Clinical trial NCT01504841: Evaluating the Safety and Tolerability of Etravirine in HIV-1 Infected Infants and Children
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2012-01-05
Enrollment: 26
Sex: ALL
Minimum age (years): 2
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR)
timeFrame: From baseline to occurrence of event, up to Week 48.
measure: Adverse Events (AEs) of Grade 3 or Higher Severity
timeFrame: From baseline to occurrence of event, up to Week 48.
measure: Death
timeFrame: From baseline to occurrence of event, up to Week 48.
measure: Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR
timeFrame: 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 outcomes:
measure: AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications
timeFrame: From baseline to occurrence of event, up to Week 48.
measure: HIV-1 RNA Virologic Failure Status at Weeks 24 and 48
timeFrame: Baseline, Week 24, and Week 48
measure: Treatment Discontinued Due to Toxicity or Virologic Failure
timeFrame: From baseline to occurrence of event, up to Week 48.
measure: Change in Optimized Background Regimen Due to Virologic Failure
timeFrame: Measured at entry and at Weeks 8, 12, 24, and 48
measure: New Onset Opportunistic Infection (OI) or AIDS Diagnosis
timeFrame: From baseline to occurrence of event, up to Week 48.
measure: Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy
timeFrame: Measured at baseline and at Weeks 12, 24, and 48
Other outcomes:
Locations:
city: Miami
country: United States
facility: Pediatric Perinatal HIV Clinical Trials Unit CRS
state: Florida
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago (LCH) CRS
state: Illinois
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital Center NICHD CRS
state: New York
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS
state: Minas Gerais
city: Rio de Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS
city: Johannesburg
country: South Africa
facility: Wits RHI Shandukani Research Centre CRS
state: Gauteng
city: Durban
country: South Africa
facility: Umlazi CRS
state: KwaZulu-Natal
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Richard Rutstein, MD
role: STUDY_CHAIR
References:
citation: Jittamala P, Puthanakit T, Chaiinseeard S, Sirisanthana V. Predictors of virologic failure and genotypic resistance mutation patterns in thai children receiving non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Pediatr Infect Dis J. 2009 Sep;28(9):826-30. doi: 10.1097/INF.0b013e3181a458f9.
citation: Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers T, Bwakura-Dangarembizi M, Chi BH, Musoke P, Kamthunzi P, Schimana W, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Violari A. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 2010 Oct 14;363(16):1510-20. doi: 10.1056/NEJMoa1000931.