A Phase I/II, Open-Label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Etravirine (ETR) in Antiretroviral (ARV) Treatment-Experienced HIV-1 Infected Infants and Children, Aged 2 Months to < 6 Years (IMPAACT P1090, Version 5.0 dated, 03/10/2016)
DescriptionNevirapine (NVP) and Efavirenz, the two most widely used non nucleoside reverse transcriptase inhibitor (NNRTI) drugs, have a low genetic barrier for the development of drug resistance mutations, so that, a single amino acid substitution in the viral reverse transcriptase leads to profound reduction in viral susceptibility to both drugs. With the widespread use of first generation NNRTIs as components of combination antiretroviral therapy, and as a component of neonatal prevention of mother to child transmission (PMTCT) treatment regimens, and infant nevirapine during breastfeeding, the number of children harboring virus with one or two NNRTI-resistance mutations will continue to increase. Thus, there is an urgent need to develop alternative therapeutic options for newly diagnosed neonates and infants exposed to single dose NVP containing regimens, as well as for infants and children failing their present HAART regimens. Etravirine (ETR) is a second generation NNRTI and has a structure that allows more molecular flexibility relative to other NNRTIs, allowing ETR to maintain its binding affinity for HIV-1 reverse transcriptase despite binding site changes induced by the presence of common NNRTI resistance mutations. This is a Phase I/II, multicenter, open label 48 week study of the pharmacokinetics, safety and tolerability of ETR in combination with at least 2 active antiretrovirals (ARVs), including a boosted PI and NRTIs for treatment experienced HIV-1-infected infants and children 2 months to < 6 years cohorts. The study will, in a sequential manner, accrue subjects for an initial dose finding intensive PK component for age related cohorts. It is expected that up to 50 subjects will be accrued study wide, to yield at least 36 evaluable* subjects with a minimum of 12 subjects for each of the three cohorts (up to 18 subjects may be enrolled into Cohort 1), whose initial dose was that which was determined optimal for their age cohorts. 3 participants will be enrolled at this site. The total sample size will depend upon the number needed to complete the dose finding stage of the study, the number of subjects who discontinue the study and the number of subjects required for regulatory approval of ETR in these populations. The primary endpoints for this study will be toxicity and failure to meet PK targets. The analysis of dose finding data will consist of descriptive statistics summarizing the safety and PK data from the dose finding phase of the study.
PhasePhase 1/2 - for trials that are a combination of phases 1 and 2.
Inclusion and Exclusion Criteria
- Confirmed HIV-1 infection as described in the protocol
- At least 2 months of age but younger than 6 years of age at study entry. NOTE: Children who were born at or sooner than 37 weeks gestational age must be at least 12 weeks of age and at least 46 weeks post-conceptual age at study entry.
- HIV-1 RNA viral load greater than 1,000 copies/mL (within the previous 90 days prior to screening) and an HIV-1 RNA viral load greater than 1,000 copies/mL at screening
- Treatment-experienced children on a failing combination antiretroviral (ARV) regimen (containing at least three ARVs) for at least 8 weeks; OR, treatment-experienced children on a treatment interruption of at least 4 weeks with a history of virologic failure while on a combination ARV regimen (containing at least three ARVs)
- Ability to swallow etravirine (ETR) whole or dispersed in an appropriate liquid
- Parent or legal guardian able and willing to provide signed informed consent and to have the child followed at the clinic site
- Availability of sufficient active ARV drugs to create an optimized background regimen (OBR) consistent with protocol requirements
- Evidence of phenotypic resistance to ETR at screening (phenotypic cutoffs of greater than 10 for loss of sensitivity for cohorts I, II, III)
- Known history of HIV-2 infection in child or child's mother
- Diagnosis of a new Centers for Disease Control (CDC) Stage C (per 1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less than 13 Years of Age) criteria or opportunistic or bacterial infection diagnosed within 30 days prior to screening and not considered clinically stable
- Prior history of malignancy
- Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that in the investigator's opinion would place the child at an unacceptable risk of injury, render the child unable to meet the requirements of the protocol, compromise the outcome of this study, or lead to the child being ineligible for participation
- Current Grade 3 or higher of any of the following laboratory toxicities at screening: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lipase, or serum creatinine.
- Current or anticipated use of any disallowed medications (listed in the protocol)
- Child's family is unlikely to adhere to the study procedures or keep appointments or is planning to relocate to a non-IMPAACT study site during the study
- History of nonadherence with ARV medications that in the investigator's opinion could affect the ability of the child to comply with the protocol/procedures
- Child is currently participating, or has participated within the previous 30 days prior to screening, in a study with a compound or device that is not commercially available
- Grade 3 or higher QTc or PR interval prolongation from the electrocardiogram (ECG) at screening. More information on this criterion can be found in the protocol.
- Usc La Nichd Crs, Alhambra, California, 91803
- Univ. of Colorado Denver NICHD CRS, Aurora, Colorado, 80045
- Seattle Children's Research Institute CRS, Seattle, Washington, 98101
- Rush Univ. Cook County Hosp. Chicago NICHD CRS, Chicago, Illinois, 60612