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

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Etravirine (ETR)
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections

Eligibility Criteria

2 Months - 6 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Pediatric Perinatal HIV Clinical Trials Unit CRS
  • Lurie Children's Hospital of Chicago (LCH) CRS
  • Bronx-Lebanon Hospital Center NICHD CRS
  • Jacobi Med. Ctr. Bronx NICHD CRS
  • SOM Federal University Minas Gerais Brazil NICHD CRS
  • Hospital Federal dos Servidores do Estado NICHD CRS
  • Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
  • Hosp. Geral De Nova Igaucu Brazil NICHD CRS
  • Univ. of Sao Paulo Brazil NICHD CRS
  • Wits RHI Shandukani Research Centre CRS
  • Umlazi CRS

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort I: Treatment experienced, 2 to 6 years of age

Cohort II: Treatment experienced, 1 to 2 years of age

Cohort III: Treatment experienced, 2 months to 1 year of age

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.
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.
Death
Number (%) of deaths on study by Cohort.
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.

Secondary Outcome Measures

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.
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.
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.
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.
New Onset Opportunistic Infection (OI) or AIDS Diagnosis
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
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.

Full Information

First Posted
December 30, 2011
Last Updated
October 29, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01504841
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
March 14, 2013 (Actual)
Primary Completion Date
July 17, 2018 (Actual)
Study Completion Date
August 26, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort I: Treatment experienced, 2 to 6 years of age
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort II: Treatment experienced, 1 to 2 years of age
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort III: Treatment experienced, 2 months to 1 year of age
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Etravirine (ETR)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR)
Description
Number (%) of participants who discontinued treatment due to a suspected adverse drug reaction (SADR) by Cohort.
Time Frame
From baseline to occurrence of event, up to Week 48.
Title
Adverse Events (AEs) of Grade 3 or Higher Severity
Description
Number (%) of participants who experienced a Grade 3 or higher severity adverse event through Week 48 by Cohort, with Clopper-Pearson confidence intervals.
Time Frame
From baseline to occurrence of event, up to Week 48.
Title
Death
Description
Number (%) of deaths on study by Cohort.
Time Frame
From baseline to occurrence of event, up to Week 48.
Title
Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR
Description
Geometric Mean (Standard Deviation) of the area under the plasma concentration-time curve over 12 hours (AUC12h) 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)
Secondary Outcome Measure Information:
Title
AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications
Description
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.
Time Frame
From baseline to occurrence of event, up to Week 48.
Title
HIV-1 RNA Virologic Failure Status at Weeks 24 and 48
Description
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.
Time Frame
Baseline, Week 24, and Week 48
Title
Treatment Discontinued Due to Toxicity or Virologic Failure
Description
Number (%) of participants who discontinued study treatment (ETR) due to a toxicity or Virologic Failure (VF), by Cohort.
Time Frame
From baseline to occurrence of event, up to Week 48.
Title
Change in Optimized Background Regimen Due to Virologic Failure
Description
Number (%) of participants who initiated a change in their optimized background regimen (OBR) due to virologic failure, by Cohort.
Time Frame
Measured at entry and at Weeks 8, 12, 24, and 48
Title
New Onset Opportunistic Infection (OI) or AIDS Diagnosis
Description
Number (%) of participants with a new onset opportunistic infection (OI) or AIDS diagnosis, by Cohort.
Time Frame
From baseline to occurrence of event, up to Week 48.
Title
Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy
Description
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.
Time Frame
Measured at baseline and at Weeks 12, 24, and 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Months
Maximum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard Rutstein, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Study Chair
Facility Information:
Facility Name
Pediatric Perinatal HIV Clinical Trials Unit CRS
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Lurie Children's Hospital of Chicago (LCH) CRS
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614-3393
Country
United States
Facility Name
Bronx-Lebanon Hospital Center NICHD CRS
City
Bronx
State/Province
New York
ZIP/Postal Code
10457
Country
United States
Facility Name
Jacobi Med. Ctr. Bronx NICHD CRS
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Facility Name
SOM Federal University Minas Gerais Brazil NICHD CRS
City
Belo Horizonte
State/Province
Minas Gerais
ZIP/Postal Code
30.130-100
Country
Brazil
Facility Name
Hospital Federal dos Servidores do Estado NICHD CRS
City
Rio de Janeiro
ZIP/Postal Code
20221-903
Country
Brazil
Facility Name
Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
City
Rio de Janeiro
ZIP/Postal Code
21941-612
Country
Brazil
Facility Name
Hosp. Geral De Nova Igaucu Brazil NICHD CRS
City
Rio de Janeiro
ZIP/Postal Code
26030
Country
Brazil
Facility Name
Univ. of Sao Paulo Brazil NICHD CRS
City
Sao Paulo
ZIP/Postal Code
14049-900
Country
Brazil
Facility Name
Wits RHI Shandukani Research Centre CRS
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2001
Country
South Africa
Facility Name
Umlazi CRS
City
Durban
State/Province
KwaZulu-Natal
ZIP/Postal Code
4001
Country
South Africa

12. IPD Sharing Statement

Citations:
PubMed Identifier
19654564
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.
Results Reference
background
PubMed Identifier
20942667
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.
Results Reference
background
Links:
URL
https://rsc.niaid.nih.gov/sites/default/files/table-for-grading-severity-of-adult-pediatric-adverse-events.pdf
Description
Description DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009
URL
https://rsc.niaid.nih.gov/sites/default/files/manual-exped-aes-v2_0.pdf
Description
Description Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

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

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