Recurrent Tuberculosis
Conditions
Brief summary
This is an open label randomized controlled clinical trial comparing two regimens for treatment of smear-positive pulmonary TB, among patients previously treated for TB. The primary objective is to determine if a moxifloxacin-containing regimen, substituting moxifloxacin for ethambutol, of 24 weeks duration is superior to a control regimen of 24 weeks duration in improving treatment outcomes in patients with recurrent TB and shortens the duration of TB treatment.
Detailed description
Intervention Arm :12 months (6 months treatment + 12 months post treatment follow up) Control Arm :12 months (6 months treatment + 12 months post treatment follow up) Total sample size is 330.
Interventions
DRUGmoxifloxacin
\[isoniazid (H), rifampicin (R), pyrazinamide (Z), moxifloxacin (M)\]
Sponsors
Centre for the AIDS Programme of Research in South Africa
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults ≥ 18 years of age * Previous history of anti-TB chemotherapy * HIV status: HIV infected and uninfected patients are allowed in the study: * All patients must agree to HIV testing to confirm HIV status. * Patients already on ARVs will be allowed in the study provided that the ART regimen is not contraindicated with any of the study agents . * HIV infected patients at any CD4 count irrespective of ART commencement and duration will be included in the study * Smear positive or Gene Xpert positive pulmonary tuberculosis * Rifampicin susceptible as determined by Gene Xpert at screening. Gene Xpert will be used to determine rifampicin resistance, hence the study team will made aware of resistance within 48 hours and prior to study enrolment. * Karnofsky score greater than 70 * Female candidates of reproductive potential must agree to use two reliable methods of contraception while on study: a barrier method of contraception (condoms or cervical cap) together with another reliable form of contraceptive (condoms with a spermicidal agent, a diaphragm or cervical cap with spermicide, an Intrauterine Device (IUD), or hormone-based contraceptive) * A negative pregnancy test * Laboratory parameters done at, or 14 days prior to, screening: * Haemoglobin level of at least 7.0 g/dL * Serum aspartate transaminase (AST) and alanine transaminase (ALT) activity less than 3 times the upper limit of normal * Serum total bilirubin level less than 2.5 times upper limit of normal * Creatinine clearance (CrCl) level greater than 60 mls/min * Platelet count of at least 50 x109cells/L * Serum potassium greater than 3.0 mmol/L
Exclusion criteria
* Patients on a Nevirapine (NVP)-containing ART regimen at screening * Pregnant or breastfeeding * Received an antibiotic active against M. tuberculosis in the last 14 days (e.g. fluoroquinolones, macrolides, standard anti-tuberculosis drugs). * Patients with known M. tuberculosis resistance to any of the study drugs at screening * History of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during the intensive phase of tuberculosis treatment. * Known allergies or intolerance to any of the study drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sputum Culture Conversion Rates at Week 8 and Month 6 Post Tuberculosis Treatment Initiation | 24 weeks | The proportion of patients with negative sputum cultures at the end of the intensive phase (8 weeks) and the proportion of patients with negative sputum cultures at 6 months were compared between the two study arms. All participants with sputum culture results at week 8 and month 6 were included in the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Culture-conversion of the Moxifloxacin Regimen and the Ethambutol Regimen | Up to 2 years | To determine the time to culture-conversion of the moxifloxacin regimen and the ethambutol regimen. |
| Proportion of Patients With Any Grade 3 or 4 Adverse Reactions in the Two Study Arms | Up to 2 years | To compare the proportion of patients with any Grade 3 or 4 adverse reactions in the two study arms. Outcome measured in terms of number of participants with at least one grade 3 or 4 events, and not in number of events. |
| Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | up to 2 years for adverse events and 8 weeks for culture conversion rates | To compare adverse events and 8-week culture conversion rates among HIV-infected patients vs. HIV-uninfected patients. The proportion of participants with at least one grade 3 or 4 adverse event was measured. |
| Proportion of Patients With Unfavourable Outcomes or Tuberculosis Recurrence in the Moxifloxacin and Control Arm. | up to 2 years | A patient was defined as having an unfavourable outcome if he/she was not cured at the end of treatment or did not successfully complete treatment. Recurrence after completion of treatment was defined as two positive cultures within a period of four months without an intervening negative culture. |
Countries
South Africa
Participant flow
Pre-assignment details
One individual in the control arm was terminated one month after enrollment owing to discovery of pre-existing violation of entry criteria. The individual was excluded from all statistical analyses.
