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Efficacy and Tolerability of Delamanid, Linezolid, Pyrazinamide and Levofloxacin (DAZZLE)

This study is not yet open for participant recruitment.
See Contacts and Locations
Verified April 2017 by Charles R Horsburgh, Boston University
Sponsor:
Collaborators:
Westat
University of Florida
Information provided by (Responsible Party):
Charles R Horsburgh, Boston University
ClinicalTrials.gov Identifier:
NCT02975570
First received: October 21, 2016
Last updated: April 25, 2017
Last verified: April 2017
  Purpose

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.

Condition Intervention Phase
Tuberculosis Multi Drug Resistant Active Drug: Delamanid Drug: Linezolid Drug: Levofloxacin Drug: Pyrazinamide Drug: WHO MDR-TB regimen Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Prospective, Randomized, Open Label Phase 3 Study of the Efficacy and Tolerability of Delamanid, Linezolid, Pyrazinamide and Levofloxacin for Treatment of Patients With Fluoroquinolone-susceptible Multidrugresistant-‐Tuberculosis (MDR-TB)

Resource links provided by NLM:


Further study details as provided by Charles R Horsburgh, Boston University:

Primary Outcome Measures:
  • Successful outcome at 18 months after randomization using culture results, follow up visits, [ Time Frame: 18 months ]
    Successful outcome:if they have a -ve liq culture result 18 mos post rand not having been prev. classified as unsuccessful. If pt unable to produce sputum at 18 mos, the outcome will be classified as successful if they have a -ve culture at last visit at which they were able to produce sputum. Unsuccessful outcome: any of the foll occur, if patient 1)d/c from allocated study treatment & restarted on a diff MDR-TB regimen; 2)has surgery for MDR-TB; 3)treatment extended beyond the scheduled end of treatment for any reason other than making up of missed treatment; 4)restarted on MDR-TB treatment post the sched end of treatment; 5)Allocated treatment changed for any reason other than d/c of PZA when isolate is resistant to PZA; 6)death at any point up to 18 mos post-rand; 7)has a +ve sputum culture 8 wks before the sched completion; 8)has +ve sputum culture after culture conversion by dates specified in criterion number 7; 9)ltfu at any time post rand & before completion of the 18 mos f/u


Secondary Outcome Measures:
  • Secondary - Adverse Events [ Time Frame: 18 months ]
    Adverse Events (AE) grade 3 and above, regardless of relatedness to drugs in the patient's MDR-TB treatment regimen


Estimated Enrollment: 300
Anticipated Study Start Date: August 2017
Estimated Study Completion Date: August 2022
Estimated Primary Completion Date: August 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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).
Drug: 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.
Other Name: Deltyba
Drug: Linezolid
Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.
Other Name: Zyvox
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.
Other Name: Levaquin
Drug: Pyrazinamide
Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.
Other Name: Zinamide
Experimental: 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).
Drug: 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.
Other Name: Deltyba
Drug: Linezolid
Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.
Other Name: Zyvox
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.
Other Name: Levaquin
Drug: Pyrazinamide
Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.
Other Name: Zinamide
Experimental: 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).
Drug: 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.
Other Name: Deltyba
Drug: Linezolid
Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.
Other Name: Zyvox
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.
Other Name: Levaquin
Drug: Pyrazinamide
Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.
Other Name: Zinamide
Experimental: 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).
Drug: 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.
Other Name: Deltyba
Drug: Linezolid
Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.
Other Name: Zyvox
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.
Other Name: Levaquin
Drug: Pyrazinamide
Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.
Other Name: Zinamide
Experimental: 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).
Drug: 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.
Other Name: Deltyba
Drug: Linezolid
Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics.
Other Name: Zyvox
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.
Other Name: Levaquin
Drug: Pyrazinamide
Pyrazinamide is a medication used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis.
Other Name: Zinamide
Active Comparator: 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.
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.
Other Name: 5-agent treatment regimen for MDR-TB

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02975570

Contacts
Contact: C.Robert Horsburgh, MD 617-638-7775 rhorsbu@bu.edu
Contact: Pawandeep Kaur, MPH 617-414-1282 kaurp@bu.edu

Sponsors and Collaborators
Boston University
Westat
University of Florida
Investigators
Principal Investigator: C. Robert Horsburgh, MD Boston University
  More Information

Responsible Party: Charles R Horsburgh, Professor of Epidemiology, Boston University
ClinicalTrials.gov Identifier: NCT02975570     History of Changes
Other Study ID Numbers: H-36160
Study First Received: October 21, 2016
Last Updated: April 25, 2017
Individual Participant Data  
Plan to Share IPD: Yes

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Aminosalicylic Acid
Cycloserine
Pyrazinamide
Linezolid
Levofloxacin
Ofloxacin
Fluoroquinolones
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents
Antibiotics, Antitubercular
Antimetabolites
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on June 22, 2017