Tuberculosis
Conditions
Keywords
Brazil, Philippines, Tuberculosis, Uganda
Brief summary
Tuberculosis (TB) is a serious infection that can affect the lungs and other parts of the body. The usual way to treat TB is to take 4 medicines by mouth every day for 2 months, then take 2 of the same medicines for 4 more months, for a total of 6 months. The purpose of this study is to see if taking 4 months of TB medicines is as effective in curing some TB patients as taking 6 months of TB medicines. Study participants will include 758 human immunodeficiency virus (HIV)-non-infected individuals, ages 18-60. Participants will be treated with 4 standard drugs called isoniazid, rifampicin, pyrazinamide and ethambutol. All individuals will take TB medicines for at least 4 months. After 4 months of treatment, if no TB germs are growing in sputum samples, participants will be assigned to either stop taking TB medicine (4 months of treatment) or to continue taking TB drugs for 2 more months (6 months of treatment). Participants will be involved in study procedures for up to 30 months.
Detailed description
Tuberculosis (TB) is a major global health problem. TB is the current leading cause of death due to an identifiable infectious agent worldwide. One of the highest priorities for tuberculosis control programs is to shorten anti-TB treatment while maintaining its effectiveness. Current 6-month short course chemotherapy regimens are over 95% effective for the treatment of tuberculosis when fully administered. Six months is a long time, however, and patients frequently discontinue anti-TB treatment once their symptoms have improved. The duration of standard short course chemotherapy is one of the major obstacles to its successful application and poses substantial challenges to programs with respect to patient adherence, program resource needs, and logistical requirements for directly observed therapy. The primary objective of this study is to assess the efficacy of shortening anti-TB treatment to 4 months in human immunodeficiency virus (HIV)-non-infected adults with drug-susceptible, non-cavitary pulmonary tuberculosis who convert their sputum culture to negative after 2 months of treatment. Secondary objectives of this study include: comparing pre-treatment sputum bacillary load in patients with and without cavitary disease; compare time after inoculation of BACTEC or Mycobacteria growth indicator tube (MGIT) liquid culture media until positive with semi-quantitative sputum acid fast bacteria (AFB) smear and culture on solid media as measures of pre-treatment sputum bacillary load; and determining the influence of immunologic characteristics of subjects pre-treatment, during treatment and at the end of therapy on rate of bacillary clearance and risk for relapse. A total of 758 HIV-non-infected adults, male or female, 18-60 years of age, with newly diagnosed initial episodes of sputum AFB smear-positive or -negative, culture-positive, non-cavitary, drug-susceptible pulmonary TB who are sputum culture negative after 2 months of anti-TB treatment will be randomly assigned to complete a total of 4 or 6 months of anti-TB therapy. The experimental regimen will include a total of 4 months of anti-TB treatment \[2 months of daily isoniazid (INH), rifampicin, pyrazinamide and ethambutol followed by 2 months of daily INH and rifampicin\]. The comparative regimen will include a total of 6 months standard short course anti-TB chemotherapy (2 months of daily INH, rifampicin, pyrazinamide and ethambutol followed by 4 months of daily INH and rifampicin). Subjects will be involved in study related procedures for approximately 30 months after beginning the initial anti-TB treatment.
Interventions
DRUGEthambutol
Mycobacteriostatic agent given to prevent emergence of drug resistance to other 1st line drugs; dosages are 15-25 milligram (mg)/ kilogram (kg)/day (d).
DRUGIsoniazid
Hydrazide of isonicotininc acid; antimicrobial activity is limited to mycobacteria where it inhibits the synthesis of mycolic acids.
DRUGPyrazinamide
1st line bactericidal agent; dosages are 15-30 mg/kg/d, up to 2 grams (gm)/d.
DRUGRifampin
1st line bactericidal agent which inhibits deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase; dosages are 10 mg/kg/d (up to 600 mg/d).
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
-Adults, male or female, aged 18-60. -Newly diagnosed initial episodes of pulmonary tuberculosis. Sputum smear-positive and -negative patients are eligible for enrollment. The diagnosis of tuberculosis must be confirmed by culture. Acid fast bacteria (AFB) smear positive patients found later not to have tuberculosis (TB) (i.e. those with non-tuberculous mycobacterial disease) and those without culture confirmation \[at least one culture on solid media growing \> 10 colonies of Mycobacterium tuberculosis (MTB) or a positive BACTEC or Mycobacteria growth indicator tube (MGIT) enriched liquid culture growing MTB\] will be removed from the study. -Chest X-ray and clinical findings consistent with tuberculosis. -Hemoglobin greater than or equal to 8 gm/dL (greater than or equal to 5.0 mmol/L). -Serum creatinine \< 2 mg/dL (\< 177 micro mol/L). -Serum aspartate aminotransferase (AST) \< 1.5 times the upper limit of normal for the testing laboratory, and serum total bilirubin \< 1.3 mg/dL (22.2 micro mol/L). -Random serum glucose less than or equal to 150 mg/dl (8.3 mmol/L). -Ambulatory. -Willing to provide informed consent for study participation, provide required specimens for examination, and to undergo and receive results of human immunodeficiency virus (HIV) testing. -Willing to receive supervised anti-TB treatment. -Completion of the required 112 doses of chemotherapy within 18 weeks of starting treatment.
