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Lamivudine and Adefovir to Treat Chronic Hepatitis B

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Marc Ghany, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT00023309
First received: September 3, 2001
Last updated: July 18, 2014
Last verified: July 2014
Results First Received: July 7, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: HBV (Hepatitis B Virus)
Hepatitis B
Hepatitis
Interventions: Drug: Lamivudine and adefovir
Drug: Adefovir alone

  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
Forty-one patients were enrolled, twenty-two were randomized to receive the combination lamivudine and adefovir and nineteen to receive adefovir alone.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Lamivudine and Adefovir Patients to receive combination lamivudine and adefovir, with lamivudine of 100 mg daily and adefovir of 10 mg daily
Adefovir Patients to receive adefovir alone (10 mg daily).

Participant Flow:   Overall Study
    Lamivudine and Adefovir     Adefovir  
STARTED     22     19  
COMPLETED     22     19  
NOT COMPLETED     0     0  



  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
Lamivudine and Adefovir Patients to receive combination lamivudine and adefovir
Adefovir Patients to receive adefovir alone
Total Total of all reporting groups

Baseline Measures
    Lamivudine and Adefovir     Adefovir     Total  
Number of Participants  
[units: participants]
  22     19     41  
Age  
[units: years]
Mean ± Standard Deviation
  46  ± 14     45  ± 13     45  ± 14  
Gender  
[units: participants]
     
Female     6     1     7  
Male     16     18     34  
Race/Ethnicity, Customized  
[units: participants]
     
White     9     8     17  
Asian     9     10     19  
Black     4     1     5  
Region of Enrollment  
[units: participants]
     
United States     22     19     41  
Treatment Naive  
[units: participants]
     
Yes     17     14     31  
No     5     5     10  
HBeAg positive  
[units: participants]
     
Yes     17     14     31  
No     5     5     10  
ALT [1]
[units: IU/ml]
Mean ± Standard Deviation
  183  ± 250     87  ± 56     139  ± 187  
HBV DNA Log 10 copies per ml [2]
[units: log10(copies/ml)]
Mean ± Standard Deviation
  8.1  ± 1.3     7.8  ± 1.6     8.0  ± 1.4  
HAI [3]
[units: Units on a scale]
Mean ± Standard Deviation
  8.1  ± 2.7     7.9  ± 2.4     8.0  ± 2.6  
Ishak [4]
[units: Units on a scale]
Mean ± Standard Deviation
  3.3  ± 1.7     2.4  ± 1.5     2.9  ± 1.6  
Cirrhosis  
[units: participants]
     
Yes     5     2     7  
No     17     17     34  
[1] Alanine transaminase
[2] Hepatitis B virus DNA logarithm 10 copies per ml
[3] HAI Fibrosis score for liver histology, which has a range 0–18 and higher values represent a worse outcome
[4] Ishak Fibrosis Score, (range 0–6, where 0 = no fibrosis and 6 = cirrhosis)



  Outcome Measures
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1.  Primary:   Maintained Combined Response (Virological, Biochemical and Histological Response).   [ Time Frame: 196 weeks from randomization ]

Measure Type Primary
Measure Title Maintained Combined Response (Virological, Biochemical and Histological Response).
Measure Description A maintained combined response was defined as a combination of a virological, biochemical and histological responses at weeks 48 and 192. A virological response was defined as a decrease in HBV DNA levels to undetectable by the Amplicor assay (<500 copies/mL). A biochemical response was defined as a decrease in serum ALT levels into the normal range (<41 U/L). A histological response was defined as a decrease in the HAI score by at least three points with no worsening of the Ishak fibrosis score.
Time Frame 196 weeks from randomization  
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.
The analysis was intention to treat. Patients with missing values at week 196 were treated as random missing. No imputation was applied.

