name
Dr M Gyaneshwar
Designation
Principal Investigator
Affiliation
Axis Clinicals Limited
Address
CU Department, First Floor, 1-121/1, Miyapur
Hyderabad TELANGANA 500049 India
Phone
9642990039
Fax
04040408060
Email
Gyaneswar.Mandugula@axisclinicals.com
Details of Contact Person Public Query
Name
Dr M Gyaneshwar
Designation
Principal Investigator
Affiliation
Axis Clinicals Limited
Address
CU Department, First Floor, 1-121/1, Miyapur
Hyderabad TELANGANA 500049 India
Phone
9642990039
Fax
04040408060
Email
Gyaneswar.Mandugula@axisclinicals.com
Source of Monetary or Material Support
APL Research Centre,
Aurobindo Pharma Limited
Primary Sponsor
Name
APL Research Centre Aurobindo Pharma Limited
Address
Survey No. 313 & 314, Bachupally, Medchal-Malkajgiri District
Hyderabad–500 090, India.
Type of Sponsor
Pharmaceutical industry-Indian
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India
Sites of Study
No of Sites = 1
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr M Gyaneshwar
AXIS Clinicals Limited
CU Department, First Floor, 1–121/1, Miyapur Hyderabad -500 049 Hyderabad TELANGANA
Abacavir, Dolutegravir and Lamivudine Tablets for Oral Suspension 60mg/5mg/30mg
Five tablets of Abacavir,
Dolutegravir and Lamivudine
Tablets for Oral Suspension
60mg/5mg/30mg as a single
dose in a two period study with a wash out of 07 days between each period.
Five tablets of Dolutegravir (GSK1349572)/Abacavir/Lamivudine Dispersible Tablets 5 mg/60mg/30 mg as a single dose in a two period study with a washout of 07 days between each period.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
45.00 Year(s)
Gender
Both
Details
1.Healthy, adult, human subjects within the age range of 18 to 45 years (inclusive of both)
2.A body mass index within the range of 18.50-29.99 Kg/m2 (inclusive of both)
3.Participation is truly voluntarily
4.Given written informed consent to participate in the study
5.Absence of disease markers of HIV 1 and 2, hepatitis B and C virus and RPR
6.Absence of significant diseases and abnormalities in medical history, systemic and physical examination during the screening
7.Absence of clinically significant abnormal laboratory values on laboratory evaluation (any laboratory values which are beyond the normal ranges, have been evaluated with appropriate justification by the investigator/ physician) during screening (refer Appendix-V)
8.A normal 12-lead ECG
9.Normal values in the assessment of depression using depression scale (refer Appendix-XV) during check-in of each period
10.Normal values of Creatinine clearance (CrCl) test during period-I check-in
11.Normal levels of serum amylase test, serum creatine phosphokinase (CPK) test and serum triglycerides test during check-in of period-I
12.The subject is negative for the HLA-B X 5701 allele test
13.A normal chest X-ray (PA view) (done within past 06 months)
14.Compliance with requirement of the entire protocol
15.Individuals of childbearing potential may be eligible to enter and participate in the study if they are of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and equal to or older than 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy
16.Male subject should be agreed to use an approved form of birth control from period-I dosing till 01 month after the last dose of the study medication as a birth control restriction. Approved birth control methods (barrier forms) during this period are:
a.Male latex condom with or without spermicide
b.Condom with diaphragm
c.Have undergone vasectomy (vasectomy must have been done more than 06 months prior to first dosing)
17.Subjects who are able to read the medication guide (Appendix-XIII) and Informed Consent Document
ExclusionCriteria
Details
2.History or evidence of known hypersensitivity to Dolutegravir, Abacavir and Lamivudine or any component of the formulations
3.History or evidence of moderate to severe renal impairment or moderate to severe hepatic impairment
4.History or evidence of depression, suicidal ideation or behaviour
6.ytomegalovirus, pneumocystis jirovecii pneumonia or tuberculosis, Graves disease and polymyositis
7.History or evidence of unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypo-albuminemia, esophageal or gastric varices or persistent jaundice), cirrhosis, known biliary abnormalities (apart from hyperbilirubinemia or jaundice due to Gilberts syndrome or asymptomatic gallstones)
8.History or evidence of myocardial infarction
9.History or evidence of lactic acidosis and severe hepatomegaly with steatosis
