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

NCT01504841 | Completed Phase 1 Results DMC

• 2 other identifiers: P109010850
• Study Type: interventional
• Target: 26
• Locations: 3 countries
• Sites: 11

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (6)

• AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications

  From baseline to occurrence of event, up to Week 48.

• HIV-1 RNA Virologic Failure Status at Weeks 24 and 48

  Baseline, Week 24, and Week 48

• Treatment Discontinued Due to Toxicity or Virologic Failure

  From baseline to occurrence of event, up to Week 48.

• Change in Optimized Background Regimen Due to Virologic Failure

  Measured at entry and at Weeks 8, 12, 24, and 48

• New Onset Opportunistic Infection (OI) or AIDS Diagnosis

  From baseline to occurrence of event, up to Week 48.

Study Arms (3)

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

EXPERIMENTAL

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)

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

EXPERIMENTAL

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)

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

EXPERIMENTAL

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)

Interventions

Etravirine (ETR) DRUG

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.

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

Eligibility Criteria

• Age: 2 Months - 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (11)

Pediatric Perinatal HIV Clinical Trials Unit CRS

Miami, Florida, 33136, United States

Location

Lurie Children's Hospital of Chicago (LCH) CRS

Chicago, Illinois, 60614-3393, United States

Location

Bronx-Lebanon Hospital Center NICHD CRS

The Bronx, New York, 10457, United States

Location

Jacobi Med. Ctr. Bronx NICHD CRS

The Bronx, New York, 10461, United States

Location

SOM Federal University Minas Gerais Brazil NICHD CRS

Belo Horizonte, Minas Gerais, 30.130-100, Brazil

Location

Hospital Federal dos Servidores do Estado NICHD CRS

Rio de Janeiro, 20221-903, Brazil

Location

Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS

Rio de Janeiro, 21941-612, Brazil

Location

Hosp. Geral De Nova Igaucu Brazil NICHD CRS

Rio de Janeiro, 26030, Brazil

Location

Univ. of Sao Paulo Brazil NICHD CRS

São Paulo, 14049-900, Brazil

Location

Wits RHI Shandukani Research Centre CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Umlazi CRS

Durban, KwaZulu-Natal, 4001, South Africa

Location

Related Publications (2)

• 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.

  PMID: 19654564 BACKGROUND

• 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.

  PMID: 20942667 BACKGROUND

Related Links

• 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
• Description Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Interventions

etravirine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Limitations and Caveats

Due to the slow rate of accrual and the challenging accrual into the youngest cohort, enrollment was stopped early.

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Richard Rutstein, MD

  Children's Hospital of Philadelphia

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 30, 2011
• First Posted: January 5, 2012
• Study Start: March 14, 2013
• Primary Completion: July 17, 2018
• Study Completion: August 26, 2020
• Last Updated: November 2, 2021
• Results First Posted: September 17, 2019

Record last verified: 2021-10

Locations

US (4); BR (5); ZA (2)