Tuberculosis Treatment Shortening Trial

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00130247
First received: August 12, 2005
Last updated: January 31, 2013
Last verified: April 2010
Results First Received: August 20, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Tuberculosis
Interventions: Drug: Pyrazinamide
Drug: Rifampin
Drug: Isoniazid
Drug: Ethambutol

  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-uninfected 18 to 60 year old adults with suspected or newly diagnosed pulmonary tuberculosis were eligible for enrollment at participating sites in Kampala, Uganda; Vitória, Brazil; and Manila/Makati City, the Philippines. Screening began in April 2002 in Uganda, December 2002 in Brazil, and November 2003 in the Philippines.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects who met eligibility criteria were started on standard chemotherapy and routinely followed during anti-TB therapy. Patients with drug-susceptible TB who were sputum culture negative after 2 months of treatment were randomly assigned at 4 months to stop treatment or received an additional 2 months of daily isoniazid (INH) and rifampicin.

Reporting Groups
  Description
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Participant Flow:   Overall Study
    4-Month Arm     6-Month Arm  
STARTED     196     198  
COMPLETED     194     194  
NOT COMPLETED     2     4  
Pregnancy                 1                 0  
Post-randomization exclusion                 1                 2  
Not compliant with DOT                 0                 2  



  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
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.
Total Total of all reporting groups

Baseline Measures
    4-Month Arm     6-Month Arm     Total  
Number of Participants  
[units: participants]
  196     198     394  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     196     198     394  
>=65 years     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  31.2  ± 10     30.3  ± 10     30.8  ± 10  
Gender  
[units: participants]
     
Female     77     78     155  
Male     119     120     239  
Region of Enrollment  
[units: participants]
     
Philippines     47     48     95  
Brazil     81     81     162  
Uganda     68     69     137  



  Outcome Measures
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1.  Primary:   Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat   [ Time Frame: 30 months ]

Measure Type Primary
Measure Title Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat
Measure Description Patients who presented with TB after completion of study phase treatment but before the end of follow-up were classified as relapses. A bacteriologic relapse was defined as a patient who became consistently culture-positive [defined as at least 1 of the following]: (a) at least 1 sputum mycobacterial culture growing at least 10 colonies of MTB on solid medium; (b) 2 or more respiratory secretion cultures that are positive for MTB in liquid media; or (c) any culture from an extrapulmonary site that is positive for MTB during follow-up after successful completion of initial anti-TB treatment.
Time Frame 30 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.
The intention to treat (ITT) analysis included all 394 fully eligible and randomized patients allocated to the shortened 4-month treatment group (N=196) or the standard 6-month treatment group (N=198). There were no allocated patients excluded in the ITT analysis dataset.

Reporting Groups
  Description
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Measured Values
    4-Month Arm     6-Month Arm  
Number of Participants Analyzed  
[units: participants]
  196     198  
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat  
[units: Participants]
  13     3  


Statistical Analysis 1 for Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Cox
Risk Difference (RD) [4] 0.051
95% Confidence Interval ( 0.01 to 0.09 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Comparison of binomial proportion of relapse: Intention-to-treat
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  This two-sided equivalence trial compared the efficacy of 4 and 6 months of treatment. We assumed that the risk of relapse for patients in the 6 month arm was 3.5% and that an absolute difference of 5% (i.e. relapse rate of 8.5%) was clinically meaningful. For a level of significance of 0.05 and 80% power (two sided), we estimated that 284 evaluable subjects per arm were required.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Other relevant estimation information:
  Confidence interval for difference of binomial proportions adjusted with Hauck Anderson continuity correction.



