Pulmonary Tuberculosis
Conditions
Keywords
DOTS plus, DOTS, multidrug resistant tuberculosis (MDR TB)
Brief summary
This is a prospective, randomized, parallel, controlled study comparing the efficacy and outcomes in the retreatment of pulmonary Tuberculosis (TB) in Guangzhou in a group using pretreatment susceptibility tests in selection of chemotherapy regimens and that in another group without using pretreatment susceptibility test results. The investigators hypothesize that selecting drug treatment on the basis of known susceptibility tests would lead to improved outcome compared with empiric treatment.
Detailed description
The aims are:1) To evaluate the efficacy and outcomes in the retreatment of pulmonary TB in Guangzhou by the use of pretreatment susceptibility tests in selection of chemotherapy regimens & 2) To study the predictive factors of unfavourable outcomes in the retreatment of pulmonary TB in Guangzhou, where unfavourable outcomes include treatment failures and relapses. The patients will be randomized into either a) The DOTS strategy consisting of the following measures: political commitment, case detection through bacteriologic evaluation, standardized treatment with supervision and patient support, an effective drug supply system, and a reporting and recording system that allows assessment of treatment; or b) The DOTS-Plus strategy includes additional measures including continuous drug resistance surveillance, culture, drug susceptibility testing for TB patients, and tailoring of individual drug regimen through the use of first and second-line drugs. The Primary end point is the 18-month combined treatment failure/ relapse (unfavourable outcome) among rifampicin resistant group. Secondary endpoints include the 30-month combined treatment failure/ relapse (unfavourable outcome) among rifampicin resistant group, multidrug resistant tuberculosis (MDR-TB) cases and all retreatment cases; Sputum smear/conversion rate at 2m, 3m, 8m, 12m, 18m, and 24m; Drug resistance rates to various drugs in particular rifampicin, and rate of MDR-TB. The predictive factors of unfavourable treatment outcomes (including failure and relapse) will be analysed. The management of retreatment cases by DOTS alone is often problematic, especially when there is resistance to rifampicin, and treatment failure / relapse with further resistances might result. With implementation of the DOTS-plus strategy, Hong Kong (HK) has achieved a low MDR-TB prevalence of around 1%. This study will provide important data on the predictors of treatment failure/ relapse of retreatment cases and whether the DOTS-plus strategy can effectively reduce the failure/relapse rate and the prevalence rate of MDR-TB in Guangzhou. The project will provide useful data on the surveillance, epidemiology and public health control of TB with a regional (cross-border) significance.
Interventions
OTHERDirectly Observed Therapy (DOTS) plus
The regimen used to treat MDR-TB comprises 5 to 6 drugs to which the organism is or likely to be susceptible for the initial 6 months, and then 3 to 4 drugs subsequently. In addition, TB cases with rifampicin resistance but not amounting to MDR-TB are also at risk of unfavourable treatment outcomes. The availability of pretreatment susceptibility test results will provide a guide in selection of drugs in treating such cases.
OTHERDirectly Observed Therapy (DOTS)
The DOTS strategy (current strategy) consists of the following measures: political commitment, case detection through bacteriologic evaluation, standardized treatment with supervision and patient support, an effective drug supply system, and a reporting and recording system that allows assessment of treatment. The standard regimen for treatment of new cases of pulmonary TB consists of 6 months treatment, with 4 drugs in the initial phase including isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin, followed by two drugs in the continuation phase including isoniazid and rifampicin. In the treatment of previously treated cases, a standard regimen consisting of 8 months treatment will be used.
Sponsors
Guangzhou Institute of Respiratory Disease
Chinese University of Hong Kong
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
All consecutive smear positive pulmonary TB patients aged at least 18 years, with past history of TB treatment, diagnosed with a new episode of active pulmonary TB requiring treatment will be recruited and randomized into two groups, with Group A with management based essentially on the DOTS strategy, while Group B based essentially on the DOTS-plus strategy.
Exclusion criteria
* Age \< 18 yrs; * New TB cases (without past history of anti-TB treatment) will be excluded because they have a much lower risk for MDR-TB than the retreatment cases.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | 18-month | Cure (Completed for 8 months or more of therapy and culture converted in the last month of treatment, and on at least one previous occasion; for multidrug resistant TB (MDR-TB) switched to definitive second line therapy per protocol in the DOTS-plus group, sustained culture conversion for at least 6 months after initiation of second line therapy and no evidence of culture reversion up to the scheduled follow-up point); Treatment failure: not culture converted at 5 months or later; Defaulted: having interrupted treatment for 2 consecutive months or more; Transfer out: having been transferred to another recording and reporting unit and for whom the treatment outcome is not known; Death: a patient who died for any reason during the course of treatment Diagnosis revised: diagnosis revised to non-tuberculous mycobacterial infection or colonisation. Withdrawal: physician-initiated withdrawal for adverse effects, protocol violation or patient's decision to withdraw. |
Countries
China
Participant flow
Recruitment details
All consecutive patients suffering from tuberculosis (TB) of aged 18 years or older with past history of TB treatment of at least 1 month within 5 years and diagnosed with a new episode of sputum smear-positive pulmonary TB requiring treatment were recruited after informed consent.
