Efficacy and Tolerability of Delamanid, Linezolid, Pyrazinamide and Levofloxacin

NCT ID: NCT02975570

Last Updated: 2017-09-11

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-31
• Study Completion Date: 2022-08-31

Brief 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.

Detailed Description

Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least isoniazid and rifampicin, the two most important anti-TB drugs. WHO has estimated that over 480,000 new cases of MDR-TB occurred in 127 countries in 2014, causing 150,000 deaths; this represents a 70% increase in the number of cases since 2000. MDR-TB cure rates are substantially lower than the 85+% cure expected in drug-susceptible TB. The MDR-TB treatment regimen currently recommended by WHO includes at least 4 second-line drugs plus PZA for 18-24 months, including an injectable agent for the induction phase of 6-8 month. However, the average global success rate of such treatment among patients treated in TB programs is only 50%. More recently, an alternative treatment regimen, known as the "Bangladesh" regimen, has become available.This regimen uses 7 drugs given for 9 months but still includes an injectable agent, which is the cause of the most common and severe toxicities seen when treating MDR-TB. In selected patients this regimen has been able to achieve over 80% cures, but use has been restricted to geographic areas where previous use of second-line drugs is rare. Alternatives will be necessary for other settings and patients with prior second-line drug exposure.

Treatment-limiting side effects are common when using second-line drugs for long periods of time. Overall, 69-73% of patients with MDR-TB treated with the WHO standard regimen are reported to have experienced at least one side effect, and 29%-55% discontinued one or more study drugs because of inability to tolerate a drug. The Bangladesh regimen also has substantial toxicity, with 63% of participants experiencing adverse drug reactions in one report. Thus, while this regimen is shorter and slightly better tolerated than the WHO standard regimen, it still does not provide an easily tolerated alternative, largely because it contains an injectable agent.

The 20-24 month regimen currently in use exposes patients to drug toxicity over prolonged periods of time and demands substantial human resources. Patients receiving these regimens require two years of directly observed therapy with careful monitoring for drug toxicity. Reduction in the duration of treatment would free up program staff to treat additional MDR-TB patients. Development of a shorter treatment regimen will greatly enhance the ability of programs to keep up with the anticipated increase in patients needing treatment.

This application proposes a study to determine whether the 9-month oral regime that uses Delaminid, Linezolid, Levofloxacin and Pyrazinamide is as good as the current WHO standard of care regimen.

The study proposes to randomize approximately 300 adults in Peru, Moldova and Phillipines where MDR-TB is common.

Conditions

Tuberculosis Multi Drug Resistant Active

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DAZZLE-24 wks

Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 24 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).

Group Type: EXPERIMENTAL

Delamanid

Intervention Type: DRUG

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Linezolid

Intervention Type: DRUG

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Levofloxacin

Intervention Type: DRUG

Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.

DAZZLE-32 wks

Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 32 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).

Group Type: EXPERIMENTAL

Delamanid

Intervention Type: DRUG

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Linezolid

Intervention Type: DRUG

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Levofloxacin

Intervention Type: DRUG

Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.

DAZZLE-40 wks

Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen: delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 40 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).

Group Type: EXPERIMENTAL

Delamanid

Intervention Type: DRUG

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Linezolid

Intervention Type: DRUG

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Levofloxacin

Intervention Type: DRUG

Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.

DAZZLE-48 wks

Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 48 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).

Group Type: EXPERIMENTAL

Delamanid

Intervention Type: DRUG

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Linezolid

Intervention Type: DRUG

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Levofloxacin

Intervention Type: DRUG

Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.

DAZZLE-56 wks

Delamanid, Linezolid, Levofloxacin, Pyrazinamide (DAZZLE) treatment regimen- delamanid 100 mg PO BID, linezolid 600 mg PO QD, levofloxacin 1000 mg PO QD, and pyrazinamide 20-30 mg/Kg PO QD for 56 weeks, with linezolid dose reduction to 300 mg daily after 16 weeks (these doses are the usual doses for treatment of TB for all 4 study agents).

Group Type: EXPERIMENTAL

Delamanid

Intervention Type: DRUG

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Linezolid

Intervention Type: DRUG

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Levofloxacin

Intervention Type: DRUG

Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.

WHO MDR-TB regimen- 9 mos or 20-24 mos

MDR-TB treatment with 9-month or 20-24 month WHO approved regimen. The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine.

Group Type: ACTIVE_COMPARATOR

WHO MDR-TB regimen

Intervention Type: DRUG

The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine. Short (9 mos) or longer (20-24 mos) treatment schedules can be used.

Interventions

Delamanid

Delamanid is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Intervention Type: DRUG

Linezolid

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.

Intervention Type: DRUG

Levofloxacin

Levoflaxacin is an antibiotic used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis.

Intervention Type: DRUG

Pyrazinamide

Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.

Intervention Type: DRUG

WHO MDR-TB regimen

The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine. Short (9 mos) or longer (20-24 mos) treatment schedules can be used.

Intervention Type: DRUG

Other Intervention Names

Deltyba; Zyvox; Levaquin; Zinamide; 5-agent treatment regimen for MDR-TB

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Westat

OTHER

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: collaborator

Boston University

OTHER

Sponsor Role: lead

Responsible Party

Charles R Horsburgh

Professor of Epidemiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

C. Robert Horsburgh, MD

Role: PRINCIPAL_INVESTIGATOR

Boston University

Other Identifiers

H-36160

Identifier Type: -

Identifier Source: org_study_id