2.  Primary:   Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol   [ Time Frame: 30 months ]

Measure Type Primary
Measure Title Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol
Measure Description Patients who presented with TB after completion of study phase treatment but before the end of follow-up were classified as relapses. A bacteriologic relapse was defined as a patient who became consistently culture-positive [defined as at least 1 of the following]: (a) at least 1 sputum mycobacterial culture growing at least 10 colonies of MTB on solid medium; (b) 2 or more respiratory secretion cultures that are positive for MTB in liquid media; or (c) any culture from an extrapulmonary site that is positive for MTB during follow-up after successful completion of initial anti-TB treatment.
Time Frame 30 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.
The per-protocol analysis included all 370 patients (185 per treatment arm) who received the intervention, completed treatment and full follow-up and did not have exogenous reinfection of TB. The 24 excluded subjects included 2 patients with exogenous reinfection of TB, 12 lost to follow-up, 4 deaths, and 6 who did not receive the intervention.

Reporting Groups
  Description
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Measured Values
    4-Month Arm     6-Month Arm  
Number of Participants Analyzed  
[units: participants]
  185     185  
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol  
[units: Participants]
  13     3  


Statistical Analysis 1 for Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Regression, Cox
Risk Difference (RD) [4] 0.054
95% Confidence Interval ( 0.01 to 0.10 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  This two-sided equivalence trial compared the efficacy of 4 and 6 months of treatment. We assumed that the risk of relapse for patients in the 6 month arm was 3.5% and that an absolute difference of 5% (i.e. relapse rate of 8.5%) was clinically meaningful. For a level of significance of 0.05 and 80% power (two sided), we estimated that 284 evaluable subjects per arm were required.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Other relevant estimation information:
  Confidence interval for difference of binomial proportions adjusted with Hauck Anderson continuity correction.



3.  Secondary:   Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat   [ Time Frame: 2 years ]

Measure Type Secondary
Measure Title Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat
Measure Description A culture-positive treatment failure was defined as initial culture conversion but subsequent reversion to culture positivity. A clinical treatment failure was defined as a patient with clinical and/or radiographic evidence of progressive tuberculosis not confirmed by a positive culture after 4 or more months of anti-TB treatment while still receiving treatment. Patients who defaulted before completing study treatment and returned later with culture-positive tuberculosis were termed failures after non-adherence.
Time Frame 2 years  
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.
The intention to treat (ITT) analysis included all 394 fully eligible and randomized patients allocated to the shortened 4-month treatment group (N=196) or the standard 6-month treatment group (N=198). There were no allocated patients excluded in the ITT analysis dataset.

Reporting Groups
  Description
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Measured Values
    4-Month Arm     6-Month Arm  
Number of Participants Analyzed  
[units: participants]
  196     198  
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat  
[units: Participants]
   
Treatment Failures     0     0  
Relapses     13     3  

No statistical analysis provided for Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat



4.  Secondary:   Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol   [ Time Frame: 2 years ]

Measure Type Secondary
Measure Title Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol
Measure Description A culture-positive treatment failure was defined as initial culture conversion but subsequent reversion to culture positivity. A clinical treatment failure was defined as a patient with clinical and/or radiographic evidence of progressive tuberculosis not confirmed by a positive culture after 4 or more months of anti-TB treatment while still receiving treatment. Patients who defaulted before completing study treatment and returned later with culture-positive tuberculosis were termed failures after non-adherence.
Time Frame 2 years  
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.
The per-protocol analysis included all 370 patients (185 per treatment arm) who received the intervention, completed treatment and full follow-up and did not have exogenous reinfection of TB. The 24 excluded subjects included 2 patients with exogenous reinfection of TB, 12 lost to follow-up, 4 deaths, and 6 who did not receive the intervention.

Reporting Groups
  Description
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Measured Values
    4-Month Arm     6-Month Arm  
Number of Participants Analyzed  
[units: participants]
  185     185  
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol  
[units: Participants]
   
Treatment Failures     0     0  
Relapses     13     3  

No statistical analysis provided for Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol



5.  Secondary:   Relapses at 1 and 2 Years   [ Time Frame: 1 and 2 years after successful completion of initial anti-TB treatment ]

Measure Type Secondary
Measure Title Relapses at 1 and 2 Years
Measure Description No text entered.
Time Frame 1 and 2 years after successful completion of initial anti-TB treatment  
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.
Analysis includes the 386 patients who received the intervention, completed treatment, and started post-treatment follow-up (193 patients in each treatment arm). Two subjects were lost after completing treatment and contributed no follow-up time, and 6 subjects did not receive the intervention so were not included in the analysis.

