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HIV InfectionsPhase 1/2NCT01504841

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

A Phase 1/2 study testing Etravirine (ETR) in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 11 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 2 months to 6 years
Conditions the study is for
HIV Infections
What is being tested?
Etravirine (ETR)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
26 participants
Where
11 sitesin 3 countries
Study dates
14 Mar 2013to 26 Aug 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 months to 6 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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

Who cannot join

  • 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.
Show all 11Show fewer
  • 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.

Trial locations and contacts

11 sites in 3 countries.

11 sites in 3 countries

Brazil5 sites
  • SOM Federal University Minas Gerais Brazil NICHD CRS

    Belo Horizonte, Minas Gerais, 30.130-100

  • Hospital Federal dos Servidores do Estado NICHD CRS

    Rio de Janeiro, 20221-903

  • Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS

    Rio de Janeiro, 21941-612

  • Hosp. Geral De Nova Igaucu Brazil NICHD CRS

    Rio de Janeiro, 26030

  • Univ. of Sao Paulo Brazil NICHD CRS

    São Paulo, 14049-900

Other trials in Brazil

United States4 sites
  • Lurie Children's Hospital of Chicago (LCH) CRS

    Chicago, Illinois, 60614-3393

  • Pediatric Perinatal HIV Clinical Trials Unit CRS

    Miami, Florida, 33136

  • Bronx-Lebanon Hospital Center NICHD CRS

    The Bronx, New York, 10457

  • Jacobi Med. Ctr. Bronx NICHD CRS

    The Bronx, New York, 10461

Other trials in United States

South Africa2 sites
  • Umlazi CRS

    Durban, KwaZulu-Natal, 4001

  • Wits RHI Shandukani Research Centre CRS

    Johannesburg, Gauteng, 2001

Other trials in South Africa

About this study

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

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.

Read the 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.

Conditions
HIV Infections
Being tested
Etravirine (ETR)
Medical subject headings
HIV Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 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.

Study groups in NCT01504841
Study groupRoleWhat they receive
Cohort I: Treatment experienced, 2 to 6 years of ageExperimentalChildren 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.
Receives: Drug: Etravirine (ETR)
Cohort II: Treatment experienced, 1 to 2 years of ageExperimentalChildren 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.
Receives: Drug: Etravirine (ETR)
Cohort III: Treatment experienced, 2 months to 1 year of ageExperimentalChildren 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.
Receives: Drug: Etravirine (ETR)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

  2. 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.

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

  3. Death

    Number (%) of deaths on study by Cohort.

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

  4. 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.

    Measured: 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)
  1. 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.

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

  2. 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.

    Measured: Baseline, Week 24, and Week 48

  3. 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.

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

  4. 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: Measured at entry and at Weeks 8, 12, 24, and 48

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

    Number (%) of participants with a new onset opportunistic infection (OI) or AIDS diagnosis, by Cohort.

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

  6. 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: Measured at baseline and at Weeks 12, 24, and 48

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jan 2012 (estimated)
  2. Study start14 Mar 2013
  3. Primary completion17 Jul 2018
  4. Study completion26 Aug 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
26 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01504841
Sponsor's protocol ID
P1090
Other IDs
10850
Status last verified
Oct 2021
First submitted
30 Dec 2011
Last updated
2 Nov 2021
Data monitoring committee
Yes

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.

    PubMed 19654564
  • 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.

    PubMed 20942667

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Etravirine (ETR) in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 11 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Brazil, United States, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) (time frame: From baseline to occurrence of event, up to Week 48.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01504841, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Nov 2021.

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