Exclusion criteria
-Human immunodeficiency virus (HIV)-infected. -History of prior tuberculosis or history of previous tuberculosis treatment. -Pregnant or breastfeeding. -Cavitary tuberculosis on initial chest X-ray (taken within 14 days of study entry). -Exposure to person(s) with known drug resistant tuberculosis. -Patients receiving chronic steroids or other immunosuppressive medications. -Extra-pulmonary tuberculosis. -Patients with drug resistant tuberculosis (resistance to isoniazid (INH), rifampicin, pyrazinamide or ethambutol). -Professional sex worker, alcoholic and/or intravenous (IV) drug abuser. -Silicosis or other serious chronic medical problems including diabetes mellitus or chronic renal failure. Final determination of eligibility will be made after review of drug susceptibility testing results on an initial sputum isolate and results of all sputum cultures. Pregnant patients may not be enrolled in the study. Patients in the 4 month arm who become pregnant during months 5 and 6 of study participation will be dropped from the study and receive an additional 2 months of treatment with INH and rifampicin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat | 30 months | 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. |
| Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol | 30 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapses at 1 and 2 Years | 1 and 2 years after successful completion of initial anti-TB treatment | — |
| Acquired Drug Resistance in Patients Who Relapsed | 2 years | — |
| Immunologic: Changes in Cytokine Levels in Mycobacterium Tubercolosis (MTB) Antigen-stimulated Whole Blood Culture Supernatants - Results Are Pending | After 2 and 6 months of anti-TB treatment and upon relapse | — |
| Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat | 2 years | 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. |
| Immunologic: Changes in Sputum Cytokine Levels - Results Are Pending | After 1 and 2 months of anti-TB treatment | — |
| Microbiologic: Changes in Sputum Mycobacterial mRNA - Results Are Pending | At 1 and 2 months of anti-TB treatment, and upon relapse | — |
| Microbiologic: Time After Inoculation Until Culture Positive in BACTEC 460 or MGIT 960 Enriched Liquid Media After 2 Months in Treatment - Results Are Pending | Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and 30 | — |
| Immunologic: Store Peripheral Blood Mononuclear Cells (PBMC) - Results Are Pending | 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 | — |
| Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol | 2 years | 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. |
Countries
Brazil, Philippines, Uganda
Participant flow
Recruitment details
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
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 196 |
| 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. | 198 |
| Total | 394 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Not compliant with DOT | 0 | 2 |
| Overall Study | Post-randomization exclusion | 1 | 2 |
| Overall Study | Pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | 4-Month Arm | 6-Month Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 196 Participants | 198 Participants | 394 Participants |
| Age, Continuous | 31.2 years STANDARD_DEVIATION 10 | 30.3 years STANDARD_DEVIATION 10 | 30.8 years STANDARD_DEVIATION 10 |
| Region of Enrollment Brazil | 81 participants | 81 participants | 162 participants |
| Region of Enrollment Philippines | 47 participants | 48 participants | 95 participants |
| Region of Enrollment Uganda | 68 participants | 69 participants | 137 participants |
| Sex: Female, Male Female | 77 Participants | 78 Participants | 155 Participants |
| Sex: Female, Male Male | 119 Participants | 120 Participants | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 170 / 196 | 164 / 198 |
| serious Total, serious adverse events | 19 / 196 | 22 / 198 |
Outcome results
Primary
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol
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
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4-Month Arm | Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol | 13 Participants |
| 6-Month Arm | Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol | 3 Participants |
95% CI: [0.01, 0.1]Regression, Cox
Primary
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat
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
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4-Month Arm | Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat | 13 Participants |
| 6-Month Arm | Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat | 3 Participants |
Comparison: Comparison of binomial proportion of relapse: Intention-to-treat95% CI: [0.01, 0.09]Regression, Cox
Secondary
Acquired Drug Resistance in Patients Who Relapsed
Time frame: 2 years
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4-Month Arm | Acquired Drug Resistance in Patients Who Relapsed | 0 Participants |
| 6-Month Arm | Acquired Drug Resistance in Patients Who Relapsed | 0 Participants |
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
Secondary
Immunologic: Changes in Sputum Cytokine Levels - Results Are Pending
Time frame: After 1 and 2 months of anti-TB treatment
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
Secondary
Microbiologic: Changes in Sputum Mycobacterial mRNA - Results Are Pending
Time frame: At 1 and 2 months of anti-TB treatment, and upon relapse
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
Secondary
Relapses at 1 and 2 Years
Time frame: 1 and 2 years after successful completion of initial anti-TB treatment
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 4-Month Arm | Relapses at 1 and 2 Years | Relapses at 1 year | 10 Participants |
| 4-Month Arm | Relapses at 1 and 2 Years | Relapses at 2 years | 13 Participants |
| 6-Month Arm | Relapses at 1 and 2 Years | Relapses at 1 year | 3 Participants |
| 6-Month Arm | Relapses at 1 and 2 Years | Relapses at 2 years | 3 Participants |
Comparison: 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.95% CI: [0.94, 12.5]Regression, Linear
Comparison: 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.95% CI: [1.29, 15.9]Regression, Linear
Secondary
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat
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
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 4-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat | Treatment Failures | 0 Participants |
| 4-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat | Relapses | 13 Participants |
| 6-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat | Treatment Failures | 0 Participants |
| 6-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat | Relapses | 3 Participants |
Secondary
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol
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
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 4-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol | Treatment Failures | 0 Participants |
| 4-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol | Relapses | 13 Participants |
| 6-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol | Treatment Failures | 0 Participants |
| 6-Month Arm | Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol | Relapses | 3 Participants |