Pre-assignment details
Altogether 391 patients were assessed and after excluding those who did not meet inclusion criteria or refused to participate in the study, 225 patients were successfully randomized into DOTS (n=114) and DOTS plus (n=111).
Participants by arm
| Arm | Count |
|---|---|
| DOTS Strategy The standard regimen for treatment of new cases of pulmonary TB consists of 6 months treatment, with 4 drugs in the initial phase including isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin, followed by two drugs in the continuation phase including isoniazid and rifampicin. | 114 |
| DOTS Plus Directly Observed Therapy (DOTS) plus: The DOTS-Plus strategy (the strategy to be tested) includes additional measures including continuous drug resistance surveillance, culture, drug susceptibility testing for TB patients, and tailoring of individual drug regimen through the use of first and second-line drugs. The regimen used to treat MDR-TB comprises 5 to 6 drugs to which the organism is or likely to be susceptible for the initial 6 months, and then 3 to 4 drugs subsequently. In addition, TB cases with rifampicin resistance but not amounting to MDR-TB are also at risk of unfavourable treatment outcomes. The availability of pretreatment susceptibility test results will provide a guide in selection of drugs in treating such cases. | 111 |
| Total | 225 |
Baseline characteristics
| Characteristic | DOTS Strategy | DOTS Plus | Total |
|---|---|---|---|
| Age, Continuous | 47.25 years STANDARD_DEVIATION 14.5 | 48.83 years STANDARD_DEVIATION 17.07 | 48.05 years STANDARD_DEVIATION 15.04 |
| Sex: Female, Male Female | 28 Participants | 27 Participants | 55 Participants |
| Sex: Female, Male Male | 86 Participants | 84 Participants | 170 Participants |
| Sputum tuberculosis culture Culture grew Mycobacterium tuberculosis complex | 79 participants | 77 participants | 156 participants |
| Sputum tuberculosis culture Culture grew non-tuberculosis mycobacterium | 12 participants | 13 participants | 25 participants |
| Sputum tuberculosis culture not available | 23 participants | 21 participants | 44 participants |
| X ray lesions severity Mild | 34 participants | 18 participants | 52 participants |
| X ray lesions severity Moderate | 45 participants | 47 participants | 92 participants |
| X ray lesions severity Severe | 35 participants | 46 participants | 81 participants |
| X ray showing cavitation Negative | 60 participants | 52 participants | 112 participants |
| X ray showing cavitation Positive | 54 participants | 59 participants | 113 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 114 | 0 / 111 |
| serious Total, serious adverse events | 2 / 114 | 2 / 111 |
Outcome results
Primary
Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group.
Cure (Completed for 8 months or more of therapy and culture converted in the last month of treatment, and on at least one previous occasion; for multidrug resistant TB (MDR-TB) switched to definitive second line therapy per protocol in the DOTS-plus group, sustained culture conversion for at least 6 months after initiation of second line therapy and no evidence of culture reversion up to the scheduled follow-up point); Treatment failure: not culture converted at 5 months or later; Defaulted: having interrupted treatment for 2 consecutive months or more; Transfer out: having been transferred to another recording and reporting unit and for whom the treatment outcome is not known; Death: a patient who died for any reason during the course of treatment Diagnosis revised: diagnosis revised to non-tuberculous mycobacterial infection or colonisation. Withdrawal: physician-initiated withdrawal for adverse effects, protocol violation or patient's decision to withdraw.
Time frame: 18-month
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with cure | 67 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants who were still on treatment | 2 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants defaulted follow up visit | 0 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of death | 2 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with treatment completion | 0 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with diagnosis revised | 12 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants who were transferred out | 12 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants who withdrew from the study | 7 participants |
| DOTS Strategy | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with treatment failure | 12 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants who withdrew from the study | 3 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with treatment failure | 8 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with cure | 73 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with treatment completion | 0 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants defaulted follow up visit | 2 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants who were transferred out | 10 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants who were still on treatment | 0 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of death | 2 participants |
| DOTS Plus | Number of Participants Suffering From Treatment Failure/ Relapse (Unfavourable Outcome) Among Rifampicin Resistant Group. | Number of participants with diagnosis revised | 13 participants |