Reporting Groups
  Description
Lamivudine and Adefovir Patients to receive combination lamivudine and adefovir
Adefovir Patients to receive adefovir alone

Measured Values
    Lamivudine and Adefovir     Adefovir  
Number of Participants Analyzed  
[units: participants]
  22     19  
Maintained Combined Response (Virological, Biochemical and Histological Response).  
[units: participants]
   
Yes     15     6  
No     7     13  


Statistical Analysis 1 for Maintained Combined Response (Virological, Biochemical and Histological Response).
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.0294
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Null hypothesis: there is no difference in the treatment effect between the two groups
[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:   HBeAg Loss at Week 196   [ Time Frame: Week 196 from randomization ]

Measure Type Secondary
Measure Title HBeAg Loss at Week 196
Measure Description Loss of hepatitis B surface antigen (HBsAg) at week 196
Time Frame Week 196 from randomization  
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.
Analysis was intention to treat. Patients with missing values at timeframe of interest was taken as random missing. No imputation was applied.

Reporting Groups
  Description
Lamivudine and Adefovir Patients to receive combination lamivudine and adefovir
Adefovir Patients to receive adefovir alone

Measured Values
    Lamivudine and Adefovir     Adefovir  
Number of Participants Analyzed  
[units: participants]
  17     14  
HBeAg Loss at Week 196  
[units: participants]
   
Yes     13     5  
No     4     9  


Statistical Analysis 1 for HBeAg Loss at Week 196
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.0325
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Null hypothesis: there is no difference in treatment effect at week 196
[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.



3.  Secondary:   Virological Response   [ Time Frame: Week 196 from randomization ]

Measure Type Secondary
Measure Title Virological Response
Measure Description A virological response was defined as a decrease in HBV DNA levels to undetectable by the Amplicor assay (<500 copies/mL).
Time Frame Week 196 from randomization  
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.
Intention to treat

Reporting Groups
  Description
Lamivudine and Adefovir Patients to receive combination lamivudine and adefovir
Adefovir Patients to receive adefovir alone

Measured Values
    Lamivudine and Adefovir     Adefovir  
Number of Participants Analyzed  
[units: participants]
  22     19  
Virological Response  
[units: participants]
   
Yes     17     6  
No     5     13  


Statistical Analysis 1 for Virological Response
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.0049
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Null hypothesis: there is no difference in treatment effect at week 196
[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.  Secondary:   Biological Response   [ Time Frame: week 196 from randomization ]

Measure Type Secondary
Measure Title Biological Response
Measure Description A biochemical response was defined as a decrease in serum ALT levels into the normal range (<41 U/L).
Time Frame week 196 from randomization  
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.
Intention to treat

Reporting Groups
  Description
Lamivudine and Adefovir Patients to receive combination lamivudine and adefovir
Adefovir Patients to receive adefovir alone

Measured Values
    Lamivudine and Adefovir     Adefovir  
Number of Participants Analyzed  
[units: participants]
  22     19  
Biological Response  
[units: participants]
   
Yes     21     12  
No     1     7  


Statistical Analysis 1 for Biological Response
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.0157
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Null hypothesis: there is no difference in treatment effect at week 196
[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.



5.  Secondary:   Histological Response   [ Time Frame: week 196 from randomization ]

Measure Type Secondary
Measure Title Histological Response
Measure Description A histological response was defined as a decrease in the HAI score by at least three points with no worsening of the Ishak fibrosis score.
Time Frame week 196 from randomization  
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.
Analysis was intention to treat. Patients with missing values at timeframe of interest was taken as random missing. No imputation was applied.

Reporting Groups
  Description
Lamivudine and Adefovir Patients to receive combination lamivudine and adefovir
Adefovir Patients to receive adefovir alone

Measured Values
    Lamivudine and Adefovir     Adefovir  
Number of Participants Analyzed  
[units: participants]
  18     10  
Histological Response  
[units: participants]
   
Yes     15     5  
No     3     5  


Statistical Analysis 1 for Histological Response
Groups [1] All groups
Method [2] Fisher Exact
P Value [3] 0.0913
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Null hypothesis: there is no difference in treatment effect at week 196
[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.




  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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  More Information