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CTRI Number  CTRI/2019/06/019953 [Registered on: 28/06/2019] Trial Registered Prospectively
Last Modified On:
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study    
Study Design  Randomized, Crossover Trial 
Public Title of Study   Bioequivalence Study of Dolutegravir Sodium Dispersible Tablet 10 mg (Fed) 
Scientific Title of Study   Single Dose fed In-Vivo Bioequivalence Study of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
BEQ-2502-DOLU-2018, V-02, Date- 21/12/2018  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Pratip Sen 
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  02267258412  
Fax    
Email  drvijay@macleodspharma.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Pratip Sen 
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  02267258412  
Fax    
Email  drvijay@macleodspharma.com  
 
Details of Contact Person
Public Query  
Name  Dr Pratip Sen 
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  02267258412  
Fax    
Email  drvijay@macleodspharma.com  
 
Source of Monetary or Material Support  
Macleods Pharmaceuticals Ltd G-2, Mahakali Caves Road, Shanti Nagar, Andheri - (East), Mumbai – 400 093, India. Telephone No.: 91-22-61132900 
 
Primary Sponsor  
Name  Macleods Pharmaceuticals Ltd 
Address  G-2, Mahakali Caves Road, Shanti Nagar, Andheri - (East), Mumbai – 400 093, India. Telephone No.: 91-22-61132900 
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 Pratip Sen  Macleods Pharmaceuticals Ltd.  Bioequivalence Department R & D: II, Plot no. 95, Road no. 16, Opp. Suncity Hotel, MIDC, Andheri - (East)
Mumbai (Suburban)
MAHARASHTRA 		 02267258412

drvijay@macleodspharma.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Human Care Independent Ethics Committe  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Healthy Human Volunteers  Fed 
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Dolutegravir Dispersible Tablet 5 mg   To determine bioequivalence 
Intervention  Dolutegravir Sodium Dispersible Tablet 10 mg   To determine bioequivalence 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  45.00 Year(s)
Gender  Male 
Details  The subjects will be included based on the following criteria:
1.Healthy 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 clinically significant 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  The subjects will be excluded based on the following criteria:
1.Personal history of allergy or hypersensitivity to Dolutegravir or allied drugs or excipients.
2.Any major illness in the past 90 days or any clinically significant ongoing chronic medical illness
3.Presence of any clinically significant abnormal laboratory values during screening
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 and history of head trauma.
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 or having consumed alcohol within 48 hours prior to dosing.
9.Consumption of products containing xanthine derivatives or tobacco products within 48 hours prior to dosing.
10.Consumption of grapefruit or grapefruit containing products or any cruciferous vegetables or char-broiled meat prior 7 days
11.Consumption of products containing Ca/Fe/Mg within 48 hours prior to dosing.
12.Use of any recreational drug or a history of drug addiction.
13.Participation in any clinical trial within the past 90 days.
14.History of difficulty with donating blood or difficulty in accessibility of veins in left or right arm.
15.Donation of blood within 90 days prior to receiving the first dose of study medication.
16.Consumption of any other prescription drug or over the counter (OTC) drugs and receiving dofetilide within two weeks prior to receiving the first dose of study medication.
17.An unusual diet for whatever reason e.g. low sodium diet.
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 Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects under fed condition.  To evaluate the comparative oral bioavailability of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects under fed condition. 
 
Secondary Outcome  
Outcome  TimePoints 
To monitor the safety and tolerability of single oral dose of Dolutegravir Sodium Dispersible Tablet 10 mg when administered in healthy, adult, male subjects under fed condition.  Throughout the study period and 5 drug half life 
 
Target Sample Size   Total Sample Size="12"
Sample Size from India="12" 
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)   15/07/2019 
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 fed In-Vivo Bioequivalence Study of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects.

 Study Design:

An open label, balanced, analyst blind, randomized, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study on 12 healthy, adult, male subjects under fed condition.

 Objective:                               

i) Pharmacokinetic: To evaluate the comparative oral bioavailability of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects under fed condition.

 ii) Safety: To monitor the safety and tolerability of single oral dose of Dolutegravir Sodium Dispersible Tablet 10 mg when administered in healthy, adult, male subjects under fed condition.

 Number of Subjects: 12

Study Duration: Total 12 days approximately with 7 days washout.

 Investigational 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 tablet will be dispersed in 50 mL of water and will be administered to the subjects, followed by rinsing of the administration device thrice with an additional 190 mL of water and will be administered to the subjects.

ii) Reference

Formulation (R)

:

Dolutegravir Dispersible Tablet 5 mg

Lot No: N/AV

Mfg. Date: N/AV

Exp. Date: N/AV

Manufactured by: GSK, Priory Street, Ware, Hertfordshire, SG12 0DJ

Dose: 2 Dispersible Tablets

Mode of administration: The dispersible tablet will be dispersed in 50 mL of water and will be administered to the subjects, followed by rinsing of the administration device thrice with an additional 190 mL of water and will be administered to the subjects.

