HIV Infections
Conditions
Keywords
Vertical HIV exposure, Neonates, Maraviroc
Brief summary
This study aimed to evaluate the safety, tolerability, and pharmacokinetics of maraviroc in infants at risk for mother-to-child HIV transmission, and to determine an appropriate dose of maraviroc during the first six weeks of life.
Detailed description
Maraviroc is a C-C Chemokine Receptor 5 (CCR5) receptor antagonist used to treat HIV infection in adults. Adding maraviroc to a standard of care prophylaxis regimen may also reduce the risk of perinatal transmission of HIV. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of maraviroc in HIV-1-exposed infants at risk for mother-to-child HIV transmission. This study also aimed to determine an appropriate dose of maraviroc during the first six weeks of life. The study allowed up to 72 mother-infant pairs in two cohorts to achieve a target of 36 evaluable infants receiving the final recommended dose of maraviroc. Because maraviroc interacts with the antiretroviral drug efavirenz (EFV) in adults, infants in this study were stratified within the cohorts based on their exposure to maternal EFV. Cohort 1 was stratified by in utero exposure to maternal EFV, with infants in both strata receiving a single dose of maraviroc solution within three days of birth and another single dose at Week 1 of life. Stratum 1A included infants without in utero exposure to maternal EFV during the eight weeks immediately before delivery. Stratum 1B included infants with in utero exposure to maternal EFV for a minimum of two weeks immediately before delivery. Cohort 2 was stratified by exposure to maternal EFV after birth, with infants in both strata receiving maraviroc oral solution twice daily starting within three days of birth and continuing for up to 42 days. Based on evaluation of the Cohort 1 data, the initial daily dose of maraviroc oral solution to be administered in Cohort 2 was 8 mg/kg dose given twice daily. Stratum 2A included infants without any exposure to maternal EFV either in utero during the eight weeks immediately before delivery or while breastfeeding. Stratum 2B included breastfeeding infants with exposure to maternal EFV both in utero and after birth while breastfeeding, for a minimum of 2 weeks immediately before delivery and while breastfeeding. Participants attended an entry visit within three days after the infant's birth. Participants attended five to six study visits through Week 16. Visits included medical history reviews, physical examinations, blood collection from the mother and/or infant, HIV testing, and adherence counseling.
Interventions
DRUGMaraviroc
8 mg/kg oral solution as a single dose.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ViiV Healthcare
GlaxoSmithKline
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 3 Days
Healthy volunteers
No
Inclusion criteria
* Mother was of legal age to provide independent informed consent for research participation and was willing and able to provide written informed consent for her and her infant's participation in this study. * Mother had confirmed HIV-1 infection based on testing of two samples collected at different time points. More information on this criterion can be found in the protocol. * At entry, infant met EFV exposure requirements, based on mother's report and confirmed by medical records if available, as follows: * For Cohort 1, Stratum 1A: Infant born to a mother who did not receive EFV during the eight weeks immediately prior to delivery. Note: Breastfeeding and formula feeding infants were eligible for this stratum. * For Cohort 1, Stratum 1B: Infant born to a mother who received EFV for a minimum of two weeks immediately prior to delivery. Note: Breastfeeding and formula feeding infants were eligible for this stratum. * For Cohort 2, Stratum 2A: Infants born to a mother who did not receive EFV during the eight weeks immediately prior to delivery and if breastfeeding, mother was not receiving maternal EFV. Note: Breastfeeding and formula feeding infants were eligible for this stratum. * For Cohort 2, Stratum 2B: Breastfeeding infants born to a mother who received EFV for a minimum of two weeks immediately prior to delivery, intended to breastfeed for a minimum of six weeks and continued to receive maternal EFV while breastfeeding. Note: Only breastfeeding infants were eligible for this stratum. * At birth, infant's estimated gestational age was at least 37 weeks. Note: If gestational age at birth is not documented in the infant's available birth records, study staff may assess gestational age at the earliest possible opportunity during the screening period and use this assessment for purposes of eligibility determination. * At birth, infant's weight was at least 2 kg. Note: If weight at birth is not documented in the infant's available birth records, study staff may assess infant weight at the earliest possible opportunity during the screening period and use this assessment for purposes of eligibility determination. * At entry, infant was less than or equal to 3 days old. * At entry, infant had the following lab values: * Grade 0 alanine transaminase (ALT) (normal) * Less than or equal to Grade 1 aspartate aminotransferase (AST) and total bilirubin * Less than or equal to Grade 2 hemoglobin, white blood cell counts, platelet counts * At entry, infant had initiated antiretroviral prophylaxis that did not include a potent CYP3A4 inhibitor or inducer. See the protocol for more information. * At entry, infant was assessed by the site investigator or designee as generally healthy based on review of available medical records, other available medical history information, and physical examination findings. * Born after singleton delivery (not after multiple birth).
