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

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)

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.

Study Overview

• Status: Withdrawn
• Conditions: Tuberculosis Multi Drug Resistant Active
• Intervention / Treatment: Drug: Delamanid; Drug: Linezolid; Drug: Levofloxacin; Drug: Pyrazinamide; Drug: WHO MDR-TB 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.

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 5-agent treatment regimen for MDR-TB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful outcome at 18 months after randomization using culture results, follow up visits,	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	18 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Boston University
• Collaborators: University of Florida; Westat
• Investigators: Principal Investigator: C. Robert Horsburgh, MD, Boston University

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2017
• Primary Completion (Anticipated): August 1, 2021
• Study Completion (Anticipated): August 1, 2022

Study Registration Dates

• First Submitted: October 21, 2016
• First Submitted That Met QC Criteria: November 28, 2016
• First Posted (Estimate): November 29, 2016

Study Record Updates

• Last Update Posted (Actual): September 11, 2017
• Last Update Submitted That Met QC Criteria: September 7, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antitubercular Agents; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Linezolid; Levofloxacin; Ofloxacin; Pyrazinamide
• Other Study ID Numbers: H-36160

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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