Efficacy and Safety of Levofloxacin for the Treatment of MDR-TB (Opti-Q)

April 29, 2023 updated by: Charles R Horsburgh, Boston University

Prospective, Randomized, Blinded Phase II Pharmacokinetic/Pharmacodynamic Study of the Efficacy and Tolerability of Levofloxacin in Combination With Optimized Background Regimen for the Treatment of MDR-TB

Multi-drug-resistant tuberculosis (MDR-TB) affects nearly 600,000 persons each year around the world. This type of tuberculosis is very difficult to treat, and many patients die from it. Drugs of the fluoroquinolone class are very important for treating MDR-TB, but the best dose of one of the most effective fluoroquinolones, levofloxacin, is not known. This application proposes a study to determine the best dose of levofloxacin to use in treating MDR-TB. 120 patients will receive their usual treatment, plus levofloxacin at one of four doses. The study will be performed in Peru and in South Africa, where MDR-TB is common.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

MDR-TB is a growing threat to international health. A recent report from WHO estimated that over 440,000 new cases of MDR-TB occurred in 127 countries in 2008, causing 150,000 deaths; this represents a 55% increase in the number of cases since 2000. Current treatment regimens have only a 58-67% success rate, and as many as 20% of those who fail to respond to treatment die of tuberculosis; those who do not die become chronic carriers and spread MDR-TB to others.

Fluoroquinolones (FQ) are an essential part of regimens for the treatment of MDR-TB; substantially better outcomes have consistently been seen in patients with MDR-TB who are treated with FQ, and newer FQ (levofloxacin, gatifloxacin and moxifloxacin) are the most potent antituberculosis agents available for MDR-TB treatment. However, gatifloxacin has been taken off the market because of dysglycemic reactions and moxifloxacin produces marked QT prolongation, increasing risk of fatal arrhythmia. In contrast, QT studies of levofloxacin have found minimal prolongation at doses up to 20mg/kg. Levofloxacin is currently given for TB at doses of 11-14 mg/kg/day and has been well tolerated at doses up to 20 mg/kg. Although the efficacy of levofloxacin increases as exposure increases both in animal studies of TB and in human studies of gram-negative bacteria, its efficacy at higher doses against TB in humans has not been studied. Thus, determination of the most efficacious and well-tolerated dose of levofloxacin is an important research priority. In this Phase 2 study, we will determine the levofloxacin dose and exposure that achieve the greatest reduction in mycobacterial burden with acceptable tolerability by studying 120 adults with smear- and culture-positive pulmonary MDR-TB at sites in Peru and South Africa. Levofloxacin will be administered with an optimized background regimen (OBR) to address the following Specific

Aims:

Specific Aim 1: To determine the levofloxacin AUC/MIC that provides the shortest time to sputum culture conversion in solid medium.

Specific Aim 2: To determine the highest levofloxacin AUC that is both safe and associated with fewer than 25% of patients discontinuing or reducing their dose of levofloxacin.

Specific Aim 3: To develop a dosing algorithm to achieve the levofloxacin AUC associated with maximal efficacy and acceptable safety/tolerability.

This clinical trial will increase our ability to cure MDR-TB and prevent the emergence of resistance to new TB drug classes by optimizing dosing and improving the effectiveness of an existing antimycobacterial agent, using a novel and versatile study design which more rapidly and efficiently identifies advances in this critical area. Construction of an algorithm to predict the optimal levofloxacin dose will allow more effective use of levofloxacin, particularly in areas with limited resources, where the burden of MDR-TB is the greatest.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
111

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Peru
      • Lima, Peru
        • Partners In Health
      • Lima, Peru
        • University of Cayetana Heredia
  • South Africa
      • Cape Town, South Africa
        • Stellenbosch University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Patients with smear-positive, culture positive* pulmonary TB
  2. Sputum contains isoniazid* and rifampin-resistant, Ofloxacin-susceptible MTB, all by MTBDR-sl
  3. Previously treated or newly diagnosed with tuberculosis
  4. Willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 3 months prior to enrollment.
  5. Age ≥ 18 years.
  6. Weight > 40 Kg
  7. Karnofsky score of > 60 (see section 18.1)
  8. Willingness by the patient to attend scheduled follow-up visits and undergo study assessments.
  9. Women with child-bearing potential must agree to use birth control if you are having sex with men while participating in this study and for three months afterward.

  10. Laboratory parameters (performed within 14 days prior to enrollment):

    • Estimated Serum creatinine clearance should be <50, using nomogram78
    • Hemoglobin concentration ≥ 9.0 g/dL
    • Platelet count of ≥ 80,000/mm3
    • Absolute neutrophil count (ANC) > 1000/ mm3
    • Negative pregnancy test (for women of childbearing potential) within 14 days of enrollment
    • HIV viral load and CD4 count if HIV infected (within 3 months)
    • Serum ALT and total bilirubin <3 times upper limit of normal
  11. Able to provide informed consent

Note: *Subjects may be enrolled on the basis of a presumption that they will be culture positive at either screening or baseline if they are smear-positive, but they will be excluded from the analysis if cultures are subsequently negative. This will not be deemed a protocol violation. Similarly, subjects with rifampin susceptibility on a DNA-based test may be enrolled on the basis of a presumption that they will also be INH-resistant, but they will be excluded from the analysis if the isolate is subsequently shown to be INH-susceptible. This will also not be deemed a protocol violation.