Exclusion criteria
* Infant had any other condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives; for example, severe congenital malformation, other medical condition, or clinically significant finding from physical examination. * At entry, any positive infant HIV nucleic acid test result (results are not required to be available prior to entry but any positive results obtained prior to entry are exclusionary). * At entry, infant or breastfeeding mother was receiving any disallowed medication listed in the protocol. * Mother received maraviroc during pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: Trough Concentration (Ctau) | Measured at Week 1 and Week 4 Visit | Pharmacokinetic parameters were determined from plasma concentration-time profiles. Ctau was the observed concentration at the trough time of 12 hours post-dose with steady-state dosing. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose. |
| Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit). | Pharmacokinetic parameters were determined from plasma concentration-time profiles. Cmax was the observed highest concentration. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose. |
| Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit). | Pharmacokinetic parameters were determined from plasma concentration-time profiles. Tmax was the time at which Cmax, the observed highest concentration, occurred. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose. |
| Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Dose-Finding | Cohort 1: Measured from first dose of maraviroc to 7 Day Post Dose Visit (up to 25 days). Cohort 2: Measured from first dose of maraviroc to Week 6 Visit (up to 42 days). | Percentage (%) of failure and Clopper-Pearson 95% Confidence Interval (CI). Failure is defined as having: Any life threatening adverse event (AE), including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug |
| Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Analysis | Measured from first dose of maraviroc to Week 6 Visit (up to 42 days) | Percentage (%) of failure and Clopper-Pearson 95% CI. Failure is defined as: Any life threatening AE, including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug |
| Number of Participants Failing to Meet PK Target | Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit). | Number of failures. The pharmacokinetic (PK) target is Average Concentration (Cavg) greater than or equal to 75 ng/mL (based on a dose interval of every 12 hours). Failure is defined as Cavg \<75 ng/mL at each intensive PK visit. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose. |
| Pharmacokinetic (PK) Parameter: Average Concentration (Cavg) | Cohort 1: Measured at Entry and Week 1 Visit. Cohort 2: Measured at Week 1 and Week 4 Visit | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix 64, WinNonlin, Pharsight Corp., Mountain View, CA). Cavg was determined as the area-under-the-curve (AUC) divided by the dose interval, tau (τ) of every 12 hours. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose. |
| Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC) | Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit). | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix 64, WinNonlin, Pharsight Corp., Mountain View, CA). For Cohort 1 (single doses), area-under-the-curve (AUC) was determined from time zero to infinity. For Cohort 2 (at steady-state), area-under-the-curve (AUC) was determined from time pre-dose to tau (12 hours). For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Analysis | Measured from first dose of maraviroc to Week 16 Visit (up to 140 days) | Percentage (%) of failure and Clopper-Pearson 95% CI. Failure is defined as having: Any life threatening AE, including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug |
| Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Dose-Finding | Measured from first dose of maraviroc to Week 16 Visit (up to 140 days) | Percentage (%) of failure and Clopper-Pearson 95% CI. Failure is defined as having: Any life threatening AE, including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug |
Countries
Kenya, South Africa, Thailand, United States
Participant flow
Recruitment details
Accrual occurred between June 2017 and July 2019 in Kenya, Thailand, South Africa, and the United States at 9 different medical clinic sites. Pregnant mothers were screened and subsequently enrolled for 1 day at the same day their newborn infants were enrolled (within 3 days of life).