Participants by arm
| Arm | Count |
|---|---|
| Moxifloxacin A Moxifloxacin-containing oral regimen of Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Moxifloxacin (M), substituting Moxifloxacin for Ethambutol.
The intervention arm substituted moxifloxacin for ethambutol (moxifloxacin group), and consisted of daily doses of moxifloxacin, rifampicin, isoniazid and pyrazinamide for 8 weeks, followed by daily doses of moxifloxacin, rifampicin and isoniazid for 16 weeks.
Participants in the moxifloxacin arm received daily 400 mg of moxifloxacin (Avelox®, Bayer Healthcare), weight-based rifampicin at 450 or 600 mg, and 225 or 300 mg of isoniazid, for participants 38-54 and ≥55 kg, respectively, during the 2-month intensive phase and 4-month continuation phase of TB treatment. During the intensive phase of treatment, pyrazinamide was used at 1500 and 2000mg in participants between 38-54 and ≥55 kg, respectively. | 98 |
| Control An Ethambutol oral regimen of Isoniazid (H), Rifampicin(R), Pyrazinamide (Z), Ethambutol(E), substituting Ethambutol for Moxifloxacin.
Daily doses of rifampicin, isoniazid, pyrazinamide and ethambutol for 8 weeks (intensive phase), followed by daily doses of rifampicin and isoniazid for 16 weeks (Continuation phase).
During the first two months (intensive phase) of treatment, participants in the control arm received the following weight-based doses by fixed dose combination tablets: Participants who were 38 - 54kg received rifampicin 450mg, isoniazid 225mg, pyrazinamide 1200mg, ethambutol 825mg; participants who were 54 - 70kg received rifampicin 600mg, isoniazid 300mg, pyrazinamide 1600mg, ethambutol 1100mg; participants who were \> 70 kg received rifampicin 750mg, isoniazid 375mg, pyrazinamide 2000mg, ethambutol 1375mg. During the subsequent four months (continuation phase), participants continued on the same weight-based doses of rifampicin and isoniazid. | 98 |
| Total | 196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 4 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Patient Incarcerated | 1 | 0 |
| Overall Study | Relocation | 3 | 1 |
| Overall Study | Rifampicin resistant on culture | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Moxifloxacin | Control | Total |
|---|---|---|---|
| Age, Customized =>25 and <35 years | 37 Participants | 35 Participants | 72 Participants |
| Age, Customized <25 years | 7 Participants | 14 Participants | 21 Participants |
| Age, Customized =>35 and <=45 years | 35 Participants | 32 Participants | 67 Participants |
| Age, Customized >45 years | 19 Participants | 17 Participants | 36 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 96 Participants | 98 Participants | 194 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment South Africa | 98 Participants | 98 Participants | 196 Participants |
| Sex: Female, Male Female | 24 Participants | 35 Participants | 59 Participants |
| Sex: Female, Male Male | 74 Participants | 63 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 98 | 4 / 98 |
| other Total, other adverse events | 30 / 98 | 19 / 98 |
| serious Total, serious adverse events | 27 / 98 | 12 / 98 |
Outcome results
Primary
Sputum Culture Conversion Rates at Week 8 and Month 6 Post Tuberculosis Treatment Initiation
The proportion of patients with negative sputum cultures at the end of the intensive phase (8 weeks) and the proportion of patients with negative sputum cultures at 6 months were compared between the two study arms. All participants with sputum culture results at week 8 and month 6 were included in the analysis.
