A Phase 3 Open-Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of the Combination of Moxifloxacin Plus PA-824 Plus Pyrazinamide After 4 and 6 Months of Treatment in Adult Subjects With Drug-Sensitive Smear-Positive Pulmonary Tuberculosis and After 6 Months of Treatment in Adult Subjects With Multi-Drug Resistant, Smear-Positive Pulmonary Tuberculosis.
Overview
- Phase
- Phase 3
- Intervention
- Moxifloxacin
- Conditions
- Tuberculosis, Pulmonary, Drug Sensitive
- Sponsor
- Global Alliance for TB Drug Development
- Enrollment
- 284
- Locations
- 26
- Primary Endpoint
- Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Modified Intent to Treat [MITT] Population)
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments with varying doses and treatment lengths from 4 to 6 months in subjects with drug-sensitive (DS) pulmonary TB compared to standard HRZE treatment.
This study will also assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments after 6 months of treatment in subjects with multi drug-resistant (MDR) pulmonary TB compared to a combination of moxifloxacin, PA-824, and pyrazinamide treatments in DS-TB subjects.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures.
- •Male or female, aged 18 years or over.
- •Body weight (in light clothing and no shoes) ≥ 30 kg.
- •Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD) and World Health Organization (WHO) scale on smear microscopy at the trial laboratory.
- •Drug-Sensitive TB treatment arms subjects should be:
- •sensitive to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid) AND
- •either newly diagnosed for TB or have a patient history of being untreated for at least 3 years after cure from a previous episode of TB. If they are entered into the trial due to being sensitive to rifampicin by rapid sputum based test, however on receipt of the rifampicin resistance testing using an indirect susceptibility test in liquid culture this shows they are rifampicin resistant, they will be:
- •Excluded as late exclusions;
- •Possibly replaced as determined by the sponsor.
- •MDR-TB treatment arm subjects should be resistant to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid).
Exclusion Criteria
- •Any non TB related condition (including myasthenia gravis) where participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments.
- •Being or about to be treated for Malaria.
- •Is critically ill and, in the judgment of the investigator, has a diagnosis likely to result in death during the trial or the follow-up period.
- •TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as judged by the investigator.
- •History of allergy or hypersensitivity to any of the trial IMP or related substances, including known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics.
- •For HIV infected subjects any of the following:
- •CD4+ count \<100 cells/µL;
- •Karnofsky score \<60%;
- •Received intravenous antifungal medication within the last 90 days;
- •WHO Clinical Stage 4 HIV disease.
Arms & Interventions
MDR-TB
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg for 26 weeks.
Intervention: Moxifloxacin
MDR-TB
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg for 26 weeks.
Intervention: PA-824
MDR-TB
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg for 26 weeks.
Intervention: Pyrazinamide
DS-TB (HRZE), HR
26 consecutive weeks to DS-TB subjects only, as follows: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination) Weeks 1-8 with daily dose per the subjects weight HR (Rifampicin plus isoniazid combination tablets) Weeks 9 - 26 with daily dose per the subjects weight Daily dose per the subjects weight as follows: 30-39kg: 2 tablets; 40-54kg: 3 tablets; 55 - 70kg: 4 tablets; 71kg and over: 5 tablets.
Intervention: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination)
DS-TB (HRZE), HR
26 consecutive weeks to DS-TB subjects only, as follows: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination) Weeks 1-8 with daily dose per the subjects weight HR (Rifampicin plus isoniazid combination tablets) Weeks 9 - 26 with daily dose per the subjects weight Daily dose per the subjects weight as follows: 30-39kg: 2 tablets; 40-54kg: 3 tablets; 55 - 70kg: 4 tablets; 71kg and over: 5 tablets.
Intervention: HR (rifampicin plus isoniazid combination tablets)
DS-TB PA-824 200mg 26 weeks
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once daily for 26 weeks
Intervention: Moxifloxacin
DS-TB PA-824 200mg 26 weeks
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once daily for 26 weeks
Intervention: PA-824
DS-TB PA-824 200mg 26 weeks
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once daily for 26 weeks
Intervention: Pyrazinamide
DS-TB PA-824 200mg 17 weeks
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once a day for 17 weeks
Intervention: Moxifloxacin
DS-TB PA-824 200mg 17 weeks
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once a day for 17 weeks
Intervention: PA-824
DS-TB PA-824 200mg 17 weeks
moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once a day for 17 weeks
Intervention: Pyrazinamide
DS-TB PA-824 100mg 17 weeks
moxifloxacin 400 mg + PA-824 100 mg + pyrazinamide 1500 mg orally once daily for 17 weeks
Intervention: Moxifloxacin
DS-TB PA-824 100mg 17 weeks
moxifloxacin 400 mg + PA-824 100 mg + pyrazinamide 1500 mg orally once daily for 17 weeks
Intervention: PA-824
DS-TB PA-824 100mg 17 weeks
moxifloxacin 400 mg + PA-824 100 mg + pyrazinamide 1500 mg orally once daily for 17 weeks
Intervention: Pyrazinamide
Outcomes
Primary Outcomes
Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Modified Intent to Treat [MITT] Population)
Time Frame: From Day 1 to Month 12.
Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following end of treatment (EOT), had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or were dying from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required an extension, restart or change of treatment except for reinfection/pregnancy, or failed to complete adequate treatment who were unassessable at 12 months or lost to follow-up/withdrawn before EOT.
Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Per Protocol [PP] Population)
Time Frame: From Day 1 to Month 12.
Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following EOT, had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or died from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required a restart or change of treatment because of an unfavorable outcome with or without bacteriological confirmation, ie, on bacteriological, radiographic or clinical grounds.