Pre-assignment details
The sample size of the study (47) represents the infants enrolled. As multiple births are disallowed in the study, this also represents the total mother-infant pairs.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Stratum 1A Infants in this cohort received a single dose of 8 mg/kg maraviroc solution within 3 days of birth and at Week 1 (7-14 days) of life; without in utero exposure to maternal efavirenz. | 8 |
| Cohort 1 Stratum 1B Infants in this cohort received a single dose of 8 mg/kg maraviroc solution within 3 days of birth and at Week 1 (7-14 days) of life; with in utero exposure to maternal efavirenz. | 7 |
| Cohort 2 Stratum 2A Infants in this cohort received 8 mg/kg maraviroc solution twice daily starting within 3 days of birth and continuing up to Week 6 (35-42) days of life; without in utero or breast milk exposure to maternal efavirenz. | 16 |
| Cohort 2 Stratum 2B Infants in this cohort received 8 mg/kg maraviroc solution twice daily starting within 3 days of birth and continuing up to Week 6 (35-42) days of life; with in utero and breast milk exposure to maternal efavirenz | 16 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Eligibility Violation | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Cohort 2 Stratum 2B | Cohort 2 Stratum 2A | Cohort 1 Stratum 1A | Cohort 1 Stratum 1B |
|---|---|---|---|---|---|
| Age, Continuous Mean (Standard Deviation) | 2 days | 2 days | 1 days | 1.5 days | 0 days |
| Age, Continuous | 31 years | 32 years | 32 years | 29.5 years | 26 years |
| Alanine Aminotransferase (ALT) | 0.2 ukat/L | 0.2 ukat/L | 0.2 ukat/L | 0.2 ukat/L | 0.2 ukat/L |
| APGAR at 1 minute | 9.0 units on a scale | 9.0 units on a scale | 8.5 units on a scale | 9.0 units on a scale | 8.0 units on a scale |
| Aspartate Aminotransferase (AST) | 0.9 ukat/L | 1.0 ukat/L | 0.9 ukat/L | 0.7 ukat/L | 1.1 ukat/L |
| Birth Length | 49.0 centimeters | 48.5 centimeters | 49.0 centimeters | 50.0 centimeters | 50.0 centimeters |
| Birth Weight | 3.05 kilograms | 3.0 kilograms | 3.0 kilograms | 3.2 kilograms | 3.4 kilograms |
| Creatinine | 66 umol/L | 69.0 umol/L | 61.9 umol/L | 70.7 umol/L | 62.0 umol/L |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants | 16 Participants | 14 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gestational Age | 39.0 weeks | 40.0 weeks | 39.0 weeks | 38.5 weeks | 39.0 weeks |
| Hemoglobin | 170.0 g/L | 179.0 g/L | 166.5 g/L | 163.0 g/L | 178.0 g/L |
| Platelets | 289.0 10^9 platelets/L | 311.0 10^9 platelets/L | 252.5 10^9 platelets/L | 274.0 10^9 platelets/L | 297.0 10^9 platelets/L |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 38 Participants | 16 Participants | 10 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Region of Enrollment Kenya | 2 participants | 2 participants | 0 participants | 0 participants | 0 participants |
| Region of Enrollment South Africa | 22 participants | 14 participants | 0 participants | 1 participants | 7 participants |
| Region of Enrollment Thailand | 3 participants | 0 participants | 3 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 20 participants | 0 participants | 13 participants | 7 participants | 0 participants |
| Sex: Female, Male Female | 23 Participants | 7 Participants | 7 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 24 Participants | 9 Participants | 9 Participants | 3 Participants | 3 Participants |
| Total Bilirubin | 50.7 umol/L | 75.3 umol/L | 76.1 umol/L | 39.3 umol/L | 44.0 umol/L |
| White Blood Cell Count (WBC) | 14.6 10^9 cells/L | 12.6 10^9 cells/L | 15.5 10^9 cells/L | 14.6 10^9 cells/L | 17.3 10^9 cells/L |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 7 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 7 / 8 | 7 / 7 | 15 / 16 | 14 / 16 |
| serious Total, serious adverse events | 2 / 8 | 1 / 7 | 4 / 16 | 2 / 16 |
Outcome results
Primary
Number of Participants Failing to Meet PK Target
Number of failures. The pharmacokinetic (PK) target is Average Concentration (Cavg) greater than or equal to 75 ng/mL (based on a dose interval of every 12 hours). Failure is defined as Cavg \<75 ng/mL at each intensive PK visit. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose.
Time frame: Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit).
