Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis (STRIDE)

This study has been completed.
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00108862
First received: April 19, 2005
Last updated: January 4, 2016
Last verified: January 2016
Results First Received: September 27, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: HIV Infection
Tuberculosis
Interventions: Other: Strategy: Immediate ART
Other: Strategy: Deferred ART

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study participants were recruited at 26 sites from 13 countries: 4 each from U.S. and South Africa; 3 from Brazil; 2 each from Peru, Botswana, Kenya, Malawi, and India; and 1 each from Haiti, Uganda, Zambia, Zimbabwe, and Thailand, between September 2006 and August 2009.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
HIV-infected persons at least 13 years of age, naive to antiretroviral therapy, who had received 1-14 cumulative days of a rifamycin-based TB regimen within 28 days prior to study entry, and had a CD4 count <250 cells/mm3. Randomization was stratified by screening CD4 (<50 vs =>50). Three participants were deemed ineligible and taken off study.

Reporting Groups
  Description
Immediate ART These participants initiated HIV antiretroviral therapy (ART) within 72 hours of randomization, which took place at most 2 weeks after initiating rifampin (RIF)- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were efavirenz (EFV) 600 mg (provided to non-U.S. sites only; 1 tablet orally) and emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered nevirapine (NVP) 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. Food and Drug Administration (FDA)-approved or tentatively approved antiretrovirals (ARVs) that were compatible with TB therapy could be used at the discretion of the site investigator.
Deferred ART These participants deferred ART until 8 to 12 weeks after initiation of their RIF- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were EFV 600 mg (provided to non-U.S. sites only; 1 tablet orally) and FTC 200 mg/TDF 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered NVP 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. FDA-approved or tentatively approved ARVs that were compatible with TB therapy could be used at the discretion of the site investigator.

Participant Flow:   Overall Study
    Immediate ART   Deferred ART
STARTED   405   401 [1] 
COMPLETED   337   339 
NOT COMPLETED   68   62 
Death                31                37 
Withdrawal by Subject                10                6 
Lost to Follow-up                27                19 
[1] Three participants who were deemed clinically ineligible and taken off study were omitted.



  Baseline Characteristics
  Hide Baseline Characteristics

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
Immediate ART These participants initiated HIV antiretroviral therapy (ART) within 72 hours of randomization, which took place at most 2 weeks after initiating rifampin (RIF)- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were efavirenz (EFV) 600 mg (provided to non-U.S. sites only; 1 tablet orally) and emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered nevirapine (NVP) 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. Food and Drug Administration (FDA)-approved or tentatively approved antiretrovirals (ARVs) that were compatible with TB therapy could be used at the discretion of the site investigator.
Deferred ART These participants deferred ART until 8 to 12 weeks after initiation of their RIF- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were EFV 600 mg (provided to non-U.S. sites only; 1 tablet orally) and FTC 200 mg/TDF 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered NVP 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. FDA-approved or tentatively approved ARVs that were compatible with TB therapy could be used at the discretion of the site investigator.
Total Total of all reporting groups

Baseline Measures
   Immediate ART   Deferred ART   Total 
Overall Participants Analyzed 
[Units: Participants]
 405   401   806 
Age 
[Units: Participants]
     
<=18 years   0   2   2 
Between 18 and 65 years   403   398   801 
>=65 years   2   1   3 
Age 
[Units: Years]
Median (Inter-Quartile Range)
 34 
 (29 to 40) 
 34 
 (29 to 42) 
 34 
 (29 to 41) 
Gender 
[Units: Participants]
     
Female   139   166   305 
Male   266   235   501 
Region of Enrollment 
[Units: Participants]
     
South Africa   109   112   221 
Malawi   69   68   137 
Brazil   57   56   113 
Kenya   36   36   72 
Peru   23   25   48 
India   26   21   47 
Zambia   17   17   34 
Zimbabwe   16   17   33 
Uganda   15   14   29 
Botswana   13   15   28 
Haiti   12   8   20 
United States   9   10   19 
Thailand   3   2   5 
TB Diagnosis Level at Entry 
[Units: Participants]
     
Confirmed TB   193   181   374 
Probable TB   208   218   426 
Not TB   4   2   6 
Drug-Resistant TB Status at Entry 
[Units: Participants]
     
Rifampin (RIF) Resistant TB   1   0   1 
Isoniazid (INH) Resistant TB   3   5   8 
RIF and INH Resistant TB (Multi-Drug Resistant TB)   1   4   5 
RIF and INH Sensitive TB   400   392   792 
Time to ART Start from Start of TB Medications 
[Units: Days]
Median (Inter-Quartile Range)
 10 
 (7 to 12) 
 70 
 (66 to 75) 
 14 
 (10 to 70) 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percent of Participants Who Survived Without AIDS Progression.   [ Time Frame: Through week 48 ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Percent of Participants Who Survived Without AIDS Progression.
Measure Description As this was a study of the strategy of providing antiretroviral therapy (ART) during the initial treatment of TB versus deferring ART until TB was treated for 8-12 weeks, all eligible participants randomized were followed for 48 weeks, whether they started ART as scheduled, whether they started ART at all, or even if the participant did not have TB and discontinued TB treatment. The percent surviving without a new AIDS-defining illness was calculated using a Kaplan-Meier estimator with an associated standard error.
Time Frame Through week 48  
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.
Numbers presented use the intent-to-treat approach (i.e., ignoring changes from randomized treatment strategy).