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.

 Dietary Plan:

Following an overnight fast of at least 10 hours, subjects will start the recommended high fat, high calorie, non-vegetarian breakfast (comprising of 800 to 1000 kilocalories), 30 minutes prior to administration of the investigational product. Study subjects will eat this meal in 30 minutes or less. Fasting will continue for four hours post-dose, then meals will be provided at 5.00, 9.00 and 13.00 hours post dose on dosing day (day 1) and 24.50, 28.00, 32.00 and 37.00 hours post dose on day 2 during both the periods

 Study Restriction:

Drinking water will be disallowed for one hour pre-dose and one hour post-dose. Subsequently, drinking water will be provided ad libitum. Subjects will be dosed while in upright sitting posture and will be instructed to remain seated or be ambulatory (avoiding any strenuous activity) for first two hours following the investigational product administration (except during recording of vitals and blood collection time point).

 Collection Schedules:

Blood samples (1 ´ 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 0.50, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 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).  

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 46 (23 per period). The total volume of blood withdrawn will not exceed 272 mL (including 13 mL for safety assessment, 6 mL blood for liver function test (SGPT, SGOT and GGT) and 23 mL discarded normal saline blood).

 Handling of Blood Samples:   

The blood samples collected at each time point will be centrifuged between 4±2 ºC (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. The separated plasma will be transferred 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 for storage.

Special condition:

·         During check out of period I at 48.00 hours liver function test (SGPT, SGOT and GGT) will be carried out. If any clinically significant liver chemistry elevations are observed, subject will be withdrawn from study.

·         For post study safety assessment

o        In the event of a suspected drug induced liver injury, or other clinically significant liver chemistry elevations, dolutegravir should be stopped and subjects should not be rechallenged with a dolutegravir-containing product due to the risk of a recurrent reaction.

§         Provision shall be made in the volunteer database to avoid such subjects to get enrolled in dolutegravir-containing product.

 

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, 48.00 and 72.00 hours post-dose (Time points being relative to the investigational product dosing).

Note: subject will be kept in supine position for at least 5 minutes before start of Blood Pressure recording on each time point.

During check out of period I at 48.00 hours liver function test (SGPT, SGOT and GGT) will be carried out. If any clinically significant liver chemistry elevations are observed, subject will be withdrawn from study.

If any adverse events are observed by either clinical staff or reported by subjects at times other than scheduled times will be recorded.

In each period, the breath of the subject will be checked to see whether they have consumed alcohol or not at the time of check-in and during each ambulatory visit of the study using breath alcohol analyzer. (Note: If subjects found breath alcohol test positive during ambulatory visit, further blood sample will not be taken for the respective period but subject questionnaire and vital signs will be taken).

Medical examination, ECG and clinical laboratory tests will be performed to cater to the post-study safety assessments after the last ambulatory blood sample collection of period II.

Medical examination will be carried out during check-in, check-out and at 72.00 hrs ambulatory visit of each period of the study and whenever attending medical officer thinks necessary.

Urine test for drugs of abuse will be carried out at the time of check-in of both the study periods.

 Risk Evaluation and Mitigation Strategies:

Risk evaluated:

The study Investigational product can bring out various adverse effects.

Mitigation strategies:

·         Ambulance will be made available before start of study.

·         All medical staff including nurses and doctors will be informed to be available at clinical site.

·         ICU will be checked for availability of all emergency medicines and other devices will be checked for proper functioning

·         Toxicity Management

In the event of a discontinuation of dolutegravir for suspected drug induced liver injury, other clinically significant liver chemistry elevations, severe skin reaction or hypersensitivity reaction, subjects should not be rechallenged with a dolutegravir-containing product due to the risk of a recurrent reaction. These subjects should be withdrawn from study. Further details on this are provided in Appendix III.

 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:

Dolutegravir will be estimated in plasma using validated LC-MS/MS method.

 Pharmacokinetic Parameters:

1) Primary parameters                      : Cmax, AUC0-t and AUC0-Â¥.

2) Secondary parameters                  : T1/2, Kel, Tmax, npoints, Ke_first and Ke_last.

All the above parameters will be calculated using SAS®.

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-¥.of Dolutegravir will form the basis for concluding the bioequivalence of Dolutegravir sodium in product R and T. If the 90% confidence intervals are entirely included in the range of 80.00 – 125.00% for Cmax, AUC0-t and AUC0-¥.of Dolutegravir log-transformed then the treatments will be claimed to be bioequivalent.

 
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