Population: Analysis population included dose-finding evaluable participants with intensive pharmacokinetic (PK) results.~In Cohort 1 Stratum 1A and 1B at the week 1 visit (Second Visit), only 3 PK sample were drawn (pre-dose, 1-2 hours post-dose, and 22-26 hours post-dose). Maraviroc was only measurable (above assay limit) at 1 time point (1-2 hours post-dose). Therefore, AUC (hence Cavg) could not be estimated with non-compartmental methods from only 1 concentration and thus the number analyzed was 0.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 Stratum 1A | Number of Participants Failing to Meet PK Target | First Visit | 0 participants |
| Cohort 1 Stratum 1B | Number of Participants Failing to Meet PK Target | First Visit | 0 participants |
| Cohort 2 Stratum 2A | Number of Participants Failing to Meet PK Target | First Visit | 3 participants |
| Cohort 2 Stratum 2A | Number of Participants Failing to Meet PK Target | Second Visit | 4 participants |
| Cohort 2 Stratum 2B | Number of Participants Failing to Meet PK Target | First Visit | 4 participants |
| Cohort 2 Stratum 2B | Number of Participants Failing to Meet PK Target | Second Visit | 5 participants |
Primary
Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Analysis
Percentage (%) of failure and Clopper-Pearson 95% CI. Failure is defined as: Any life threatening AE, including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug
Time frame: Measured from first dose of maraviroc to Week 6 Visit (up to 42 days)
Population: Analysis Endpoint includes all treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 Stratum 1A | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
| Cohort 1 Stratum 1B | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
| Cohort 2 Stratum 2A | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
| Cohort 2 Stratum 2B | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
Primary
Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Dose-Finding
Percentage (%) of failure and Clopper-Pearson 95% Confidence Interval (CI). Failure is defined as having: Any life threatening adverse event (AE), including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug
Time frame: Cohort 1: Measured from first dose of maraviroc to 7 Day Post Dose Visit (up to 25 days). Cohort 2: Measured from first dose of maraviroc to Week 6 Visit (up to 42 days).
Population: Safety-evaluable population are those who were taking maraviroc for the expected time-frame (Cohort 1: through 7 day post-dose visit, Cohort 2: Through week 6)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 Stratum 1A | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |
| Cohort 1 Stratum 1B | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |
| Cohort 2 Stratum 2A | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |
| Cohort 2 Stratum 2B | Percentage of Participants Failing to Meet Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |
Primary
Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC)
Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix 64, WinNonlin, Pharsight Corp., Mountain View, CA). For Cohort 1 (single doses), area-under-the-curve (AUC) was determined from time zero to infinity. For Cohort 2 (at steady-state), area-under-the-curve (AUC) was determined from time pre-dose to tau (12 hours). For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose.
Time frame: Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit).
Population: Analysis population included dose-finding evaluable participants with intensive pharmacokinetic (PK) results.~In Cohort 1 Stratum 1A and 1B at the week 1 visit (Second Visit), only 3 PK sample were drawn (pre-dose, 1-2 hours post-dose, and 22-26 hours post-dose). Maraviroc was only measurable (above assay limit) at 1 time point (1-2 hours post-dose). Therefore, AUC (hence Cavg) could not be estimated with non-compartmental methods from only 1 concentration and thus the number analyzed was 0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC) | First Visit | 2285.68 ng*hr/mL |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC) | First Visit | 4506.17 ng*hr/mL |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC) | First Visit | 1826.87 ng*hr/mL |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC) | Second Visit | 1122.99 ng*hr/mL |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC) | First Visit | 1496.05 ng*hr/mL |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Area-under-the-curve (AUC) | Second Visit | 1216.62 ng*hr/mL |
Primary
Pharmacokinetic (PK) Parameter: Average Concentration (Cavg)
Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix 64, WinNonlin, Pharsight Corp., Mountain View, CA). Cavg was determined as the area-under-the-curve (AUC) divided by the dose interval, tau (τ) of every 12 hours. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose.
Time frame: Cohort 1: Measured at Entry and Week 1 Visit. Cohort 2: Measured at Week 1 and Week 4 Visit
Population: Analysis population included dose-finding evaluable participants with intensive pharmacokinetic (PK) results.~In Cohort 1 Stratum 1A and 1B at the week 1 visit (Second Visit), only 3 PK sample were drawn (pre-dose, 1-2 hours post-dose, and 22-26 hours post-dose). Maraviroc was only measurable (above assay limit) at 1 time point (1-2 hours post-dose). Therefore, AUC (hence Cavg) could not be estimated with non-compartmental methods from only 1 concentration and thus the number analyzed was 0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Average Concentration (Cavg) | First Visit | 190.47 ng/mL |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Average Concentration (Cavg) | First Visit | 375.47 ng/mL |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Average Concentration (Cavg) | Second Visit | 93.58 ng/mL |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Average Concentration (Cavg) | First Visit | 152.24 ng/mL |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Average Concentration (Cavg) | First Visit | 124.67 ng/mL |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Average Concentration (Cavg) | Second Visit | 101.39 ng/mL |
Primary
Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax)
Pharmacokinetic parameters were determined from plasma concentration-time profiles. Cmax was the observed highest concentration. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose.
