Trial record 11 of 28 for:    " December 07, 2011":" January 06, 2012"[FIRST-RECEIVED-DATE]AND HIV[CONDITION]

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01504841
First received: December 30, 2011
Last updated: August 18, 2014
Last verified: August 2014
  Purpose

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 will test the safety, tolerability, and dosing levels of etravirine (ETR), a new NNRTI.


Condition Intervention Phase
HIV Infections
Drug: Etravirine (ETR)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Death [ Time Frame: Measured through Week 48, or for up to 5 years if individual participates in long-term safety follow-up ] [ Designated as safety issue: Yes ]
  • Failure to meet PK targets [ Time Frame: Measured at intensive PK visit (within 7-10 days of study drug administration) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 1 to 4 weeks) [ Time Frame: Measured at Weeks 24 and/or 48 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Change in optimized background regimen due to virologic failure [ Time Frame: Measured at entry and at Weeks 8, 12, 24, and 48 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: March 2012
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort I: Treatment experienced, 2 to 6 years of age
Children in this arm will be at least 2 but younger than 6 years of age; they will receive 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)
ETR will be administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children will take an initial starting dose orally twice daily within 30 minutes following a meal. Dose will be decided according to dosing tables in protocol. For Cohort III, children 2 months to younger than 6 months of age may take 3 doses daily instead of 2 (see dosing tables).
Experimental: Cohort II: Treatment experienced, 1 to 2 years of age
Children in this arm will be at least 1 but younger than 2 years of age; they will receive ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug.
Drug: Etravirine (ETR)
ETR will be administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children will take an initial starting dose orally twice daily within 30 minutes following a meal. Dose will be decided according to dosing tables in protocol. For Cohort III, children 2 months to younger than 6 months of age may take 3 doses daily instead of 2 (see dosing tables).
Experimental: Cohort III: Treatment experienced, 2 months to 1 year of age
Children in this arm will be at least 2 months but younger than 1 year of age; they will receive ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug.
Drug: Etravirine (ETR)
ETR will be administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children will take an initial starting dose orally twice daily within 30 minutes following a meal. Dose will be decided according to dosing tables in protocol. For Cohort III, children 2 months to younger than 6 months of age may take 3 doses daily instead of 2 (see dosing tables).

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 will be tested for safety, tolerability, and appropriate dosing.

Children will be 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 less than 1 year of age

Children in all cohorts will be 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).

Enrollment will move in a sequential manner, starting with the oldest cohort. All cohorts will begin with enrollment into a mini-cohort of 6 children that will be followed for 4 weeks to assess safety. If the analysis results of the mini-cohort suggest that a higher or lower dose of ETR is needed, a new dose will be agreed upon by the protocol team and 6 new children will be enrolled as a new mini-cohort. If the mini-cohort passes the safety evaluation, 6 additional children will be enrolled to complete the full enrollment for that cohort (12 children) and the mini-cohort for the next younger cohort will open.

Children will receive 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 will be based on clinical status, treatment history, resistance data, and availability of dosing guidelines. Some ARVs used as part of the OBR may be provided by the study. Most children will receive an oral dose of ETR twice daily; some children 2 months to 6 months of age in Cohort III may receive three daily doses.

Most children will have 11 visits: at screening, entry (Day 0), once between Day 7 and Day 14 (intensive pharmacokinetic [PK] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits will include a physical exam, giving a medical history, discussion of adherence, and blood and urine collection. The screening and intensive PK visits will also include an electrocardiogram (ECG). During the intensive PK visit, the child will have blood drawn approximately 7 times over 12 hours. After the Week 48 visit, children will enter the long-term follow-up phase of the study and will have a visit every 12 weeks for up to 5 years. These follow-up visits will include giving a medical history and undergoing a physical exam and blood draw.

  Eligibility

Ages Eligible for Study:   2 Months to 6 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed HIV-1 infection as described in the protocol
  • At least 2 months of age but younger than 6 years of age at study entry. 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.
  • Prior HIV-1 RNA viral load greater than 1000 copies/mL (within the previous 90 days prior to screening) and an HIV-1 RNA viral load greater than 1000 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 greater than 10 for loss of sensitivity for all cohorts)
  • 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. More information on this criterion can be found in the protocol.
  • 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 an 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 in, 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 corrected QTc or PR interval prolongation from the electrocardiogram (ECG) at screening. More information on this criterion can be found in the protocol.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01504841

  Show 25 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Richard Rutstein, MD Children's Hospital of Philadelphia
  More Information

Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01504841     History of Changes
Other Study ID Numbers: P1090, 10850
Study First Received: December 30, 2011
Last Updated: August 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Etravirine
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 28, 2014