Efficacy and Tolerability of Delamanid, Linezolid, Pyrazinamide and Levofloxacin

• Status: Withdrawn
• Trial end date: 2022-08-01
• Target enrollment: 0
• Participant gender: All

Summary

The proposed study will randomize adults (18 years of age or older) with pulmonary MDR-TB with sputum that contains M. tuberculosis that is isoniazid and rifampin resistant by MTBDRplus and fluoroquinolone susceptible by MTBDRsl HIV seropositive (with or without antiretroviral therapy) or negative (but not unknown) and Karnofsky score of >60 at sites in Moldova, Peru, and the Philippines.

Patients with MDR-TB will be randomized to oral regimen of delamanid (DLM), linezolid (LZD), levofloxacin (LFX) and pyrazinamide (PZA) for 24, 32, 40, 48 or 56 weeks or World Health Organization (WHO) standard of care MDR-TB regimen (9-month "modified Bangladesh" regimen or WHO standard MDR-TB regimen).

Primary Objective

1. Determine the shortest duration of the delamanid-containing oral regimen that is non-inferior to the blended WHO standard regimen.

Secondary Objective

1. Define the safety and tolerability of the oral delamanid, linezolid, levofloxacin and pyrazinamide regimen.

2. Determine if baseline PZA susceptibility is associated with shorter time to non-inferior treatment duration.

3. Identify the relationship between delamanid and linezolid serum drug levels and time to sputum culture conversion among patients on the delamanid-containing oral regimen.

4. Identify the relationship between delamanid and linezolid serum drug levels and occurrence of adverse events among patients on the delamanid-containing oral regimen.

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

Details

• Lead Sponsor: Boston University
• Collaborators: University of Florida; Westat
• Treatments: Levofloxacin; Linezolid; Ofloxacin; Pyrazinamide

Criteria

Inclusion Criteria:

1. Men and women age ≥18 years

2. Subject has pulmonary TB

3. Sputum Smear, culture or Xpert MTB/RIF assay positive, with Hain MTBDRplus showing Rifampin (RIF) resistance and Isoniazid (INH) resistance and Hain MTBDRsl showing Fluoroquinolone susceptibility.

4. Patients within two weeks (≤14 days) of starting second-line anti-TB drugs

5. HIV seropositive or seronegative but not unknown HIV serostatus. If the last documented negative HIV test was more than 3 months prior to randomization the current serostatus must be assessed.

6. Karnofsky score of > 60 (see Appendix B) at screening and randomization

7. Willingness by the patient to attend scheduled follow-up visits and undergo study assessments.

8. Women with child-bearing potential must agree to practice an adequate birth control or to abstain from heterosexual intercourse during study regimen.

9. Laboratory parameters (performed within 14 days prior to randomization):

• Estimated Serum creatinine < 2.0

• Hemoglobin concentration ≥ 7.0 g/dL

• Platelet count of ≥ 80,000/mm3

• Absolute neutrophil count (ANC) > 2000/ mm3

• Negative pregnancy test (for women of childbearing potential) during randomization/baseline

• CD4 count if HIV infected (within 6 months)

• Serum ALT and total bilirubin <3 times upper limit of normal

• Serum albumin > 2.8 g/dL

10. Able to provide informed consent

Exclusion Criteria:

1. Known quinolone-resistance

2. History of serotonin syndrome

3. History of symptomatic arrhythmia, or taking anti-arrhythmic agents

4. Previous treatment with delamanid or linezolid

5. Known allergy or intolerability to quinolone or pyrazinamide

6. Patients who are pregnant or who are unwilling to use proper contraceptives at childbearing age

7. Medical history of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption

8. The need for ongoing use of prohibited drugs while on study drugs (see section 5.6 below)

9. History of optic neuropathy or peripheral neuropathy

10. History of hypersensitivity reaction to the study drugs

11. Patient is eligible for delamanid or bedaquiline under national program criteria