Reporting Groups
  Description
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Measured Values
    4-Month Arm     6-Month Arm  
Number of Participants Analyzed  
[units: participants]
  193     193  
Relapses at 1 and 2 Years  
[units: Participants]
   
Relapses at 1 year     10     3  
Relapses at 2 years     13     3  


Statistical Analysis 1 for Relapses at 1 and 2 Years
Groups [1] All groups
Method [2] Regression, Linear
Incidence rate ratio [3] 3.43
95% Confidence Interval ( 0.94 to 12.5 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Rate of relapse at 1 year. All patients adherent with treatment and remaining in follow-up at 1 year were included in the calculation of the relapse incidence rate.
[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 Relapses at 1 and 2 Years
Groups [1] All groups
Method [2] Regression, Linear
Incident rate ratio [3] 4.52
95% Confidence Interval ( 1.29 to 15.9 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Rate of relapse at 2 years. All patients adherent with treatment and remaining in follow-up at 2 years were included in the calculation of the relapse incidence rate.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



6.  Secondary:   Acquired Drug Resistance in Patients Who Relapsed   [ Time Frame: 2 years ]

Measure Type Secondary
Measure Title Acquired Drug Resistance in Patients Who Relapsed
Measure Description No text entered.
Time Frame 2 years  
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.
This analysis was per protocol and looked for acquired drug resistance among the 13 patients in the 4-Month Arm who relapsed and the 3 patients in the 6-Month Arm who relapsed.

Reporting Groups
  Description
4-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.
6-Month Arm Daily treatment with INH, rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Measured Values
    4-Month Arm     6-Month Arm  
Number of Participants Analyzed  
[units: participants]
  13     3  
Acquired Drug Resistance in Patients Who Relapsed  
[units: Participants]
  0     0  

No statistical analysis provided for Acquired Drug Resistance in Patients Who Relapsed



7.  Secondary:   Immunologic: Changes in Cytokine Levels in Mycobacterium Tubercolosis (MTB) Antigen-stimulated Whole Blood Culture Supernatants - Results Are Pending   [ Time Frame: After 2 and 6 months of anti-TB treatment and upon relapse ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

8.  Secondary:   Immunologic: Store Peripheral Blood Mononuclear Cells (PBMC) - Results Are Pending   [ Time Frame: Pre-treatment and serum pre-treatment after 2 and 6 months of anti-TB treatment, and at the time of relapse for future immunologic analysis ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

9.  Secondary:   Immunologic: Changes in Sputum Cytokine Levels - Results Are Pending   [ Time Frame: After 1 and 2 months of anti-TB treatment ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

10.  Secondary:   Microbiologic: Changes in Sputum Mycobacterial mRNA - Results Are Pending   [ Time Frame: At 1 and 2 months of anti-TB treatment, and upon relapse ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

11.  Secondary:   Microbiologic: Time After Inoculation Until Culture Positive in BACTEC 460 or MGIT 960 Enriched Liquid Media After 2 Months in Treatment - Results Are Pending   [ Time Frame: Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and 30 ]
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
Enrollment was stopped early and the number of patients enrolled was 1/2 of the original sample size. The study was completed.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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:  
Name/Title: John L. Johnson, M.D., Principal Investigator
Organization: Case Western Reserve University, Tuberculosis Research Unit
phone: (216) 368-1949
e-mail: jlj@case.edu


Publications of Results:
Other Publications:

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00130247     History of Changes
Other Study ID Numbers: 01-009, TBRU 8
Study First Received: August 12, 2005
Results First Received: August 20, 2009
Last Updated: January 31, 2013
Health Authority: United States: Food and Drug Administration
United States: Federal Government
United States: Institutional Review Board
Philippines: Institutional Review Board or Ethics Committee of Makerere University
Uganda: Institutional Review Board