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Tuberculosis, Multidrug-ResistantPhase 2Opti-QNCT01918397

Efficacy and Safety of Levofloxacin for the Treatment of MDR-TB

A Phase 2 study testing Levofloxacin and Optimized background regimen (OBR) in people with Tuberculosis, Multidrug-Resistant, run by Boston University at 3 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Tuberculosis, Multidrug-Resistant
What is being tested?
Levofloxacin and Optimized background regimen (OBR)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
111 participants
Where
3 sitesin 2 countries
Study dates
Jan 2015to 29 Mar 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with smear-positive, culture positive* pulmonary TB
  • Sputum contains isoniazid* and rifampin-resistant, Ofloxacin-susceptible MTB, all by MTBDR-sl
  • Previously treated or newly diagnosed with tuberculosis
  • 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.
  • Age ≥ 18 years.
  • Weight > 40 Kg
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  • Karnofsky score of > 60 (see section 18.1)
  • Willingness by the patient to attend scheduled follow-up visits and undergo study assessments.
  • 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.
  • 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
  • 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.

Who cannot join

  • Currently breast-feeding or pregnant.
  • Known allergy or intolerance to or toxicity from fluoroquinolones or other medications utilized in this study.
  • In the judgment of the physician the patient is not expected to survive for 6 months
  • Anticipated surgical intervention for the treatment of pulmonary tuberculosis
  • Participation in another investigational drug trial within the past 30 days
  • 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
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  • Poorly controlled diabetes
  • Known g-6-phosphate dehydrogenase deficiency
  • Use of quinolone for 7 days within past 30 days
  • QTc interval greater than 450 msec for men or greater than 470 msec for women

Trial locations and contacts

3 sites in 2 countries.

3 sites in 2 countries

Peru2 sites
  • Partners in Health

    Lima

  • University of Cayetana Heredia

    Lima

Other trials in Peru

South Africa1 site
  • Stellenbosch University

    Cape Town

Other trials in South Africa

About this study

Official title: 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.

Read the 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.

Being tested
Levofloxacin, Optimized background regimen (OBR)
Keywords
Levofloxacin, Optimized background regimen
Medical subject headings
Tuberculosis, Multidrug-Resistant

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LevofloxacinDrug

    Also called Levaquin, Quixin, and Iquix

    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.

  • Optimized background regimen (OBR)Drug

    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.

Study groups in NCT01918397
Study groupRoleWhat they receive
Dose 1Active comparatorLevofloxacin 11mg/kg daily + Optimized Background Regimen (OBR)
Receives: Drug: Levofloxacin; Drug: Optimized background regimen (OBR)
Dose 2ExperimentalLevofloxacin 14mg/kg daily + Optimized Background Regimen (OBR)
Receives: Drug: Levofloxacin; Drug: Optimized background regimen (OBR)
Dose 3ExperimentalLevofloxacin 17mg/kg daily + Optimized Background Regimen (OBR)
Receives: Drug: Levofloxacin; Drug: Optimized background regimen (OBR)
Dose 4ExperimentalLevofloxacin 20mg/kg daily + Optimized Background Regimen (OBR)
Receives: Drug: Levofloxacin; Drug: Optimized background regimen (OBR)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Time to Sputum Culture Conversion

    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.

    Measured: 28 weeks

  2. Number of Grade 3,4, and 5 AEs

    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.

    Measured: 28 weeks

Secondary outcomes (1)
  1. Number of Patients Completing Treatment

    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).

    Measured: 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Aug 2013 (estimated)
  2. Study startJan 2015
  3. Primary completion29 Mar 2022
  4. Study completion29 Mar 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
111 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01918397
Sponsor's protocol ID
H-32150
Other IDs
1U01AI100805-01A1
Acronym
Opti-Q
Status last verified
Apr 2023
First submitted
5 Aug 2013
Last updated
24 May 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Phillips PPJ, Peloquin CA, Sterling TR, Kaur P, Diacon AH, Gotuzzo E, Benator D, Warren RM, Sikes D, Lecca L, Gandhi NR, Streicher EM, Dianis N, Eisenach K, Mitnick CD, Horsburgh CR Jr. Efficacy and Safety of Higher Doses of Levofloxacin for Multidrug-resistant Tuberculosis: A Randomized, Placebo-controlled Phase II Clinical Trial. Am J Respir Crit Care Med. 2025 Jul;211(7):1277-1287. doi: 10.1164/rccm.202407-1354OC.

    PubMed 40080768
  • Schwalb A, Cachay R, Wright A, Phillips PPJ, Kaur P, Diacon AH, Ugarte-Gil C, Mitnick CD, Sterling TR, Gotuzzo E, Horsburgh CR. Factors associated with screening failure and study withdrawal in multidrug-resistant TB. Int J Tuberc Lung Dis. 2022 Sep 1;26(9):820-825. doi: 10.5588/ijtld.21.0729.

    PubMed 35996282
  • van den Elsen SHJ, Sturkenboom MGG, Van't Boveneind-Vrubleuskaya N, Skrahina A, van der Werf TS, Heysell SK, Mpagama S, Migliori GB, Peloquin CA, Touw DJ, Alffenaar JC. Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01092-18. doi: 10.1128/AAC.01092-18. Print 2018 Dec.

    PubMed 30373800
  • Peloquin CA, Phillips PPJ, Mitnick CD, Eisenach K, Patientia RF, Lecca L, Gotuzzo E, Gandhi NR, Butler D, Diacon AH, Martel B, Santillan J, Hunt KR, Vargas D, von Groote-Bidlingmaier F, Seas C, Dianis N, Moreno-Martinez A, Kaur P, Horsburgh CR Jr. Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis. Antimicrob Agents Chemother. 2018 Sep 24;62(10):e00770-18. doi: 10.1128/AAC.00770-18. Print 2018 Oct.

    PubMed 30012767
  • Bouton TC, Phillips PPJ, Mitnick CD, Peloquin CA, Eisenach K, Patientia RF, Lecca L, Gotuzzo E, Gandhi NR, Butler D, Diacon AH, Martel B, Santillan J, Hunt KR, Vargas D, von Groote-Bidlingmaier F, Seas C, Dianis N, Moreno-Martinez A, Horsburgh CR Jr. An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial. Trials. 2017 Nov 25;18(1):563. doi: 10.1186/s13063-017-2292-x.

    PubMed 29178937

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Levofloxacin and Optimized background regimen (OBR) in people with Tuberculosis, Multidrug-Resistant, run by Boston University at 3 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 May 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Peru, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 May 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Time to Sputum Culture Conversion (time frame: 28 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01918397, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 May 2023.

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