Clinical Trial Results:
A Study to Compare the Pharmacokinetics of a Fixed-Dose Combination of Raltegravir and Lamivudine to Co-administered Raltegravir and Lamivudine
Summary
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EudraCT number |
2015-002237-22 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
25 Sep 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Mar 2016
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First version publication date |
15 Jul 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MK-0518B-196
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Merck Sharp & Dohme Corp.
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Sponsor organisation address |
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001442-PIP01-13 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 Sep 2011
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Sep 2011
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Sep 2011
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Assess the plasma pharmacokinetic profiles of raltegravir and lamivudine after administration of MK-0518B (Formulation #6) and coadministration of the marketed Isentress 400 mg and Epivir 150 mg tablets.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Sep 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 24
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Worldwide total number of subjects |
24
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
24
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
Pre-assignment
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Screening details |
The study population included non-smoking, male and female volunteers from 18 to 55 years of age, with a BMI ≤ 31kg/m2,who were judged to be healthy based on a medical history, ECG, laboratory evaluation and physical examination and vital signs measurements. Twenty-four (24) male and female participants met all selection criteria. | ||||||||||||||||||
Period 1
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Period 1 title |
Period 1
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sequence 1: Isentress™ + Epivir™ then MK-0518B | ||||||||||||||||||
Arm description |
Participants received single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 1 then a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
raltegravir
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Investigational medicinal product code |
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Other name |
Isentress™
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Isentress™ (raltegravir) 400 mg tablets were administered with 240 mL water after a fast of at least 10 hours.
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Investigational medicinal product name |
lamivudine
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Investigational medicinal product code |
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Other name |
Epivir™
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Epivir™ (lamivudine) 150 mg tablets were administered with 240 mL water after a fast of at least 10 hours
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Investigational medicinal product name |
MK-0518B
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
MK-0518B 300 mg reformulated raltegravir / 150 mg lamivudine monolithic tablets were administered with 240 mL water after a fast of at least 10 hours.
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Arm title
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Sequence 2: MK-0518B then Isentress™ + Epivir™ | ||||||||||||||||||
Arm description |
Participants received a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 1 then single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
raltegravir
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Investigational medicinal product code |
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Other name |
Isentress™
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Isentress™ (raltegravir) 400 mg tablets were administered with 240 mL water after a fast of at least 10 hours.
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Investigational medicinal product name |
lamivudine
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Investigational medicinal product code |
|||||||||||||||||||
Other name |
Epivir™
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Epivir™ (lamivudine) 150 mg tablets were administered with 240 mL water after a fast of at least 10 hours
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Investigational medicinal product name |
MK-0518B
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
MK-0518B 300 mg reformulated raltegravir / 150 mg lamivudine monolithic tablets were administered with 240 mL water after a fast of at least 10 hours.
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Period 2
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Period 2 title |
Period 2
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sequence 1: Isentress™ + Epivir™ then MK-0518B | ||||||||||||||||||
Arm description |
Participants received single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 1 then a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
raltegravir
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Investigational medicinal product code |
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Other name |
Isentress(TM)
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Isentress™ (raltegravir) 400 mg tablets were administered with 240 mL water after a fast of at least 10 hours.
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Investigational medicinal product name |
lamivudine
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Investigational medicinal product code |
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Other name |
Epivir(TM)
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Epivir™ (lamivudine) 150 mg tablets were administered with 240 mL water after a fast of at least 10 hours
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Investigational medicinal product name |
MK-0518B
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
MK-0518B 300 mg reformulated raltegravir / 150 mg lamivudine monolithic tablets were administered with 240 mL water after a fast of at least 10 hours.
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Arm title
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Sequence 2: MK-0518B then Isentress™ + Epivir™ | ||||||||||||||||||
Arm description |
Participants received a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 1 then single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
raltegravir
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Investigational medicinal product code |
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Other name |
Isentress(TM)
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Isentress™ (raltegravir) 400 mg tablets were administered with 240 mL water after a fast of at least 10 hours.
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Investigational medicinal product name |
lamivudine
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Investigational medicinal product code |
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Other name |
Epivir(TM)
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Epivir™ (lamivudine) 150 mg tablets were administered with 240 mL water after a fast of at least 10 hours
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Investigational medicinal product name |
MK-0518B
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
MK-0518B 300 mg reformulated raltegravir / 150 mg lamivudine monolithic tablets were administered with 240 mL water after a fast of at least 10 hours.
