Evaluating the Safety and Pharmacokinetics of Maraviroc in HIV-1-Exposed Infants at Risk of Acquiring HIV-1 Infection

NCT02778204 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: IMPAACT 200720734
• Study Type: interventional
• Target: 47
• Locations: 4 countries
• Sites: 9

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.

Conditions

HIV Infections

Keywords

Vertical HIV exposure; Neonates; Maraviroc

Outcome Measures

Primary Outcomes (8)

• 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).

• 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.

  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

Secondary Outcomes (2)

• 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 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)

Study Arms (4)

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.

Drug: Maraviroc

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.

Drug: Maraviroc

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.

Drug: Maraviroc

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

Drug: Maraviroc

Interventions

Maraviroc DRUG

8 mg/kg oral solution as a single dose.

Cohort 1 Stratum 1A; Cohort 1 Stratum 1B

Eligibility Criteria

• Age: Up to 3 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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, infant or breastfeeding mother was receiving any disallowed medication listed in the protocol.
• Mother received maraviroc during pregnancy.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• ViiV Healthcare: collaborator
• GlaxoSmithKline: collaborator

Study Sites (9)

Usc La Nichd Crs

Los Angeles, California, 90089, United States

Location

Univ. of Colorado Denver NICHD CRS

Aurora, Colorado, 80045, United States

Location

Rush Univ. Cook County Hosp. Chicago NICHD CRS

Chicago, Illinois, 60612, United States

Location

Lurie Children's Hospital of Chicago (LCH) CRS

Chicago, Illinois, 60614-3393, United States

Location

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, 38105-3678, United States

Location

Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS

Kericho, 20200, Kenya

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Umlazi CRS

Durban, KwaZulu-Natal, 4001, South Africa

Location

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Related Links

• Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, dated July 2017

MeSH Terms

Conditions

HIV Infections

Interventions

Maraviroc

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

As with other Antiretrovirals (ARVs) in young infants, maraviroc PK parameters showed high intra- and inter-participant variability.

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Mark Mirochnick, MD

  Boston University School of Medicine/Boston Medical Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2016
• First Posted: May 19, 2016
• Study Start: June 5, 2017
• Primary Completion: September 6, 2019
• Study Completion: November 20, 2019
• Last Updated: January 4, 2022
• Results First Posted: November 23, 2020

Record last verified: 2021-12

Locations

US (5); KE (1); ZA (2); TH (1)