Evaluating the Safety and Tolerability of Etravirine in HIV-1 Infected Infants and Children

Study Overview
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Brief Summary
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used as part of combination antiretroviral therapy (ART) for infants and children, but NNRTI resistance is increasing, leading to treatment failure. This study tested the safety, tolerability, and dosing levels of etravirine (ETR), a new NNRTI.

Detailed Description
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Use of NNRTI-based regimens as initial therapy for HIV-infected children is increasing, especially in areas where newborns exposed to HIV-1 receive single-dose nevirapine (NVP) as part of prevention of mother-to-child transmission (PMTCT) regimens and/or daily NVP for prevention of transmission through breastfeeding. First-generation NNRTIs have a low genetic barrier to the development of resistance; in two of the most widely used NNRTIs, NVP and efavirenz (EFV), even a single amino acid mutation in the virus can lead to a reduction in the drug's effectiveness. Even short-term use of these NNRTIs, including only a single dose of NVP, can cause NNRTI resistance. Second-generation NNRTIs are needed as part of ARV regimens for newly diagnosed infants and children who have been exposed to single-dose NVP or who have failed their current antiretroviral (ARV) regimens. In this study, the second-generation NNRTI ETR was tested for safety, tolerability, and appropriate dosing. Children were assigned to one of three cohorts based on age: Cohort I: At least 2 but younger than 6 years of age Cohort II: At least 1 but younger than 2 years of age Cohort III: At least 2 months but younger than 1 year of age Children in all three cohorts were treatment experienced, defined as being on a failing combination ARV regimen (containing at least 3 ARVs) for at least 8 weeks or having a treatment interruption of at least 4 weeks with a history of virologic failure while on a combination ARV regimen (containing at least 3 ARVs). Children received ETR together with an optimized background regimen (OBR) consisting of at least 2 active agents (a boosted protease inhibitor [PI] and at least 1 additional active ARV drug). OBR were based on clinical status, treatment history, resistance data, and availability of appropriate pediatric dosing and formulations. The children received an oral dose of ETR twice daily. Most children had 11 visits: at screening, entry (Day 0), Day 14 (intensive pharmacokinetic [PK] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits included a physical exam, giving a medical history, discussion of adherence, and blood and urine collection. The screening and intensive PK visits also included an electrocardiogram (ECG). During the intensive PK visit, the child had blood drawn approximately 7 times over 12 hours. After the Week 48 visit, children entered the long-term follow-up phase of the study and have a visit every 12 weeks for up to 5 years. These follow-up visits included giving a medical history and undergoing a physical exam and blood draw.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Etravirine (ETR)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV-1 infection as described in the protocol 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I: Treatment experienced, 2 to 6 years of age<br>Children in this arm were at least 2 but younger than 6 years of age; they received the study drug etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. | Drug: Etravirine (ETR)<br>* ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol.<br>|
| Experimental: Cohort II: Treatment experienced, 1 to 2 years of age<br>Children in this arm were at least 1 but younger than 2 years of age; they received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug. | Drug: Etravirine (ETR)<br>* ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol.<br>|
| Experimental: Cohort III: Treatment experienced, 2 months to 1 year of age<br>Children in this arm were at least 2 months but younger than 1 year of age; they received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug. | Drug: Etravirine (ETR)<br>* ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) | Number (%) of participants who discontinued treatment due to a suspected adverse drug reaction (SADR) by Cohort. | From baseline to occurrence of event, up to Week 48. | 
| Adverse Events (AEs) of Grade 3 or Higher Severity | Number (%) of participants who experienced a Grade 3 or higher severity adverse event through Week 48 by Cohort, with Clopper-Pearson confidence intervals. | From baseline to occurrence of event, up to Week 48. | 
| Death | Number (%) of deaths on study by Cohort. | From baseline to occurrence of event, up to Week 48. | 
| Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR | Geometric Mean (Standard Deviation) of the area under the plasma concentration-time curve over 12 hours (AUC12h) of ETR. | Pre-dose, 1, 2, 4, 6, 9, and 12 hours post-dose measured at intensive PK visit (within 7-10 days after last dose of study drug administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications | Number (%) of Participants with AEs of Grade 3 or higher severity judged, by the Study Team, to be at least possibly attributable to the study medications by Cohort, including Clopper-Pearson confidence intervals. | From baseline to occurrence of event, up to Week 48. | 
| HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Number (%) of participants with confirmed Virologic Failure, defined as: failure to suppress plasma HIV-1 RNA to fewer than 400 copies/ml and failure to achieve at least a 2-log10 reduction (from baseline) in HIV-1 RNA at Weeks 24 or 48, by Cohort, with Clopper-Pearson confidence intervals. The initial HIV-1 RNA results that met the Virologic Failure definition were each confirmed by a second result obtained within 1 to 4 weeks of the initial result obtained at Week 24 and/or 48. | Baseline, Week 24, and Week 48 | 
| Treatment Discontinued Due to Toxicity or Virologic Failure | Number (%) of participants who discontinued study treatment (ETR) due to a toxicity or Virologic Failure (VF), by Cohort. | From baseline to occurrence of event, up to Week 48. | 
| Change in Optimized Background Regimen Due to Virologic Failure | Number (%) of participants who initiated a change in their optimized background regimen (OBR) due to virologic failure, by Cohort. | Measured at entry and at Weeks 8, 12, 24, and 48 | 
| New Onset Opportunistic Infection (OI) or AIDS Diagnosis | Number (%) of participants with a new onset opportunistic infection (OI) or AIDS diagnosis, by Cohort. | From baseline to occurrence of event, up to Week 48. | 
| Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Number (%) of participants with a >5% decline in absolute CD4 percent from baseline at weeks 12, 24, and 48, by Cohort, including Clopper-Pearson confidence intervals. | Measured at baseline and at Weeks 12, 24, and 48 |