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| ID | Type | Description | Link |
|---|---|---|---|
| 20734 | Registry Identifier | DAIDS-ES Registry Number |
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
| ViiV Healthcare | INDUSTRY |
| GlaxoSmithKline | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 Stratum 1A | Experimental | 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. |
|
| Cohort 1 Stratum 1B | Experimental | 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. |
|
| Cohort 2 Stratum 2A | Experimental | 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. |
|
| Cohort 2 Stratum 2B | Experimental | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Maraviroc | Drug | 8 mg/kg oral solution as a single dose. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 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 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 | Measured from first dose of maraviroc to Week 6 Visit (up to 42 days) |
| 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. | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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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:
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:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Mark Mirochnick, MD | Boston University School of Medicine/Boston Medical Center | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Usc La Nichd Crs | Los Angeles | California | 90089 | United States | ||
| Univ. of Colorado Denver NICHD CRS |
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| Label | URL |
|---|---|
| Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, dated July 2017 | View source |
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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.
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).
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Cohort 1 Stratum 1B |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 13, 2016 | Sep 2, 2020 |
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| Maraviroc | Drug | 8 mg/kg oral solution given twice daily. |
|
| 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 (Ï„) 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. |
| Cohort 1: Measured at Entry and Week 1 Visit. Cohort 2: Measured at Week 1 and Week 4 Visit |
| 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. | 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 (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. | 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 (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. | 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 (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. | Measured at Week 1 and Week 4 Visit |
| Measured from first dose of maraviroc to Week 16 Visit (up to 140 days) |
| 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 | Measured from first dose of maraviroc to Week 16 Visit (up to 140 days) |
| Aurora |
| Colorado |
| 80045 |
| United States |
| Rush Univ. Cook County Hosp. Chicago NICHD CRS | Chicago | Illinois | 60612 | United States |
| Lurie Children's Hospital of Chicago (LCH) CRS | Chicago | Illinois | 60614-3393 | United States |
| St. Jude Children's Research Hospital CRS | Memphis | Tennessee | 38105-3678 | United States |
| Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS | Kericho | 20200 | Kenya |
| Soweto IMPAACT CRS | Johannesburg | Gauteng | 1862 | South Africa |
| Umlazi CRS | Durban | KwaZulu-Natal | 4001 | South Africa |
| Siriraj Hospital ,Mahidol University NICHD CRS | Bangkok | Bangkoknoi | 10700 | Thailand |
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.
| FG002 | 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. |
| FG003 | 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 |
| COMPLETED |
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| NOT COMPLETED |
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|
Includes all infants.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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 |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | This is the Infant age at baseline. | Median | Inter-Quartile Range | days |
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| Age, Continuous | This is the Maternal Age at baseline. | Median | Inter-Quartile Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Birth Weight | Median | Inter-Quartile Range | kilograms |
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| Birth Length | Median | Inter-Quartile Range | centimeters |
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| Gestational Age | Median | Inter-Quartile Range | weeks |
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| APGAR at 1 minute | APGAR Score ranges from 1-10, with 1 being the worst and 10 being the best. | Median | Inter-Quartile Range | units on a scale |
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| Alanine Aminotransferase (ALT) | Median | Inter-Quartile Range | ukat/L |
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| Aspartate Aminotransferase (AST) | Median | Inter-Quartile Range | ukat/L |
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| Total Bilirubin | Median | Inter-Quartile Range | umol/L |
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| Creatinine | Median | Inter-Quartile Range | umol/L |
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| Platelets | Median | Inter-Quartile Range | 10^9 platelets/L |
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| Hemoglobin | Median | Inter-Quartile Range | g/L |
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| White Blood Cell Count (WBC) | Median | Inter-Quartile Range | 10^9 cells/L |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||
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| 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 | 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) | Posted | Number | 95% Confidence Interval | percentage of participants | 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). |
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| 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 | Analysis Endpoint includes all treated participants | Posted | Number | 95% Confidence Interval | percentage of participants | Measured from first dose of maraviroc to Week 6 Visit (up to 42 days) |
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| 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. | 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. | Posted | Number | participants | 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). |
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| 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 (Ï„) 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. | 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. | Posted | Median | Full Range | ng/mL | Cohort 1: Measured at Entry and Week 1 Visit. Cohort 2: Measured at Week 1 and Week 4 Visit |
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| 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. | 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. | Posted | Median | Full Range | ng*hr/mL | 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). |
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| 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. | Analysis population included dose-finding evaluable participants with intensive pharmacokinetic (PK) results. | Posted | Median | Full Range | ng/mL | 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). |
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| 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. | Analysis population included dose-finding evaluable participants with intensive pharmacokinetic (PK) results. | Posted | Median | Full Range | hours | 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). |
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| 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. | Analysis population included Cohort 2 dose-finding evaluable participants with intensive pharmacokinetic (PK) results. | Posted | Median | Full Range | ng/mL | Measured at Week 1 and Week 4 Visit |
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| 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 | 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) | Posted | Number | 95% Confidence Interval | percentage of participants | Measured from first dose of maraviroc to Week 16 Visit (up to 140 days) |
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| 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 | All treated participants | Posted | Number | 95% Confidence Interval | percentage of participants | Measured from first dose of maraviroc to Week 16 Visit (up to 140 days) |