Time frame: Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit).
Population: Analysis population included dose-finding evaluable participants with intensive pharmacokinetic (PK) results.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | First Visit | 227.3 ng/mL |
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | Second Visit | 128.9 ng/mL |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | First Visit | 550.5 ng/mL |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | Second Visit | 163.4 ng/mL |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | Second Visit | 416.5 ng/mL |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | First Visit | 256.9 ng/mL |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | Second Visit | 221.8 ng/mL |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Maximum Concentration (Cmax) | First Visit | 308.8 ng/mL |
Primary
Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax)
Pharmacokinetic parameters were determined from plasma concentration-time profiles. Tmax was the time at which Cmax, the observed highest concentration, occurred. For Cohort 1: For the Entry Visit, PK samples were drawn at: pre-dose and at 1-2, 4-8, 11-13, 20-24, and 48-72 hours post-dose. For the Week 1 Visit, PK samples were drawn at: pre-dose and 1-2 and 22-26 hours post-dose. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose.
Time frame: Cohort 1: Measured at Entry (First visit) and Week 1 Visit (Second visit). Cohort 2: Measured at Week 1 (First visit) and Week 4 Visit (Second visit).
Population: Analysis population included dose-finding evaluable participants with intensive pharmacokinetic (PK) results.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | First Visit | 4.68 hours |
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | Second Visit | 1.18 hours |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | First Visit | 1.52 hours |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | Second Visit | 1.08 hours |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | First Visit | 1.50 hours |
| Cohort 2 Stratum 2A | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | Second Visit | 1.50 hours |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | Second Visit | 2.19 hours |
| Cohort 2 Stratum 2B | Pharmacokinetic (PK) Parameter: Time of Maximum Concentration (Tmax) | First Visit | 3.00 hours |
Primary
Pharmacokinetic (PK) Parameter: Trough Concentration (Ctau)
Pharmacokinetic parameters were determined from plasma concentration-time profiles. Ctau was the observed concentration at the trough time of 12 hours post-dose with steady-state dosing. For Cohort 2: For both intensive PK visits, PK samples were drawn at: pre-dose and 1-2, 3-5, 6-8, and 11-13 hours post-dose.
Time frame: Measured at Week 1 and Week 4 Visit
Population: Analysis population included Cohort 2 dose-finding evaluable participants with intensive pharmacokinetic (PK) results.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Trough Concentration (Ctau) | Week 1 Visit | 27.9 ng/mL |
| Cohort 1 Stratum 1A | Pharmacokinetic (PK) Parameter: Trough Concentration (Ctau) | Week 4 Visit | 34.4 ng/mL |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Trough Concentration (Ctau) | Week 1 Visit | 23.4 ng/mL |
| Cohort 1 Stratum 1B | Pharmacokinetic (PK) Parameter: Trough Concentration (Ctau) | Week 4 Visit | 54.9 ng/mL |
Secondary
Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Analysis
Percentage (%) of failure and Clopper-Pearson 95% CI. Failure is defined as having: Any life threatening AE, including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug
Time frame: Measured from first dose of maraviroc to Week 16 Visit (up to 140 days)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 Stratum 1A | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
| Cohort 1 Stratum 1B | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
| Cohort 2 Stratum 2A | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
| Cohort 2 Stratum 2B | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Analysis | 0 percentage of participants |
Secondary
Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Dose-Finding
Percentage (%) of failure and Clopper-Pearson 95% CI. Failure is defined as having: Any life threatening AE, including death, assessed as at least possibly related to the study drug, AEs of Grade 3 or higher judged by the Core Protocol Team to be probably or definitely related to the study drug, or that result in permanent discontinuation of study drug due to an AE, judged by Core Protocol Team to be at least possibly related to study drug
Time frame: Measured from first dose of maraviroc to Week 16 Visit (up to 140 days)
Population: Safety-evaluable population are those who were taking maraviroc for the expected time-frame (Cohort 1: through 7 day post-dose visit, Cohort 2: Through week 6)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 Stratum 1A | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |
| Cohort 1 Stratum 1B | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |
| Cohort 2 Stratum 2A | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |
| Cohort 2 Stratum 2B | Percentage of Participants Failing to Meet Long-Term Safety Endpoint Related to Maraviroc for Dose-Finding | 0 percentage of participants |