Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00074412
First received: December 11, 2003
Last updated: July 5, 2013
Last verified: July 2013
Results First Received: May 30, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver);   Primary Purpose: Prevention
Condition: HIV Infections
Interventions: Drug: Nevirapine
Drug: Nevirapine placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
HIV-infected pregnant women were recruited from antenatal clinics at DAIDS Clinical Trials Sites in Zimbabwe, South Africa, Uganda & Tanzania between May 14, 2008 & January 20th 2010. 1700 mother/infant pairs were enrolled & infants were given daily doses of Nevirapine for 6 weeks at which point there were randomized to placebo or extended NVP.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Infants were excluded from randomization if in first 42 days: had a positive HIV-1 DNA PCR, breastfeeding was discontinued, never initiated or permanently discontinued open-label NVP, certain graded abnormal labs, skin rash grade2B or higher, clinical hepatitis, serious illness/condition that prevented compliance, or use of rifampin/ketoconazole.

Reporting Groups
  Description
Placebo For infants: extended treatment with NVP placebo
Nevirapine For infants: extended treatment with NVP

Participant Flow:   Overall Study
    Placebo     Nevirapine  
STARTED     763 [1]   759 [1]
Week 8 Visit     759     759  
Month 3 Visit     759     755  
Month 4 Visit     758     752  
Month 5 Visit     756     750  
Month 6 Visit     748     748  
Month 9 Visit     741     741  
Month 12 Visit     733     735  
COMPLETED     681 [2]   675 [2]
NOT COMPLETED     82     84  
Death                 30                 26  
Lost to Follow-up                 52                 58  
[1] Number of infants randomized at 6 weeks.
[2] Number of infants who completed final 18 month visit: out of 733 infants who were expected.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Nevirapine For infants: extended treatment with NVP
Placebo For infants: extended treatment with NVP placebo
Total Total of all reporting groups

Baseline Measures
    Nevirapine     Placebo     Total  
Number of Participants  
[units: participants]
  759     763     1522  
Age  
[units: participants]
     
<=18 years     759     763     1522  
Between 18 and 65 years     0     0     0  
>=65 years     0     0     0  
Gender, Customized  
[units: participants]
     
Ambiguous     1     0     1  
Male     363     398     761  
Female     395     365     760  
Region of Enrollment  
[units: participants]
     
Tanzania     98     99     197  
Uganda     259     261     520  
South Africa     171     171     342  
Zimbabwe     231     232     463  
Categorical Infant Birthweight (g)  
[units: participants]
     
Missing     0     1     1  
2000-2499     50     52     102  
2500-2999     214     211     425  
3000-3499     329     336     665  
>=3500     166     163     329  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study   [ Time Frame: At Month 6 ]

Measure Type Primary
Measure Title HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study
Measure Description No text entered.
Time Frame At Month 6  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All infants who were randomly allocated to either treatment or placebo at 6 weeks of age under version 3.0 of the protocol were included in the analysis of the primary endpoint, HIV infection at 6 months. 127/1700 infants were enrolled but excluded from randomization at 6 weeks for various reasons as mentioned in the flow-through.

Reporting Groups
  Description
Nevirapine For infants: extended treatment with NVP
Placebo For infants: extended treatment with NVP Placebo

Measured Values
    Nevirapine     Placebo  
Number of Participants Analyzed  
[units: participants]
  759     763  
HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study  
[units: participants]
   
# of HIV infections at 6 months     8     18  
# of Infants at risk for HIV infection at 6 months     700     699  


Statistical Analysis 1 for HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study
Groups [1] Nevirapine
Method [2] Kaplan-Meier Method
6 month Rate of Cum. HIV Infection (%) [3] 1.1
95% Confidence Interval ( 0.3 to 1.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study
Groups [1] Placebo
Method [2] Kaplan-Meier Method
6 month Rate of Cum. HIV Infection (%) [3] 2.4
95% Confidence Interval ( 1.3 to 3.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.049
Z statistic [4] 1.973
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Assuming the cumulative HIV infection rate in placebo group would be 4.2% (2.6 at 6 wk. & 6.7 at 6 mon.), we estimated 1500 mother/infant pairs would provide 90% power to detect a reduction in HIV infection from 4.2% to 1.4% at 6 mon. with a Pearson χ² test statistic and a one-sided false positive error rate of 0.025. Rate of cumulative infection was calculated using Kaplan-Meier method and rates between extended NVP group and placebo were done with the Z statistic.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value has not been adjusted for interim analysis or multiple testing. A priori threshold for statistical significance was 0.05.
[4] Other relevant estimation information:
  No text entered.



2.  Primary:   Frequency and Severity of Adverse Reactions Among Participating Infants   [ Time Frame: 6 weeks through 18 months ]

Measure Type Primary
Measure Title Frequency and Severity of Adverse Reactions Among Participating Infants
Measure Description For those infants who were randomized at 6 weeks and who initiated study drug we looked at the frequency and severity of adverse reactions through 18 months of study. The severity of all AEs was graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. The term severity is described as the intensity grade or level for specific event (i.e. mild, moderate, severe, or life-threatening). Severity is not the same as seriousness.
Time Frame 6 weeks through 18 months  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
A total of 1519 infants, 758 in the NVP arm and 761 in the placebo arm, initiated study product and were thus included in the analysis for the frequency and severity of adverse reactions.

Reporting Groups
  Description
Nevirapine For infants: extended treatment with NVP
Placebo For infants: extended treatment with NVP placebo

Measured Values
    Nevirapine     Placebo  
Number of Participants Analyzed  
[units: participants]
  758     761  
Number of Adverse Events Analyzed  
[units: Adverse Events]
  2014     1964  
Frequency and Severity of Adverse Reactions Among Participating Infants  
[units: Number of Adverse Events]
   
Death     26     30  
Life-Threatening     87     87  
Severe     375     332  
Moderate     694     677  
Mild     832     838  

No statistical analysis provided for Frequency and Severity of Adverse Reactions Among Participating Infants



3.  Secondary:   Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms   [ Time Frame: At Months 6 and 18 ]

Measure Type Secondary
Measure Title Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Measure Description No text entered.
Time Frame At Months 6 and 18  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
There were 1522 infants randomized at 6 weeks of birth to either the extended Nevirapine arm (759) or the placebo arm (763).

Reporting Groups
  Description
Nevirapine For infants: extended treatment with NVP
Placebo For infants: extended treatment with NVP placebo

Measured Values
    Nevirapine     Placebo  
Number of Participants Analyzed  
[units: participants]
  759     763  
Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms  
[units: participants]
   
Number of Infants Alive and HIV-free at 6 months     689     683  
Number of Infants Alive and HIV-free at 18 months     629     616  


Statistical Analysis 1 for Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Groups [1] Nevirapine
Method [2] Kaplan-Meier Method
Cum. Rate of HIV-free Survival 6mon (%) [3] 97.7
95% Confidence Interval ( 96.6 to 98.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rate of HIV-free survival at 6 months in the extended NVP arm was calculated using the Kaplan-Meier method; while the 95% CI was calculated using Greenwood's formula.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Groups [1] Placebo
Method [2] Kaplan-Meier Method
Cum. Rate of HIV-free Survival 6mon (%) [3] 96.8
95% Confidence Interval ( 95.5 to 98.0 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rate of HIV-free survival at 6 months in the placebo arm was calculated using the Kaplan-Meier method; while the 95% CI was calculated using Greenwood's formula.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.274
Z statistic [4] 1.095
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rates of HIV-free survival at 6 months were compared between the two groups using a Z-statistic.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value was not adjusted for interim analysis or multiple testing.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Groups [1] Nevirapine
Method [2] Kaplan-Meier Method
Cum. Rate of HIV-free Survival 18mon (%) [3] 94.5
95% Confidence Interval ( 92.9 to 96.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rate of HIV-free survival at 18 months in the extended NVP arm was calculated using the Kaplan-Meier method; while 95% confidence intervals were calculated using Greenwood's formula.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Groups [1] Placebo
Method [2] Kaplan-Meier Method
Cum. Rate of HIV-free Survival 18mon (%) [3] 93.3
95% Confidence Interval ( 91.5 to 95.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rate of HIV-free survival at 18 months in the placebo arm was calculated using the Kaplan-Meier method; while the 95% confidence interval was calculated using Greenwood's formula.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.323
Z statistic [4] 0.988
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rates of HIV-free survival at 18 months were compared between the two groups using a Z statistic.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value was not adjusted for interim analysis or multiple testing.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Relative Rates of HIV Infection in the Two Arms   [ Time Frame: At Month 18 ]

Measure Type Secondary
Measure Title Relative Rates of HIV Infection in the Two Arms
Measure Description No text entered.
Time Frame At Month 18  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
A total of 1527 infants were randomized to either placebo or extended NVP. 5 of these infants were later found to be infected at the time of randomization (2 in NVP and 3 in Placebo). Thus, only 1522 infants were included in the analysis.

Reporting Groups
  Description
Nevirapine For infants: extended treatment with NVP
Placebo For infants: extended treatment with NVP placebo

Measured Values
    Nevirapine     Placebo  
Number of Participants Analyzed  
[units: participants]
  759     763  
Relative Rates of HIV Infection in the Two Arms  
[units: participants]
   
# of infants with HIV infection at 18 months     16     23  
# of infants @ risk for HIV infection at 18 months     664     663  


Statistical Analysis 1 for Relative Rates of HIV Infection in the Two Arms
Groups [1] Nevirapine
Method [2] Kaplan-Meier Method
18 mon. Rate of Cum HIV Infection (%) [3] 2.2
95% Confidence Interval ( 1.1 to 3.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rate of HIV infection at 18 months in the extended NVP arm was calculated using the Kaplan-Meier method; while the 95% confidence interval was calculated using Greenwood's formula.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Relative Rates of HIV Infection in the Two Arms
Groups [1] Placebo
Method [2] Kaplan-Meier Method
18 mon. Rate of Cum. HIV Infection (%) [3] 3.1
95% Confidence Interval ( 1.9 to 4.4 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rate of HIV infection at 18 months in the placebo arm was calculated using the Kaplan-Meier method; while the 95% confidence interval was calculated using Greenwood's formula.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Relative Rates of HIV Infection in the Two Arms
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.280
Z statistic [4] 1.081
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rates of HIV infection at 18 months were calculated using the Kaplan-Meier method and were compared between arms using a Z statistic.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value was not adjusted for interim analysis or multiple testing.
[4] Other relevant estimation information:
  No text entered.



5.  Secondary:   Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms   [ Time Frame: At Month 18 ]

Measure Type Secondary
Measure Title Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Measure Description No text entered.
Time Frame At Month 18  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Nevirapine For infants: extended treatment with NVP
Placebo For infants: extended treatment with NVP placebo

Measured Values
    Nevirapine     Placebo  
Number of Participants Analyzed  
[units: participants]
  759     763  
Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms  
[units: participants]
   
# Infant Deaths at 18 months     26     30  
# Infants at risk of death at 18 months     678     684  


Statistical Analysis 1 for Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Groups [1] Nevirapine
Method [2] Kaplan-Meier Method
Cumulative Mortality Rate at 18mon (%) [3] 4.7
95% Confidence Interval ( 2.0 to 7.4 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Groups [1] Placebo
Method [2] Kaplan-Meier Method
Cumulative Mortality Rate at 18mon (%) [3] 4.1
95% Confidence Interval ( 2.7 to 5.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.805
Z statistic [4] -0.247
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative rates of mortality at 6 months, as calculated by Kaplan-Meier, were compared between the two groups using a Z-statistic.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value was not adjusted for interim analysis or multiple testing
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Groups [1] Nevirapine
Method [2] Kaplan-Meier Method
Cumulative Mortality Rate at 6mon (%) [3] 1.2
95% Confidence Interval ( 0.4 to 2.0 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Groups [1] Placebo
Method [2] Kaplan-Meier Method
Cumulative Mortality Rate at 6mon (%) [3] 1.1
95% Confidence Interval ( 0.3 to 1.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.719
Z statistic [4] -0.360
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The cumulative mortality rates at 18 months, as calculated by Kaplan-Meier, were compared between the two groups using a Z statistic.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value was not adjusted for interim analysis or multiple testing.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 7 for Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.611
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  We compared the cumulative mortality rates, as calculated using Kaplan-Meier, between the two study groups over all 18 months of the study follow-up using a log-rank test.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



6.  Secondary:   Frequency and Duration of Maternal Plasma and Breast Milk NVP-resistant HIV Strains and the Relationship With HIV Transmission   [ Time Frame: Throughout study ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

7.  Secondary:   Relationship Between Maternal Plasma and Breast Milk RNA Levels and the Risk of MTCT   [ Time Frame: Throughout study ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

8.  Secondary:   Frequency and Duration of NVP-resistant HIV Strains in Plasma of HIV-infected Infants   [ Time Frame: Throughout study ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

9.  Secondary:   Rates of Disease Progression as Defined by CD4 Counts, HIV-1 RNA PCR, and Mortality in Infected Infants in the Two Arms   [ Time Frame: Throughout study ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

10.  Secondary:   NVP Concentrations in Infants Determined to be HIV-infected and in a Sample of HIV-uninfected Infants   [ Time Frame: Week 8 and Month 3 ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The rate of maternal highly active antiretroviral therapy use was higher than expected in our study. Thus there were fewer infant infections which decreased the power to detect differences in HIV transmission risks between study groups.


  More Information