Reporting Groups
  Description
Immediate ART These participants initiated HIV antiretroviral therapy (ART) within 72 hours of randomization, which took place at most 2 weeks after initiating rifampin (RIF)- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were efavirenz (EFV) 600 mg (provided to non-U.S. sites only; 1 tablet orally) and emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered nevirapine (NVP) 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. Food and Drug Administration (FDA)-approved or tentatively approved antiretrovirals (ARVs) that were compatible with TB therapy could be used at the discretion of the site investigator.
Deferred ART These participants deferred ART until 8 to 12 weeks after initiation of their RIF- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were EFV 600 mg (provided to non-U.S. sites only; 1 tablet orally) and FTC 200 mg/TDF 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered NVP 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. FDA-approved or tentatively approved ARVs that were compatible with TB therapy could be used at the discretion of the site investigator.

Measured Values
   Immediate ART   Deferred ART 
Participants Analyzed 
[Units: Participants]
 405   401 
Percent of Participants Who Survived Without AIDS Progression. 
[Units: Percent of participants]
Number (95% Confidence Interval)
 13 
 (10 to 16) 
 16 
 (12 to 20) 


Statistical Analysis 1 for Percent of Participants Who Survived Without AIDS Progression.
Groups [1] All groups
Method [2] Z-test, 2-sided
P Value [3] 0.45
Mean Difference (Final Values) [4] 3
Standard Error of the mean (3)
95.08% Confidence Interval -2 to 8
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Assuming that immediate ART was better than deferred ART and that the combined rate in the deferred ART arm was 25% compared to 15% in the immediate ART arm (a 40% reduction), and assuming 10% loss to follow-up in a two-sided, two-sample 0.05-level asymptotically-normal test with 400 participants in each arm, there was 90% power. The percents tested were Kaplan-Meier estimators at week 48 with the associated Greenwood's variance.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  A 2-sided Z-test was used to compare the two percents. The test was weighted by the inverse of the Greenwood's variance in each CD4 stratum.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The analysis was stratified by screening CD4 (<50 cells/mm3 vs =>50). Interim reviews employed group sequential monitoring using an O'Brien-Fleming use function. At final analysis, the a priori threshold for statistical significance was 0.0492.
[4] Other relevant estimation information:
  The difference in percents was calculated as the percent failed in the Deferred ART arm minus the percent failed in the Immediate ART arm.



2.  Secondary:   Percent of Participants Reporting a Grade 3 or 4 Adverse Event or Laboratory Abnormality   [ Time Frame: Through week 48 ]

3.  Secondary:   Time to First New AIDS-defining Illness or Death.   [ Time Frame: Through week 48 ]

4.  Secondary:   Percent of Participants With Culture-confirmed Tuberculosis (TB) Who Survived Without AIDS Progression.   [ Time Frame: Through week 48 ]

5.  Secondary:   Percent of Participants Who Interrupted or Discontinued at Least One Tuberculosis (TB) Medication Due to Toxicity.   [ Time Frame: Through week 48 ]

6.  Secondary:   Percent of Participants With Confirmed or Probable Tuberculosis (TB) Whose TB Resolved, or Who Required TB Treatment Through the End of Follow-up, or Died, or Were Lost to Follow-up.   [ Time Frame: Through week 48 ]

7.  Secondary:   Percent of Participants Whose CD4 Increased by at Least 100 Cells/mm^3 Between Baseline and Week 48.   [ Time Frame: Through week 48 ]

8.  Secondary:   Percent of Participants With MTB IRIS.   [ Time Frame: Through week 48 ]

9.  Secondary:   Percent of Participants With HIV IRIS.   [ Time Frame: Through week 48 ]

10.  Secondary:   Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.   [ Time Frame: Through week 48 ]

11.  Other Pre-specified:   Percent of Participants in the Less Than 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression.   [ Time Frame: Through week 48 ]

12.  Other Pre-specified:   Percent of Participants in the Greater Than or Equal to 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression.   [ Time Frame: Through week 48 ]


  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
No text entered.


  More Information