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Baseline characteristics reporting groups
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Reporting group title |
Period 1
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Reporting group description |
All participants who were enrolled in the study. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sequence 1: Isentress™ + Epivir™ then MK-0518B
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Reporting group description |
Participants received single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 1 then a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 2. | ||
Reporting group title |
Sequence 2: MK-0518B then Isentress™ + Epivir™
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Reporting group description |
Participants received a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 1 then single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 2. | ||
Reporting group title |
Sequence 1: Isentress™ + Epivir™ then MK-0518B
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Reporting group description |
Participants received single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 1 then a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 2. | ||
Reporting group title |
Sequence 2: MK-0518B then Isentress™ + Epivir™
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Reporting group description |
Participants received a single dose of MK-0518B (300 mg raltegravir/150 mg lamivudine) in Period 1 then single doses of co-administered Isentress™ 400 mg and Epivir™ 150 mg in Period 2. | ||
Subject analysis set title |
Isentress™ + Epivir™
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants who received Isentress™ + Epivir™ and completed the study.
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Subject analysis set title |
MK-0518B
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants who received MK-0518B and completed the study.
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End point title |
The area under the raltegravir concentration vs time curve from time zero to infinity (AUC0-∞) | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.
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End point type |
Primary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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Statistical analysis title |
MK-0518B vs. Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
106.71
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
83.05 | ||||||||||||
upper limit |
137.11 |
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End point title |
Maximum concentration (Cmax) of raltegravir | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.
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End point type |
Primary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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Statistical analysis title |
MK-0518B vs Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
149.68
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
105.86 | ||||||||||||
upper limit |
211.62 |
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End point title |
The area under the lamivudine concentration vs time curve of from time zero to infinity (AUC0-∞) | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.
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End point type |
Primary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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Statistical analysis title |
MK-0518B vs Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
103.88
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
97.64 | ||||||||||||
upper limit |
110.51 |
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End point title |
Maximum concentration (Cmax) of lamivudine | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.
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End point type |
Primary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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Statistical analysis title |
MK-0518B vs Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
112.98
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Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
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||||||||||||
lower limit |
102.3 | ||||||||||||
upper limit |
124.77 |
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End point title |
The area under the raltegravir concentration vs time curve of from time zero to the last sampling time with quantifiable analyte (AUC0-t) | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.
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End point type |
Secondary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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Statistical analysis title |
MK-0518B vs Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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||||||||||||
Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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||||||||||||
Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
107.55
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||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
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||||||||||||
lower limit |
82.91 | ||||||||||||
upper limit |
139.5 |
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End point title |
Concentration of raltegravir at time 12 hours (C12) | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.
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End point type |
Secondary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
|
||||||||||||
|
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Statistical analysis title |
MK-0518B vs Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
90.63
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
76.9 | ||||||||||||
upper limit |
106.81 |
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End point title |
The area under the lamivudine concentration vs time curve from time zero to the last sampling time with quantifiable analyte (AUC0-t) | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose.
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End point type |
Secondary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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Statistical analysis title |
MK-0518B vs Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
106.43
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
99.77 | ||||||||||||
upper limit |
113.53 |
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End point title |
Concentration of lamivudine at time 12 hours (C12) | ||||||||||||
End point description |
Blood samples for analysis of pharmacokinetic parameters were collected prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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End point type |
Secondary
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End point timeframe |
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
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Statistical analysis title |
MK-0518B vs Isentress™ + Epivir™ | ||||||||||||
Statistical analysis description |
Treatment differences were compared using a linear mixed effect model containing period and treatment as fixed effects. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the two treatment measurements within each subject. The same participants and number (n=24) were to have received both treatments but due to dropouts, n=24 received MK-0518B and n=22 received Isentress™ + Epivir™. GMR = (MK-0518B/Isentress™ + Epivir™)
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Comparison groups |
Isentress™ + Epivir™ v MK-0518B
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Number of subjects included in analysis |
46
|
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Analysis specification |
Pre-specified
|
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Analysis type |
other | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
geometric mean ratio | ||||||||||||
Point estimate |
102.89
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
97.76 | ||||||||||||
upper limit |
108.28 |
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Adverse events information
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Timeframe for reporting adverse events |
Predose to 14 days following the last dose of study drug (approximately 20 days).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14.1
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Reporting groups
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Reporting group title |
Isentress™ + Epivir™
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MK-0518B
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |