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

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ClinicalTrials.gov Identifier: NCT01146873
Recruitment Status : Completed
First Posted : June 22, 2010
Results First Posted : May 4, 2016
Last Update Posted : March 13, 2017
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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions HIV/AIDS
HIV Infections
Interventions Drug: Efavirenz (EFV)
Drug: Lopinavir/ritonavir (LPV/r)
Drug: Stavudine (D4T)
Drug: Abacavir (ABC)
Enrollment 300
Recruitment Details A total of 300 study participants were recruited between June 2010 and October 2012.
Pre-assignment Details Two children discontinued the study prior to randomization.
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 148 150
Completed 148 144
Not Completed 0 6
Reason Not Completed
Transfer out             0             6
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV) Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 148 150 298
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 148 participants 150 participants 298 participants
4.26  (1.0) 4.28  (0.9) 4.27  (0.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 150 participants 298 participants
Female
80
  54.1%
78
  52.0%
158
  53.0%
Male
68
  45.9%
72
  48.0%
140
  47.0%
1.Primary Outcome
Title Viral Rebound
Hide Description Probability of viral rebound defined as >=1 HIV RNA measurements >50 copies/ml using survival analysis by 48 weeks post-randomization.
Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Hide Arm/Group Description:
Participants are assigned to remain on their current LPV/r-based antiretroviral regimen
Participants are assigned to switch to an EFV-based antiretroviral regimen
Overall Number of Participants Analyzed 148 150
Mean (95% Confidence Interval)
Unit of Measure: probability of viral rebound
0.284
(0.211 to 0.357)
0.176
(0.115 to 0.238)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1: Lopinavir/Ritonavir (LPV/r), Group 2: Efavirenz (EFV)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The null hypothesis is that efavirenz is inferior to ritonavir-boosted lopinavir.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Kaplan-Meier methods
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.107
Estimation Comments [Not Specified]
2.Primary Outcome
Title Viral Failure
Hide Description Probability of viral failure defined as >= 2 HIV RNA measurements >1000 copies/ml using survival analysis by 48 weeks post-randomization.
Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Hide Arm/Group Description:
Participants are assigned to remain on their current LPV/r-based antiretroviral regimen
Participants are assigned to switch to an EFV-based antiretroviral regimen
Overall Number of Participants Analyzed 148 150
Mean (95% Confidence Interval)
Unit of Measure: probability of viral failure
0.020
(0.002 to 0.043)
0.027
(0.001 to 0.054)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1: Lopinavir/Ritonavir (LPV/r), Group 2: Efavirenz (EFV)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The null hypothesis is that efavirenz is inferior to ritonavir-boosted lopinavir.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Kaplan-Meier methods
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.007
Estimation Comments [Not Specified]
3.Secondary Outcome
Title CD4 Cell Percentage at 48 Weeks After Randomization
Hide Description CD4 Cell Percentage at 48 Weeks After Randomization
Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Hide Arm/Group Description:
Participants are assigned to remain on their current LPV/r-based antiretroviral regimen
Participants are assigned to switch to an EFV-based antiretroviral regimen
Overall Number of Participants Analyzed 148 150
Mean (95% Confidence Interval)
Unit of Measure: percentage of cells
34.7
(33.6 to 35.8)
37.5
(36.3 to 38.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1: Lopinavir/Ritonavir (LPV/r), Group 2: Efavirenz (EFV)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization
Hide Description Percentage of participants with elevated total cholesterol, elevated LDL, abnormal HDL, or abnormal triglycerides at 40 weeks after randomization
Time Frame 40 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Hide Arm/Group Description:
Participants are assigned to remain on their current LPV/r-based antiretroviral regimen
Participants are assigned to switch to an EFV-based antiretroviral regimen
Overall Number of Participants Analyzed 148 150
Measure Type: Number
Unit of Measure: percentage of participants
Elevated total cholesterol 24.8 13.3
Elevated LDL 18.6 9.8
Abnormal HDL 4.8 4.2
Abnormal triglycerides 22.8 10.5
5.Secondary Outcome
Title Highest Grade ALT After Randomization
Hide Description 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).
Time Frame through 48 weeks post randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Hide Arm/Group Description:
Participants are assigned to remain on their current LPV/r-based antiretroviral regimen
Participants are assigned to switch to an EFV-based antiretroviral regimen
Overall Number of Participants Analyzed 148 150
Measure Type: Number
Unit of Measure: number of participants
Grade 0 139 120
Grade 1 8 16
Grade 2 0 10
Grade 3 1 3
Grade 4 0 1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1: Lopinavir/Ritonavir (LPV/r), Group 2: Efavirenz (EFV)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Time Frame Through 48 weeks after randomization
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Hide Arm/Group Description 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 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.
All-Cause Mortality
Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/148 (0.00%)      2/150 (1.33%)    
Nervous system disorders     
Seizure  [1]  0/148 (0.00%)  0 2/150 (1.33%) 
Indicates events were collected by systematic assessment
[1]
Seizures resolved after efavirenz was stopped and ritonavir-boosted lopinavir was restarted.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Group 1: Lopinavir/Ritonavir (LPV/r) Group 2: Efavirenz (EFV)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/148 (0.00%)      0/150 (0.00%)    
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Louise Kuhn, PhD
Organization: Columbia University
Phone: 212-305-2398
EMail: lk24@cumc.columbia.edu
Layout table for additonal information
Responsible Party: Louise Kuhn, Columbia University
ClinicalTrials.gov Identifier: NCT01146873     History of Changes
Other Study ID Numbers: AAAE1145
R01HD061255 ( U.S. NIH Grant/Contract )
First Submitted: June 8, 2010
First Posted: June 22, 2010
Results First Submitted: February 29, 2016
Results First Posted: May 4, 2016
Last Update Posted: March 13, 2017