Time frame: 24 weeks
Population: Nine participants had missing data at week 8: 4 missed visits, 3 terminated before week 8 and 2 had MOTT cultured. Fourteen had missing data at month 6: 7 were terminated before month 6 and 7 missed their visits.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moxifloxacin | Sputum Culture Conversion Rates at Week 8 and Month 6 Post Tuberculosis Treatment Initiation | culture negative at 6 months | 84 Participants |
| Moxifloxacin | Sputum Culture Conversion Rates at Week 8 and Month 6 Post Tuberculosis Treatment Initiation | culture negative at 8 weeks | 78 Participants |
| Control | Sputum Culture Conversion Rates at Week 8 and Month 6 Post Tuberculosis Treatment Initiation | culture negative at 8 weeks | 73 Participants |
| Control | Sputum Culture Conversion Rates at Week 8 and Month 6 Post Tuberculosis Treatment Initiation | culture negative at 6 months | 92 Participants |
Comparison: comparison of culture negative results at week 8p-value: 0.46Fisher Exact
Comparison: comparison of culture negative results at month 6p-value: 0.43Fisher Exact
Secondary
Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients
To compare adverse events and 8-week culture conversion rates among HIV-infected patients vs. HIV-uninfected patients. The proportion of participants with at least one grade 3 or 4 adverse event was measured.
Time frame: up to 2 years for adverse events and 8 weeks for culture conversion rates
Population: 9 participants had missing data at 8 weeks: 4 missed visits, 3 terminated before week 8, and 2 had MOTT cultured
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moxifloxacin | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants with grade 3/4 adverse events | 30 Participants |
| Moxifloxacin | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants culture negative at 8 weeks | 57 Participants |
| Control | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants culture negative at 8 weeks | 51 Participants |
| Control | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants with grade 3/4 adverse events | 19 Participants |
| HIV Negative, Moxifloxacin | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants with grade 3/4 adverse events | 13 Participants |
| HIV Negative, Moxifloxacin | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants culture negative at 8 weeks | 21 Participants |
| HIV Negative, Control | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants with grade 3/4 adverse events | 6 Participants |
| HIV Negative, Control | Number of Participants With Adverse Events and 8-week Culture Conversion Rates Among HIV-infected Patients vs. HIV-uninfected Patients | participants culture negative at 8 weeks | 22 Participants |
Comparison: Comparison of the number of adverse events in the two arms, controlling for HIV statusp-value: 0.01Mantel Haenszel
Comparison: Comparison of the 8-week culture conversion rates in the two arms, controlling for HIV statusp-value: 0.45Mantel Haenszel
Secondary
Proportion of Patients With Any Grade 3 or 4 Adverse Reactions in the Two Study Arms
To compare the proportion of patients with any Grade 3 or 4 adverse reactions in the two study arms. Outcome measured in terms of number of participants with at least one grade 3 or 4 events, and not in number of events.
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Moxifloxacin | Proportion of Patients With Any Grade 3 or 4 Adverse Reactions in the Two Study Arms | 43 Participants |
| Control | Proportion of Patients With Any Grade 3 or 4 Adverse Reactions in the Two Study Arms | 25 Participants |
p-value: 0.011Fisher Exact
Secondary
Proportion of Patients With Unfavourable Outcomes or Tuberculosis Recurrence in the Moxifloxacin and Control Arm.
A patient was defined as having an unfavourable outcome if he/she was not cured at the end of treatment or did not successfully complete treatment. Recurrence after completion of treatment was defined as two positive cultures within a period of four months without an intervening negative culture.
Time frame: up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Moxifloxacin | Proportion of Patients With Unfavourable Outcomes or Tuberculosis Recurrence in the Moxifloxacin and Control Arm. | 13 Participants |
| Control | Proportion of Patients With Unfavourable Outcomes or Tuberculosis Recurrence in the Moxifloxacin and Control Arm. | 6 Participants |
p-value: 0.15Fisher Exact
Secondary
Time to Culture-conversion of the Moxifloxacin Regimen and the Ethambutol Regimen
To determine the time to culture-conversion of the moxifloxacin regimen and the ethambutol regimen.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moxifloxacin | Time to Culture-conversion of the Moxifloxacin Regimen and the Ethambutol Regimen | 6.0 weeks |
| Control | Time to Culture-conversion of the Moxifloxacin Regimen and the Ethambutol Regimen | 7.9 weeks |
p-value: 0.018Gehan-Breslow-Wilcoxon test