Treatment Options for Protease Inhibitor-exposed Children (NEVEREST-III)

This study has been completed.
Sponsor:
Collaborators:
University of Witwatersrand, South Africa
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Louise Kuhn, Columbia University
ClinicalTrials.gov Identifier:
NCT01146873
First received: June 8, 2010
Last updated: March 31, 2016
Last verified: March 2016

June 8, 2010
March 31, 2016
July 2010
December 2014   (final data collection date for primary outcome measure)
  • Viral Rebound [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Probability of viral rebound defined as >=1 HIV RNA measurements >50 copies/ml using survival analysis by 48 weeks post-randomization.
  • Viral Failure [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
    Probability of viral failure defined as >= 2 HIV RNA measurements >1000 copies/ml using survival analysis by 48 weeks post-randomization.
  • Maintenance of viral suppression [ Time Frame: through 24 and 48 weeks post randomization ] [ Designated as safety issue: No ]
    HIV RNA quantity < 50 copies/ml
  • Confirmed viral rebound [ Time Frame: through 24 weeks and 48 weeks post randomization ] [ Designated as safety issue: Yes ]
    HIV RNA > 1000 copies/ml twice
Complete list of historical versions of study NCT01146873 on ClinicalTrials.gov Archive Site
  • CD4 Cell Percentage at 48 Weeks After Randomization [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    CD4 Cell Percentage at 48 Weeks After Randomization
  • Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
    Percentage of participants with elevated total cholesterol, elevated LDL, abnormal HDL, or abnormal triglycerides at 40 weeks after randomization
  • Highest Grade ALT After Randomization [ Time Frame: through 48 weeks post randomization ] [ Designated as safety issue: No ]
    Highest grade ALT after randomization. Grading was determined based on the Division of AIDS (2004) Toxicity Tables to grade adverse reactions. Grading scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (potentially life-threatening).
  • Magnitude of CD4 response, hospital admissions, new stage II or greater clinical conditions [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]
  • ALT elevations, HDL, LDL, CRP, fat distribution [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]

    Drug related toxicities, Including fat distribution and metabolic parameters

    Including when co-treated for tuberculosis

  • child Adherence to medication [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]
    assessed by pharmacy reconciliation of medications brought back
Not Provided
Not Provided
 
Treatment Options for Protease Inhibitor-exposed Children
Treatment Options for Protease Inhibitor-exposed Children

The investigators hypothesize that switching to a regimen based on efavirenz will be as effective and safe as remaining on a regimen based on Lopinavir/ritonavir for HIV-infected children.

The investigators propose an unblinded randomized clinical trial to evaluate a simplification, protease-inhibitor (PI)-sparing treatment strategy among nevirapine (NVP)-exposed HIV-infected children treated initially with lopinavir/ritonavir (LPV/r). HIV-infected children aged 3-5 years, who have a history of exposure to NVP as part of prevention of mother-to-child HIV transmission (PMTCT), initiated LPV/r-based therapy in the first 36 months of life or who were enrolled on the control arm of Neverest 2 and who are virally suppressed with a viral load < 50 copies/ml will be included. These children will be randomized to either substitute efavirenz (EFV) for LPV/r or to continue on their LPV/r-based regimen. Eight weeks prior to the primary randomization, eligible children will also be randomized to either remain on stavudine (D4T) or switch to abacavir (ABC). Children will be followed with regular viral load and other clinical tests for 48 weeks after the primary randomization. Children in the experimental arm who have breakthrough viremia (-defined as two subsequent viral loads > 1000 copies/ml) on the EFV-based regimen will reinitiate the LPV/r regimen. The primary objective is to test whether the durability of viral suppression is equivalent when children are switched to EFV-based therapy. The primary study endpoint is failure to have HIV RNA < 50 copies/ml and/or confirmed viremia >1000 copies/ml. Secondary aims include comparison of immune preservation, toxicities, selection of resistance mutations, and adherence across the two arms. Antiretroviral drug concentrations and adherence will be investigated as possible explanations for the success and/or failure of this simplification regimen. The overall goal of the study is to contribute to the evidence base to allow expansion of treatment options for HIV-infected children in low resource settings.

Not Provided
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • HIV/AIDS
  • HIV Infections
  • Drug: Efavirenz (EFV)
    Children are assigned to begin a EFV-based antiretroviral based regimen.
  • Drug: Lopinavir/ritonavir (LPV/r)
    Children are assigned to stay on their current LPV/r-based antiretroviral regimen.
  • Drug: Stavudine (D4T)
    Children are assigned to stay on their current antiretroviral regimen which includes D4T.
  • Drug: Abacavir (ABC)
    Children stop taking D4T and switch to ABC.
  • Active Comparator: Group 1: Lopinavir/ritonavir (LPV/r)
    Participants are assigned to remain on their current LPV/r-based antiretroviral regimen. Ritonavir-boosted lopinavir syrup was given twice per day at 230 mg/m^2 per dose. Children able to swallow tablets were given 1 tablet twice per day (200 mg lopinavir/50 mg ritonavir) if body surface area was less than 0.9m^2 or 2 tablets twice per day if body surface area was 0.9m^2 or higher.
    Intervention: Drug: Lopinavir/ritonavir (LPV/r)
  • Experimental: Group 2: Efavirenz (EFV)
    Participants are assigned to switch to an EFV-based antiretroviral regimen. Efavirenz was prescribed once daily in the evening at 200 mg for weights of 10 kg to 13.9 kg (22-30 lb) and 300mg for weights of 14 kg to 24.9 kg (31-55 lb). Efavirenz was available in 50-mg and 200-mg capsules. If children were unable to swallow capsules, caregivers were shown how to open the capsules and dissolve the contents in water.
    Intervention: Drug: Efavirenz (EFV)
  • Active Comparator: Group D: Stavudine (D4T)
    Children are assigned to remain on their current antiretroviral regimen, which includes D4T. D4T was given at 1 mg/kg twice daily
    Intervention: Drug: Stavudine (D4T)
  • Experimental: Group A: Abacavir (ABC)
    Children stop taking D4T and switch to ABC. ABC was given at 8 mg/kg twice daily.
    Intervention: Drug: Abacavir (ABC)
Coovadia A, Abrams EJ, Strehlau R, Shiau S, Pinillos F, Martens L, Patel F, Hunt G, Tsai WY, Kuhn L. Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial. JAMA. 2015 Nov 3;314(17):1808-17. doi: 10.1001/jama.2015.13631.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
300
December 2014
December 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-infected child 3 to 5 years of age at time of screening for this trial if enrolled from outside or any age if enrolled from control arm of Neverest II.
  • Reliable history or documented exposure to NVP used as part of PMTCT
  • Initiated antiretroviral therapy with LPV/r at age less than 36 months
  • Receiving LPV/r-based ART for at least 12 months
  • At least one viral load measurement less than 50 copies/ml conducted as part of screening for the study
  • ALT measurement grade I or less (DAIDS Toxicity Tables 2004) (Appendix A). These may be repeated until ALTs normalize if necessary.

Exclusion criteria:

  • Prior treatment with any NNRTI drug as part of a therapeutic regimen
  • Substitution of other NRTI drugs (instead of 3TC and D4T which are the standard first line regimen) will be allowed.
Both
3 Years and older   (Child, Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
South Africa
 
NCT01146873
AAAE1145, R01HD061255
Yes
Not Provided
Not Provided
Louise Kuhn, Columbia University
Columbia University
  • University of Witwatersrand, South Africa
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Louise Kuhn, PhD Columbia University
Columbia University
March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP