Comparison of Three Hepatitis B Vaccination Regimens in HIV-Positive Youth

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT00106964
First received: April 1, 2005
Last updated: June 23, 2014
Last verified: April 2014
Results First Received: October 26, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Prevention
Conditions: HIV Infection
Hepatitis B
Interventions: Biological: Engerix-B 20 mcg
Biological: Engerix-B 40 mcg
Biological: Twinrix 720 EIA HAV Ag plus 20 mcg HBsAg

  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
This is a multi-site study. Accrual was open between April 2006 and January 2008. Participants were enrolled in the United States, South Africa, Brazil, and the Bahamas.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects were randomized into one of three arms using blocks of six and stratified by absolute CD4 count (less than 500 and 500 cells/mL or greater) and previous hepatitis B virus (HBV) vaccination (0,1). The randomization was restricted so that the percentage of subjects with CD4 count < = 200 cells/mL would not exceed 15% of subjects on any arm.

Reporting Groups
  Description
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
2: Engerix 40 mcg 40 mcg of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
3: Twinrix 20 mcg 20 mcg of Twinrix. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.

Participant Flow:   Overall Study
    1: Engerix 20 mcg     2: Engerix 40 mcg     3: Twinrix 20 mcg  
STARTED     118     126     127  
COMPLETED     105 [1]   111 [2]   120 [3]
NOT COMPLETED     13     15     7  
Lost to Follow-up                 8                 6                 2  
Pregnancy                 2                 3                 2  
Death                 1                 1                 0  
Incarceration                 0                 1                 0  
Site Funding Terminated                 0                 1                 1  
Failure to adhere                 2                 0                 0  
Did not meet eligibility criteria                 0                 2                 2  
Required disallowed medication                 0                 1                 0  
[1] The number of those those who completed the vaccine series was 105.
[2] The number of those who completed the vaccine series was 111.
[3] The number of those who completed the vaccine series was 120.



  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
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
2: Engerix 40 mcg 40 mcg of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
3: Twinrix 20 mcg 20 mcg of Twinrix. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
Total Total of all reporting groups

Baseline Measures
    1: Engerix 20 mcg     2: Engerix 40 mcg     3: Twinrix 20 mcg     Total  
Number of Participants  
[units: participants]
  118     126     127     371  
Age  
[units: years]
Mean ± Standard Deviation
  20.56  ± 3.42     20.96  ± 3.25     20.20  ± 3.50     20.57  ± 3.40  
Age, Customized  
[units: participants]
       
12-13 years     8     3     8     19  
14-15 years     5     11     10     26  
16-19 years     25     18     20     63  
>20 years     80     94     89     263  
Gender  
[units: participants]
       
Female     73     74     80     227  
Male     45     52     47     144  
Region of Enrollment  
[units: participants]
       
United States     52     54     49     155  
South Africa     4     6     13     23  
Brazil     52     58     58     168  
Bahamas     10     8     7     25  



  Outcome Measures
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1.  Primary:   Sero-response to Hepatitis B Surface Antigen   [ Time Frame: Week 28 ]

Measure Type Primary
Measure Title Sero-response to Hepatitis B Surface Antigen
Measure Description The primary outcome, percentage positive sero-response, was compared between Arm 1 and each of the two alternative strategy arms (Arm 2 and Arm 3) and measured 4 weeks after the third vaccination at Week 28. Response is defined as greater than or equal to 10 IU/mL of serum being present; non-response is defined as less than 10 IU/mL.
Time Frame Week 28  
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.
Participants who completed a Week 28 visit with a Hepatitis B serology result were included in this analysis.

Reporting Groups
  Description
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
2: Engerix 40 mcg 40 mcg of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
3: Twinrix 20 mcg 20 mcg of Twinrix. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.

Measured Values
    1: Engerix 20 mcg     2: Engerix 40 mcg     3: Twinrix 20 mcg  
Number of Participants Analyzed  
[units: participants]
  106     112     118  
Sero-response to Hepatitis B Surface Antigen  
[units: percentage of participants who resonded]
  60     73.2     75.4  


Statistical Analysis 1 for Sero-response to Hepatitis B Surface Antigen
Groups [1] 1: Engerix 20 mcg vs. 2: Engerix 40 mcg
Method [2] Chi-squared
P Value [3] 0.0440
[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] 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.

Statistical Analysis 2 for Sero-response to Hepatitis B Surface Antigen
Groups [1] 1: Engerix 20 mcg vs. 3: Twinrix 20 mcg
Method [2] Chi-squared
P Value [3] 0.0157
[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] 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.



2.  Secondary:   Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - POSSIBLY OR PROBABLY RELATED   [ Time Frame: Baseline through Week 72 ]

Measure Type Secondary
Measure Title Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - POSSIBLY OR PROBABLY RELATED
Measure Description The number of adverse events (AE) was described by study arm. The proportion of subjects with clinical adverse events in Arms 1 and each of the two alternative strategy arms (Arm 2 and Arm 3) were compared to assess whether or not there is a difference in patients with any grade toxicity.
Time Frame Baseline through Week 72  
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.
All enrolled participants were included in this analysis of all AEs that were possibly or probably related to study drug. There were no AEs above Grade 3 considered to be possibly or probably related to study drug.

Reporting Groups
  Description
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Number of participants with a Grade 1 event that was probably or possibly related to study drug as determined by the Site Investigator.
2: Engerix 40 mcg Engerix 40 mcg vaccine. Number of participants with a Grade 1 event that was probably or possibly related to study drug as determined by the Site Investigator.
3: Twinrix 20 mcg Twinrix 20 mcg vaccine. Number of participants with a Grade 1 event that was probably or possibly related to study drug as determined by the Site Investigator.

Measured Values
    1: Engerix 20 mcg     2: Engerix 40 mcg     3: Twinrix 20 mcg  
Number of Participants Analyzed  
[units: participants]
  118     126     127  
Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - POSSIBLY OR PROBABLY RELATED  
[units: Events]
     
Asthenia, Grade 1     0     0     1  
Arthralgia, Grade 3     1     0     0  
Headache, Grade 1     1     0     0  
Headache, Grade 2     2     0     0  
Somnolence, Grade 1     0     0     1  
Syncope Vasovagal, Grade 1     0     0     1  

No statistical analysis provided for Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - POSSIBLY OR PROBABLY RELATED



3.  Secondary:   Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - DEFINITELY RELATED   [ Time Frame: Baseline through Week 72 ]

Measure Type Secondary
Measure Title Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - DEFINITELY RELATED
Measure Description The number of AEs was described by study arm. The proportion of subjects with clinical AEs in Arms 1 and each of the two alternative strategy arms (Arm 2 and Arm 3)were compared to assess whether or not there is a difference in subjects with any grade toxicity.
Time Frame Baseline through Week 72  
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.
All enrolled participants were included in this analysis of AEs that were definitely related to study drug. There were no AEs above Grade 2 considered to be definitely related to study drug.

Reporting Groups
  Description
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Number of participants with a Grade 1 event that was definitely related to study drug as determined by the Site Investigator.
2: Engerix 40 mcg Engerix 40 mcg vaccine. Number of participants with a Grade 1 event that was definitely related to study drug as determined by the Site Investigator.
3: Twinrix 20 mcg Twinrix 20 mcg vaccine. Number of participants with a Grade 1 event that was definitely related to study drug as determined by the Site Investigator.

Measured Values
    1: Engerix 20 mcg     2: Engerix 40 mcg     3: Twinrix 20 mcg  
Number of Participants Analyzed  
[units: participants]
  118     126     127  
Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - DEFINITELY RELATED  
[units: event]
     
Injection Site Pain, Grade 1     1     0     1  
Myalgia, Grade 2     1     0     1  

No statistical analysis provided for Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth - ADVERSE EVENTS BY INTERVENTION ARM ON STUDY - DEFINITELY RELATED



4.  Secondary:   Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth – ABNORMAL LABORATORY VALUES GRADE 2 OR ABOVE BY INTERVENTION ARM ON STUDY   [ Time Frame: Baseline through Week 72 ]

Measure Type Secondary
Measure Title Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth – ABNORMAL LABORATORY VALUES GRADE 2 OR ABOVE BY INTERVENTION ARM ON STUDY
Measure Description The number of adverse events and subjects with the events were described by study arm. The proportion of subjects with abnormal labs in Arms 1 and each of the two alternative strategy arms (Arm 2 and Arm 3) were compared to assess whether or not there is a difference in subjects with grade 3 or 4 toxicity. The laboratory events included are AEs classified as probably, possibly, or definitely related to study drug as classified by the Site Investigator.
Time Frame Baseline through Week 72  
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.
All enrolled participants were included in this analysis. The following no. of participants experienced at least one Grade 2 or higher abnormal labs by study arm.

Reporting Groups
  Description
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
2: Engerix 40 mcg 40 mcg of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
3: Twindrix 20 mcg 20 mcg of Twinrix. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.

Measured Values
    1: Engerix 20 mcg     2: Engerix 40 mcg     3: Twindrix 20 mcg  
Number of Participants Analyzed  
[units: participants]
  102     109     118  
Number of Events Analyzed  
[units: Events]
  10     10     19  
Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth – ABNORMAL LABORATORY VALUES GRADE 2 OR ABOVE BY INTERVENTION ARM ON STUDY  
[units: Events]
     
Absolute Neutrophil Count     7     5     9  
Hemoglobin     0     1     2  
Platelets     0     2     1  
White Blood Cell count     3     2     7  

No statistical analysis provided for Safety of 3 Hepatitis B Vaccine Regimens in HIV+ Youth – ABNORMAL LABORATORY VALUES GRADE 2 OR ABOVE BY INTERVENTION ARM ON STUDY



5.  Secondary:   Response Rates in HIV+ Youth Within Each Study Arm by Study Duration   [ Time Frame: Entry through Week 72 ]

Measure Type Secondary
Measure Title Response Rates in HIV+ Youth Within Each Study Arm by Study Duration
Measure Description Within each arm, the duration of response in HIV-infected youth was analyzed for all subjects who were responders at 28 weeks. The possible values for response duration could be 20 weeks or less (responder at 28 weeks but not at 48 weeks), 20 to 44 weeks (responder at 28 and 48 weeks but not at 72 weeks), or greater than 44 weeks (responder at 28, 48, and 72 weeks). A response of greater than 20 weeks includes those who responded after 20 weeks, but whose exact response duration was unknown.
Time Frame Entry through Week 72  
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.
Population analyzed were those who had an antibody titer measured at Week 28.

Reporting Groups
  Description
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
2: Engerix 40 mcg 40 mcg of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
3: Twinrix 20 mcg 20 mcg of Twinrix. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.

Measured Values
    1: Engerix 20 mcg     2: Engerix 40 mcg     3: Twinrix 20 mcg  
Number of Participants Analyzed  
[units: participants]
  61     78     81  
Response Rates in HIV+ Youth Within Each Study Arm by Study Duration  
[units: percentage of participants who responded]
     
<= 20 weeks     27.87     19.23     22.22  
21 - 44 weeks     3.28     7.69     11.11  
> 20 weeks     4.92     12.82     3.70  
> 44 weeks     63.93     60.26     62.96  


Statistical Analysis 1 for Response Rates in HIV+ Youth Within Each Study Arm by Study Duration
Groups [1] 1: Engerix 20 mcg vs. 2: Engerix 40 mcg
Method [2] Regression, Cox
P Value [3] 0.5822
Hazard Ratio (HR) [4] 0.840
[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] 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.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Response Rates in HIV+ Youth Within Each Study Arm by Study Duration
Groups [1] 1: Engerix 20 mcg vs. 3: Twinrix 20 mcg
Method [2] Regression, Cox
P Value [3] 0.8698
Hazard Ratio (HR) [4] 1.050
[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] 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.
[4] Other relevant estimation information:
  No text entered.



6.  Secondary:   Sero-Response to Hepatitis B Surface Antigen; Predictor: STUDY ARM   [ Time Frame: Week 28 ]

Measure Type Secondary
Measure Title Sero-Response to Hepatitis B Surface Antigen; Predictor: STUDY ARM
Measure Description Response rate associated with the participant's study arm, baseline CD4 count, and interaction term that reflects how subjects in Arm 2 responded differently depending on their CD4 count. Response is defined as greater than or equal to 10 IU/mL of serum being present; non-response is defined as less than 10 IU/mL.
Time Frame Week 28  
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 participants who had a Week 28 Hepatitis B serology result

Reporting Groups
  Description
2: Engerix 40 mcg 40 mcg of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
1: Engerix 20 mcg Standard dose (20 mcg) of Hepatitis B vaccine. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.
3: Twinrix 20 mcg 20 mcg of Twinrix. Dose #1 at Entry; Dose #2 at Week 4; Dose #3 at Week 24.

Measured Values
    2: Engerix 40 mcg     1: Engerix 20 mcg     3: Twinrix 20 mcg  
Number of Participants Analyzed  
[units: participants]
  112     106     118  
Sero-Response to Hepatitis B Surface Antigen; Predictor: STUDY ARM  
[units: percentage of participants who responded]
  73.2     60     75.4  


Statistical Analysis 1 for Sero-Response to Hepatitis B Surface Antigen; Predictor: STUDY ARM
Groups [1] 2: Engerix 40 mcg vs. 1: Engerix 20 mcg
Method [2] Regression, Logistic
P Value [3] 0.0853
Odds Ratio (OR) [4] 0.29
95% Confidence Interval ( 0.07 to 1.19 )
[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] 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.
[4] Other relevant estimation information:
  Adjusted odds ratio (OR) Odds ratio depends on CD4 count resulting from interaction. For example, OR=0.29 for CD4 count = 0; OR= 2.91 for CD4 count = 460 (median CD4 count for the evaluable study population).

Statistical Analysis 2 for Sero-Response to Hepatitis B Surface Antigen; Predictor: STUDY ARM
Groups [1] 1: Engerix 20 mcg vs. 3: Twinrix 20 mcg
Method [2] Regression, Logistic
P Value [3] 0.0244
Odds Ratio (OR) [4] 1.99
95% Confidence Interval ( 1.09 to 3.63 )
[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] 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.
[4] Other relevant estimation information:
  Adjusted odds ratio




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
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