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

• ClinicalTrials.gov Identifier: NCT01504841
• Recruitment Status: Completed
• First Posted: January 5, 2012
• Results First Posted: September 17, 2019
• Last Update Posted: November 2, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: December 30, 2011
• First Posted Date: January 5, 2012
• Results First Submitted Date: July 16, 2019
• Results First Posted Date: September 17, 2019
• Last Update Posted Date: November 2, 2021
• Actual Study Start Date: March 14, 2013
• Actual Primary Completion Date: July 17, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 27, 2019)

• Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) [ Time Frame: From baseline to occurrence of event, up to Week 48. ]
  Number (%) of participants who discontinued treatment due to a suspected adverse drug reaction (SADR) by Cohort.
• Adverse Events (AEs) of Grade 3 or Higher Severity [ Time Frame: From baseline to occurrence of event, up to Week 48. ]
  Number (%) of participants who experienced a Grade 3 or higher severity adverse event through Week 48 by Cohort, with Clopper-Pearson confidence intervals.
• Death [ Time Frame: From baseline to occurrence of event, up to Week 48. ]
  Number (%) of deaths on study by Cohort.
• Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR [ Time Frame: 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) ]
  Geometric Mean (Standard Deviation) of the area under the plasma concentration-time curve over 12 hours (AUC12h) of ETR.

Original Primary Outcome Measures (submitted: January 3, 2012)

• Termination from treatment due to a suspected adverse drug reaction (SADR) [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ]
• Adverse events (AEs) of Grade 3 or higher severity [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ]
• Death [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ]
• Failure to meet pharmacokinetic (PK) targets [ Time Frame: Measured at intensive PK visit (within 7-10 days of study drug administration) ]
  The area under the plasma concentration-time curve over 12 hours (AUC12h) of ETR will be the PK criterion for determination of the acceptability of the ETR dose.

Current Secondary Outcome Measures (submitted: August 27, 2019)

• AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications [ Time Frame: From baseline to occurrence of event, up to Week 48. ]
  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.
• HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 [ Time Frame: Baseline, Week 24, and Week 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.
• Treatment Discontinued Due to Toxicity or Virologic Failure [ Time Frame: From baseline to occurrence of event, up to Week 48. ]
  Number (%) of participants who discontinued study treatment (ETR) due to a toxicity or Virologic Failure (VF), by Cohort.
• Change in Optimized Background Regimen Due to Virologic Failure [ Time Frame: Measured at entry and at Weeks 8, 12, 24, and 48 ]
  Number (%) of participants who initiated a change in their optimized background regimen (OBR) due to virologic failure, by Cohort.
• New Onset Opportunistic Infection (OI) or AIDS Diagnosis [ Time Frame: From baseline to occurrence of event, up to Week 48. ]
  Number (%) of participants with a new onset opportunistic infection (OI) or AIDS diagnosis, by Cohort.
• Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy [ Time Frame: Measured at baseline and at Weeks 12, 24, and 48 ]
  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.

Original Secondary Outcome Measures (submitted: January 3, 2012)

• AEs of Grade 3 or higher severity judged to be at least possibly attributable to the study medications [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ]
• Confirmed failure to suppress plasma HIV-1 RNA to fewer than 400 copies and failure to achieve at least a 2 log reduction (from baseline) in HIV-1 RNA at weeks 24 and/or 48 (confirmed in 2-4 weeks) [ Time Frame: Measured at Weeks 24 and/or 48 ]
• Treatment discontinued due to toxicity or virologic failure [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ]
• Change in optimized background regimen due to virologic failure [ Time Frame: Measured at entry and at Weeks 8, 12, 24, and 48 ]
• New onset opportunistic infection (OI) or AIDS diagnosis [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ]
• Decline in absolute CD4 percent of greater than 5 percent any time after 12 weeks of therapy [ Time Frame: Measured at entry and at Weeks 12, 24, and 48 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV Infections

Intervention

Drug: Etravirine (ETR)

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.

Study Arms

• Experimental: Cohort I: Treatment experienced, 2 to 6 years of age
  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.
  Intervention: Drug: Etravirine (ETR)
• Experimental: Cohort II: Treatment experienced, 1 to 2 years of age
  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.
  Intervention: Drug: Etravirine (ETR)
• Experimental: Cohort III: Treatment experienced, 2 months to 1 year of age
  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.
  Intervention: Drug: Etravirine (ETR)

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 27, 2019): 26
• Original Estimated Enrollment (submitted: January 3, 2012): 80
• Actual Study Completion Date: August 26, 2020
• Actual Primary Completion Date: July 17, 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Months to 6 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, South Africa, United States
• Removed Location Countries: Argentina, Thailand

Administrative Information

• NCT Number: NCT01504841
• Other Study ID Numbers: P1090; 10850 ( Other Identifier: DAIDS-ES )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Richard Rutstein, MD; Children's Hospital of Philadelphia

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: October 2021