Exclusion Criteria:

  1. Currently breast-feeding or pregnant.
  2. Known allergy or intolerance to or toxicity from fluoroquinolones or other medications utilized in this study.
  3. In the judgment of the physician the patient is not expected to survive for 6 months
  4. Anticipated surgical intervention for the treatment of pulmonary tuberculosis
  5. Participation in another investigational drug trial within the past 30 days
  6. Concurrent use of known QT-prolonging drugs: a list of such medications can be found at http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm
  7. Poorly controlled diabetes
  8. Known g-6-phosphate dehydrogenase deficiency
  9. Use of quinolone for 7 days within past 30 days
  10. QTc interval greater than 450 msec for men or greater than 470 msec for women

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Dose 1
Levofloxacin 11mg/kg daily + Optimized Background Regimen (OBR)
Drug: Levofloxacin
Levofloxacin is a quinolone antibiotic used to treat lung, sinus, skin, and urinary tract infections caused by bacteria. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate.
Other Names:
  • Levaquin, Quixin, and Iquix
Drug: Optimized background regimen (OBR)
For this study "OBR" will mean optimized background regimen, not including a quinolone. OBR will be selected at the discretion of the study investigator to conform with standards of care and local site guidelines. In general, the OBR regimen should include at least 3 drugs (other than levofloxacin) to which the patient's isolate is not expected to be resistant, with one of these being an injectable agent, at the usual recommended doses.
Experimental: Dose 2
Levofloxacin 14mg/kg daily + Optimized Background Regimen (OBR)
Drug: Levofloxacin
Levofloxacin is a quinolone antibiotic used to treat lung, sinus, skin, and urinary tract infections caused by bacteria. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate.
Other Names:
  • Levaquin, Quixin, and Iquix
Drug: Optimized background regimen (OBR)
For this study "OBR" will mean optimized background regimen, not including a quinolone. OBR will be selected at the discretion of the study investigator to conform with standards of care and local site guidelines. In general, the OBR regimen should include at least 3 drugs (other than levofloxacin) to which the patient's isolate is not expected to be resistant, with one of these being an injectable agent, at the usual recommended doses.
Experimental: Dose 3
Levofloxacin 17mg/kg daily + Optimized Background Regimen (OBR)
Drug: Levofloxacin
Levofloxacin is a quinolone antibiotic used to treat lung, sinus, skin, and urinary tract infections caused by bacteria. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate.
Other Names:
  • Levaquin, Quixin, and Iquix
Drug: Optimized background regimen (OBR)
For this study "OBR" will mean optimized background regimen, not including a quinolone. OBR will be selected at the discretion of the study investigator to conform with standards of care and local site guidelines. In general, the OBR regimen should include at least 3 drugs (other than levofloxacin) to which the patient's isolate is not expected to be resistant, with one of these being an injectable agent, at the usual recommended doses.
Experimental: Dose 4
Levofloxacin 20mg/kg daily + Optimized Background Regimen (OBR)
Drug: Levofloxacin
Levofloxacin is a quinolone antibiotic used to treat lung, sinus, skin, and urinary tract infections caused by bacteria. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate.
Other Names:
  • Levaquin, Quixin, and Iquix
Drug: Optimized background regimen (OBR)
For this study "OBR" will mean optimized background regimen, not including a quinolone. OBR will be selected at the discretion of the study investigator to conform with standards of care and local site guidelines. In general, the OBR regimen should include at least 3 drugs (other than levofloxacin) to which the patient's isolate is not expected to be resistant, with one of these being an injectable agent, at the usual recommended doses.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Time to Sputum Culture Conversion
Time Frame: 28 weeks
The primary efficacy endpoint is the time to sputum culture conversion from positive to negative for M. tuberculosis growth on solid medium. This is defined as the time from initiation of study treatment to the first of two successive negative cultures one study visit apart that are not followed by a culture-positive specimen within 28 weeks of treatment initiation. To ensure that each subject will be evaluable for the primary endpoint, bi-weekly sputum cultures will be collected for 12 weeks, then every 4 weeks through 24 weeks of treatment.
28 weeks
Number of Grade 3,4, and 5 AEs
Time Frame: 28 weeks
The primary safety endpoint will be the number of grade 3, 4 and 5 adverse events (AEs), occurring up to and including the time on study drug plus four weeks post study drug completion.
28 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of Patients Completing Treatment
Time Frame: 24 weeks
The primary endpoint for the analysis of tolerability will be the ability to complete 24 weeks of treatment with the assigned levofloxacin dose (in mg/kg at enrollment).
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Boston University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Allergy and Infectious Diseases (NIAID)
Centers for Disease Control and Prevention
Macleods Pharmaceuticals, Ltd

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Charles R Horsburgh, MD, Boston University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 29, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 29, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 5, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 5, 2013

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 7, 2013

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 24, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 29, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • H-32150
  • 1U01AI100805-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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