|
From study entry to study completion at Week 16 or premature study discontinuation
All new diagnoses, signs/symptoms and laboratory events of ≥Grade 1 and all signs/symptoms and laboratory events that led to a change in treatment, regardless of grade, were collected. Adverse events (AE) were graded according to the 246 Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, dated July 2017
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 0 | 8 | 2 | 8 | 7 | 8 |
| EG001 | 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. | 0 | 7 | 1 | 7 | 7 | 7 |
| EG002 | 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. | 0 | 16 | 4 | 16 | 15 | 16 |
| EG003 | 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 | 0 | 16 | 2 | 16 | 14 | 16 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Haemolytic anaemia | Blood and lymphatic system disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Cyanosis | Cardiac disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hypospadias | Congenital, familial and genetic disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Jaundice | Hepatobiliary disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Escherichia urinary tract infection | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Pneumonia bacterial | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Sepsis neonatal | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Staphylococcal sepsis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Haemoglobin decreased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Failure to thrive | Metabolism and nutrition disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Slow response to stimuli | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Tremor | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Haemolytic anaemia | Blood and lymphatic system disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Tachycardia | Cardiac disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Congenital melanocytic naevus | Congenital, familial and genetic disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Congenital syphilis | Congenital, familial and genetic disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hypospadias | Congenital, familial and genetic disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Conjunctival pallor | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Eye discharge | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Ocular hyperaemia | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Orbital oedema | Eye disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Abdominal distension | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Infantile colic | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Infantile vomiting | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Mouth ulceration | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Teething | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Face oedema | General disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Feeling hot | General disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hyperbilirubinaemia neonatal | Hepatobiliary disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Jaundice | Hepatobiliary disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Acarodermatitis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Conjunctivitis bacterial | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Escherichia urinary tract infection | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Genital candidiasis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Impetigo | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Ophthalmia neonatorum | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Oral candidiasis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Pneumonia bacterial | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Sepsis neonatal | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Staphylococcal sepsis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Tinea versicolour | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA 21.1 | Systematic Assessment |
| |
| Eyelid injury | Injury, poisoning and procedural complications | MedDRA 21.1 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Bilirubin conjugated increased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Blood bilirubin increased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Blood potassium increased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Cardiac murmur | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Haemoglobin decreased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| White blood cell count decreased | Investigations | MedDRA 21.1 | Systematic Assessment |
| |
| Failure to thrive | Metabolism and nutrition disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Malnutrition | Metabolism and nutrition disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Poor feeding infant | Metabolism and nutrition disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Underweight | Metabolism and nutrition disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Acquired macrocephaly | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hypertonia | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hypotonia | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Jaundice neonatal | Pregnancy, puerperium and perinatal conditions | MedDRA 21.1 | Systematic Assessment |
| |
| Small for dates baby | Pregnancy, puerperium and perinatal conditions | MedDRA 21.1 | Systematic Assessment |
| |
| Irritability | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Neonatal hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Sneezing | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Tachypnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Use of accessory respiratory muscles | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Dermatitis diaper | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Erythema toxicum neonatorum | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Intertrigo | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Miliaria | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Papule | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Petechiae | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Rash neonatal | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Rash papular | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Seborrhoeic dermatitis | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
| |
| Haematoma | Vascular disorders | MedDRA 21.1 | Systematic Assessment |
|
As with other Antiretrovirals (ARVs) in young infants, maraviroc PK parameters showed high intra- and inter-participant variability.
In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Melissa Allen, Director, IMPAACT Operations Center | Family Health International (FHI 360) | (919) 405-1429 | mallen@fhi360.org |
| Prot_003.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan: Primary Statistical Analysis Plan | Jun 11, 2018 | Aug 11, 2020 | SAP_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan: PK Statistical Analysis Plan | Jan 24, 2020 | Aug 11, 2020 | SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 21, 2018 | Dec 4, 2019 | ICF_000.pdf |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000077592 | Maraviroc |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
Not provided
Not provided
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| South Africa |
|
| Thailand |
|
| Kenya |
|
| OG003 | 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 |
|
|
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. |
| OG002 | 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. |
| OG003 | 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 |
|
|
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. |
| OG002 | 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. |
| OG003 | 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 |
|
|
| OG001 | 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. |
| OG002 | 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. |
| OG003 | 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 |
|
|
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. |
| OG003 | 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 |
|
|
| 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. |
| OG003 | 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 |
|
|
|
|
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. |
| OG003 | 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 |
|
|
| OG003 | 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 |
|
|
| Title | Measurements |
|---|---|
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| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|