Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients

• Status: Active, not recruiting
• Trial end date: 2022-02-25
• Target enrollment: 0
• Participant gender: All

Summary

To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: Drug Sensitive TB (DS-TB) patients given BPaMZ for 17 Weeks ( or 4 months) vs. Standard HRZE/HR treatment given for 26 weeks (or 6 months) and Drug Resistant TB (DR-TB) patients given BPaMZ for 26 Weeks (or 6 months)

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Global Alliance for TB Drug Development
• Treatments: Bedaquiline; Diarylquinolines; Ethambutol; Fluoroquinolones; Isoniazid; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination; Pyrazinamide; Rifampin

Criteria

Inclusion Criteria:

Participants are required to meet all of the following inclusion criteria during the screening period in order to be randomized.

1. Signed written consent prior to undertaking any trial-related procedures.

2. Male or female, aged 18 years or over.

3. Body weight (in light clothing and no shoes) ≥ 30 kg.

4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) at the trial laboratory.

5. Disease Characteristics:

• Participants with one of the following pulmonary TB conditions:

DS-TB treatment arm participants should be:

1. sensitive to rifampicin and isoniazid by rapid sputum based test AND

2. either newly diagnosed for TB or have a 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 and isoniazid by rapid molecular sputum based test, however on receipt of the rifampicin and/or isoniazid phenotypic resistance testing in liquid culture this shows they are rifampicin or isoniazid resistant, they will be:

1. Excluded as late exclusions;

2. Possibly replaced as determined by the Sponsor.

DR-TB treatment arm participants should be:

a. Resistant to rifampicin and/or isoniazid. A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB.

1. Contraception:

Be of non-childbearing potential or using effective methods of birth control, as defined below:

Non-childbearing potential:

1. Participant - not heterosexually active or practice sexual abstinence; or

2. Female participant or male participants female sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or

3. Male participant or female participants male sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening;

Effective birth control methods:

1. Double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or

2. Female participant: Barrier method combined with hormone-based contraceptives or an intra-uterine device for the female participant.

3. Male participants' female sexual partner: Double barrier method or hormone-based contraceptives or an intra-uterine device for the female partner.

And both male and female participants are willing to continue practicing birth control methods and are not planning to conceive throughout treatment and for 12 weeks after the last dose of trial medication or discontinuation from trial medication in case of premature discontinuation.

(Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy).

Exclusion Criteria:

Participants will be excluded from participation if they meet any of the following criteria:

Medical History and Concurrent Conditions:

1. Any non-TB related condition where participation in the trial, as judged by the investigator, could compromise the well-being of the participant or prevent, limit or confound protocol specified assessments.

2. Being, or about to be, treated for Malaria.

3. 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.

4. 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.

5. 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.

6. For HIV infected participants any of the following:

1. CD4+ count <100 cells/µL

2. Karnofsky score <60% (Appendix 5)

3. Received intravenous antifungal medication within the last 90 days

4. WHO Clinical Stage 4 HIV disease (Appendix 3)

7. Participants recently started or expected to need to start ART within 1 month after randomization. Participants may be included who have been on ARTs for greater than 30 days prior to start of screening, or who are expected to start ART greater than 30 days after randomization.

8. Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests).

a. If they are entered into the trial due to being sensitive to fluoroquinolones by rapid sputum based test, however on receipt of the moxifloxacin phenotypic resistance testing in liquid culture they are found to be fluoroquinolones resistant, they will be excluded as late exclusions;

9. Having participated in other clinical trials with investigational agents within 8 weeks prior to start of trial medication or currently enrolled in an investigational trial;

10. Participants with any of the following at screening (per measurements and reading done by ECG):

11. Cardiac arrhythmia requiring medication;

12. Prolongation of QT/QTc interval with QTcF (Fridericia correction) >450 ms;

13. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);

14. Any clinically significant ECG abnormality, in the opinion of the investigator.

15. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.

Previous and Concomitant Therapy

1. Previous treatment with pretomanid or bedaquiline as part of a clinical trial.

2. Previous treatment for TB which includes, but is not limited to, gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, quinolones, thioamides, and metronidazole:

3. For DS-TB treatment arms: Previous treatment for tuberculosis within 3 years prior to Day -9 to -1 (Screening). Participants who have previously received isoniazid prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial.

4. For the DR-TB/MDR-TB participants: Previous treatment for DR-TB/MDR-TB, although may have been on a DR-TB treatment regimen for no longer than 7 days at start of screening.

5. Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to drug allergy.

6. Use of any drug within 30 days prior to randomisation known to prolong QTc interval (including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, sparfloxacin, thioridazine).

7. Use of systemic glucocorticoids within one year of start of screening (inhaled or intranasal glucocorticoids are allowed) due to visual opacities or cataracts

8. For HIV infected participants, only the following types of ART are permissible:

• Nevirapine (NVP) based regimen consisting of NVP in combination with any two nucleosidase reverse transcriptase inhibitors (NRTIs) tenofovir (TDF)/abacavir (ABC) and emtricitabine (FTC)/lamivudine (3TC).

• Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any two NRTI. TDF/ABC and FTC/3TC.

• Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC.

• In participants who have viral load suppressed on efavirenz at the time of screening, their ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, the same nucleoside backbone should be used.

9. In the case where participants are randomized to a rifampicin containing regime

• EFV can be used with rifampicin.

• LPV needs to be double dosed.

• Rilpivirine cannot be given with rifampicin