10.History or evidence of pancreatitis
11.History or evidence of ALT greater than 1.5 ULN and or total bilirubin ALT greater than 1.5 at baseline
12.History or evidence of concomitant use of Dofetilide (or pilsicainide), Etravirine, Trimethoprim, Efavirenz, Nevirapine, Fosamprenavir/ ritonavir and Tipranavir/ ritonavir, Dalfampridine, Carbamazepine, Oxcarbazepine, Phenytoin, Phenobarbital, St. Johns wort (Hypericum perforatum), medications containing polyvalent cations (example: Mg or Al): Cation-containing antacids or laxatives, Sucralfate buffered medications, oral calcium and iron supplements, including multivitamins containing calcium or iron, Metformin, Rifampin, Methadone and Sorbitol
13.Blood pressure: Systolic greater than 140 mm Hg and less than 110 mm Hg, Diastolic less than 70 mm Hg and greater than 90 mm Hg
14.History of significant systemic diseases, seizures, psychiatric disorders, neurological disorders, metabolic disorders, nutritional disorders and/or allergic rash
15.Family history of neurological disorder
16.Habit of consuming high caffeine (more than 5 cups of coffee or tea per day) or tobacco (more than 9 cigarettes/ beedies/ cigars per day)
17.History of alcohol consumption for more than two units/day (1 unit equals to 30 mL of spirit or 1 pint of beer)
18.History of difficulty with donating blood or difficulty in accessibility of veins
19.Donation of blood (one unit or 350 mL) within 90 days prior to study check-in
20.History of addiction to any recreational drug or drug dependence
21.Participation in any clinical study within the past 90 days
22.An unusual or abnormal diet, for whatever reason for at least 48.00 hours prior to check-in of each period, example: fasting due to religious reasons
23.Use of any prescription drugs or over-the-counter drugs (example: cold preparations, antacid preparations, vitamins or natural products etc.) within 14 days prior to check-in of period-I and unwilling to refrain from the same till the entire duration of the study
24.Consumed food or beverages containing alcohol or xanthine products (chocolate, tea, coffee, cola or energy drinks), cigarettes or tobacco products for at least 48.00 hours prior to check-in of each period
25.Consumed grapefruit or grapefruit like citrus fruits (mosambi/ sweet lime) or juice for at least 48.00 hours prior to check-in of each period
26.History of dehydration from diarrhea, vomiting or any other reason for at least a period of 24.00 hours prior to check-in of each period
27.Use of pharmacological agents known to significantly induce or inhibit drug metabolizing enzymes within 14 days prior to check-in of period-I and unwilling to refrain from the same till the entire duration of the study
28.Positive results for drugs of abuse (benzodiazepines, cocaine, opioids, amphetamines, cannabinoids and barbiturates) in urine performed during the check-in of each period.
29.Positive results for urine alcohol test will be performed at the time of check in of each period.
30.Female volunteers demonstrating a positive pregnancy test during the check-in of each period.
31.Female volunteers who are pregnant, currently breast-feeding or who are likely to become pregnant during the study.
32.Female volunteers who have used implanted or injected hormonal contraceptives anytime during the 06 months prior to study or used hormonal contraceptives within 14 days before dosing.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Not Applicable
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
To demonstrate the bioequivalence between Test product (T): Abacavir, Dolutegravir and Lamivudine Tablets for Oral Suspension 60mg/5mg/30mg (1 × 5 Tablets) of Aurobindo Pharma Limited, India with that of Reference product (R): Dolutegravir (GSK1349572)/Abacavir/Lamivudine Dispersible Tablets 5 mg/60 mg/30 mg (1 × 5 Tablets) of ViiV Healthcare, USA in 14 healthy, adult, human subjects under fed conditions.
00.00 hours predose sample and post dose samples at 00.33, 00.67, 01.00, 01.33, 01.67, 02.00, 02.33, 02.67, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 08.00, 12.00, 18.00, 24.00, 36.00, 48.00 and 72.00 hours in each period
Secondary Outcome
Outcome
TimePoints
To monitor the subjects safety and tolerability of single-dose of investigational products (IPs).
Adverse events and clinically significant deviations from laboratory tests, physical examinations and vital signs will be reported for the evaluation of safety.
