Efficacy and Tolerability of Delamanid, Linezolid, Pyrazinamide and Levofloxacin

NCT02975570 | Withdrawn Phase 3 DMC FDA Drug

• 1 other identifier: H-36160
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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. 1.Define the safety and tolerability of the oral delamanid, linezolid, levofloxacin and pyrazinamide regimen.
2. 2.Determine if baseline PZA susceptibility is associated with shorter time to non-inferior treatment duration.
3. 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. 4.Identify the relationship between delamanid and linezolid serum drug levels and occurrence of adverse events among patients on the delamanid-containing oral regimen.

Conditions

Tuberculosis Multi Drug Resistant Active

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Secondary - Adverse Events

  18 months

Study Arms (6)

DAZZLE-24 wks

EXPERIMENTAL

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; Drug: Linezolid; Drug: Levofloxacin; Drug: Pyrazinamide

DAZZLE-32 wks

EXPERIMENTAL

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; Drug: Linezolid; Drug: Levofloxacin; Drug: Pyrazinamide

DAZZLE-40 wks

EXPERIMENTAL

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; Drug: Linezolid; Drug: Levofloxacin; Drug: Pyrazinamide

DAZZLE-48 wks

EXPERIMENTAL

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; Drug: Linezolid; Drug: Levofloxacin; Drug: Pyrazinamide

DAZZLE-56 wks

EXPERIMENTAL

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; Drug: Linezolid; Drug: Levofloxacin; Drug: Pyrazinamide

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

ACTIVE COMPARATOR

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

Interventions

Delamanid 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.

Also known as: Deltyba

DAZZLE-24 wks; DAZZLE-32 wks; DAZZLE-40 wks; DAZZLE-48 wks; DAZZLE-56 wks

Linezolid DRUG

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

Also known as: Zyvox

DAZZLE-24 wks; DAZZLE-32 wks; DAZZLE-40 wks; DAZZLE-48 wks; DAZZLE-56 wks

Levofloxacin 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.

Also known as: Levaquin

DAZZLE-24 wks; DAZZLE-32 wks; DAZZLE-40 wks; DAZZLE-48 wks; DAZZLE-56 wks

Pyrazinamide DRUG

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

Also known as: Zinamide

DAZZLE-24 wks; DAZZLE-32 wks; DAZZLE-40 wks; DAZZLE-48 wks; DAZZLE-56 wks

WHO MDR-TB regimen 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.

Also known as: 5-agent treatment regimen for MDR-TB

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women age ≥18 years
• Subject has pulmonary TB
• 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.
• Patients within two weeks (≤14 days) of starting second-line anti-TB drugs
• 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.
• Karnofsky score of \> 60 (see Appendix B) at screening and randomization
• Willingness by the patient to attend scheduled follow-up visits and undergo study assessments.
• Women with child-bearing potential must agree to practice an adequate birth control or to abstain from heterosexual intercourse during study regimen.
• 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)

You may not qualify if:

• Known quinolone-resistance
• History of serotonin syndrome
• History of symptomatic arrhythmia, or taking anti-arrhythmic agents
• Previous treatment with delamanid or linezolid
• Known allergy or intolerability to quinolone or pyrazinamide
• Patients who are pregnant or who are unwilling to use proper contraceptives at childbearing age
• Medical history of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption
• The need for ongoing use of prohibited drugs while on study drugs (see section 5.6 below)
• History of optic neuropathy or peripheral neuropathy
• History of hypersensitivity reaction to the study drugs
• Patient is eligible for delamanid or bedaquiline under national program criteria

Sponsors & Collaborators

• Boston University: lead
• Westat: collaborator
• University of Florida: collaborator

MeSH Terms

Interventions

OPC-67683; Linezolid; Levofloxacin; Pyrazinamide

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrazines

Study Officials

• C. Robert Horsburgh, MD

  Boston University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Epidemiology

Study Record Dates

• First Submitted: October 21, 2016
• First Posted: November 29, 2016
• Study Start: August 1, 2017
• Primary Completion: August 1, 2021
• Study Completion: August 1, 2022
• Last Updated: September 11, 2017

Record last verified: 2017-09