Throughout the study duration
Target Sample Size
Total Sample Size="14" Sample Size from India="14" Final Enrollment numbers achieved (Total)= "0" Final Enrollment numbers achieved (India)="14"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is
an open
label, balanced, randomized, two-treatment, two-sequence, two-period,
cross-over, single-dose, oral bioequivalence study of Abacavir, Dolutegravir
and Lamivudine Tablets for Oral Suspension 60mg/5mg/30mg (1 × 5 Tablets) (Test)
of Aurobindo Pharma Limited, India with Dolutegravir
(GSK1349572)/Abacavir/Lamivudine Dispersible Tablets 5 mg/60 mg/30 mg (1 × 5
Tablets) (Reference) of ViiV Healthcare, UK in 14 healthy, adult, human
subjects under fed conditions.There will be an allowed
screening period of 28 days before randomization. The subject selection will be
carried out based on 28 days of screening validity excluding day of screening
and check-in. This will be a two-period study and at least 07 days washout
period will be maintained between each treatment administration. During
screening, healthy subjects meeting all inclusion and none of the exclusion
criteria will be randomized. If the subject will pass
through all the screening criteria and is willing to participate in the study, the
PI will enroll the subjects into the study.After an overnight fast of at least 10.00 hours and exactly 30
minutes after serving of high fat, high calorie breakfast,, subjects will be
dosed with either a single oral dose of Test product (T) or Reference product
(R) with approximately 240 mL of drinking water at room temperature under
fasting conditions as per randomization schedule. Subjects should be required
to fast overnight for at least 10.00 hours before serving of high fat, high
calorie breakfast (before dosing) and a minimum of 04.00 hours after dosing.
Drinking water will not be permitted 01.00 hour before dosing and until 01.00
hour post-dose. At other times drinking water will be permitted ad libitum.A total of 46 blood samples (23
samples in each period) will be collected in pre-labelled vacutainer tubes
containing K2EDTA as an anti-coagulant. A single pre-dose (00.00 hour) blood
sample of 10 mL (2 × 5 mL vacutainers) will be collected in each period. The
post-dose blood samples of 5 mL each will be collected at 00.33, 00.67, 01.00,
01.33, 01.67, 02.00, 02.33, 02.67, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50,
06.00, 08.00, 12.00, 18.00, 24.00, 36.00, 48.00 and 72.00 hours in each period.
Subjects will be kept in house at least 11.00 hours before dose and until 48.00
hours post-dose in each period. Subjects will be required to visit the clinical
unit for ambulatory sample at 72.00 hours post-dose in each period. Blood
samples between 00.33 and 48.00 that are collected within 2 minutes of scheduled
time will not be considered as protocol deviations. For blood samples collected
at 72.00 hours which are collected within 30 minutes of the schedule time will
not be considered protocol deviation. Adequate amount but not more than 0.5 mL
of 5 IU/mL of heparin in normal saline solution will be injected through
indwelling cannula during the collection of multiple samples. In such a case,
the blood sample would be collected after discarding the first 0.5 mL of
heparinized blood from the tubing. Blood may also be withdrawn by a fresh clean
venepuncture either by using sterile syringe and needle or disposable
sterilized needle and vacutainer if the cannula becomes blocked. For each male
or female [physically incapable of becoming pregnant], the total volume of
blood withdrawn will be 286 mL (12 mL for screening,
4mL for HLAB*5701 test on the day of ICF, 4mL for Serum amylase test, serum
creatine phosphokinase (CPK) test, creatinine clearance (CrCl) test and serum
triglyceride test at period-I check-in, 20mL for Pre-dose samples, 110 mL for
Post-dose samples in period-I, 110mL for Post-dose samples in period-II, 18mL
for Heparinized blood and 8mL for post study safety assessments. Additional
blood sample may be collected for safety reasons as per investigator’s discretion.
The collected pharmacokinetic (PK) samples would be anaysed for
measurement of Dolutegravir, Abacavir and Lamivudine concentrations in plasma.
Tmax, Cmax, AUC0-t,
AUC0-∞, AUC %extrapolation, Kel and T½
will be determined from the plasma Dolutegravir,
Abacavir and Lamivudine concentration
data by using Phoenix WinNonlin software (or) SAS®
software version 9.4 or higher at
AXIS Clinicals Limited, Hyderabad
Summary statistics, ANOVA, 90% confidence
interval, ratio analysis, intra subject variability and power will be
calculated for Dolutegravir, Abacavir and Lamivudine pharmacokinetic data using SAS®
Version 9.4 or higher software at AXIS Clinicals Limited, Hyderabad.
The Test product (T) is considered
as bioequivalent to the Reference product (R) if the 90% confidence intervals (CI)
for geometric least square mean ratios of Ln-transformed parameters Cmax,
AUC0-t and AUC0-∞ of Dolutegravir,
Abacavir and Lamivudine falls
within the acceptance range of 80.00%-125.00%.