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

NCT01918397 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: H-321501U01AI100805-01A1
• Study Type: interventional
• Target: 111
• Locations: 2 countries
• Sites: 3

Brief 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. 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.

Conditions

Tuberculosis, Multidrug-Resistant

Keywords

Levofloxacin; Optimized background regimen

Outcome Measures

Primary Outcomes (2)

• 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.

  28 weeks

• 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.

  28 weeks

Secondary Outcomes (1)

• Number of Patients Completing Treatment

  24 weeks

Study Arms (4)

Dose 1

ACTIVE COMPARATOR

Levofloxacin 11mg/kg daily + Optimized Background Regimen (OBR)

Drug: Levofloxacin; Drug: Optimized background regimen (OBR)

Dose 2

EXPERIMENTAL

Levofloxacin 14mg/kg daily + Optimized Background Regimen (OBR)

Drug: Levofloxacin; Drug: Optimized background regimen (OBR)

Dose 3

EXPERIMENTAL

Levofloxacin 17mg/kg daily + Optimized Background Regimen (OBR)

Drug: Levofloxacin; Drug: Optimized background regimen (OBR)

Dose 4

EXPERIMENTAL

Levofloxacin 20mg/kg daily + Optimized Background Regimen (OBR)

Drug: Levofloxacin; Drug: Optimized background regimen (OBR)

Interventions

Levofloxacin DRUG

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.

Also known as: Levaquin, Quixin, and Iquix

Dose 1; Dose 2; Dose 3; Dose 4

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.

Dose 1; Dose 2; Dose 3; Dose 4

Eligibility Criteria

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

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Boston University: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Centers for Disease Control and Prevention: collaborator
• Macleods Pharmaceuticals Ltd: collaborator

Study Sites (3)

Partners in Health

Lima, Peru

Location

University of Cayetana Heredia

Lima, Peru

Location

Stellenbosch University

Cape Town, South Africa

Location

Related Publications (5)

• 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.

  PMID: 40080768 DERIVED

• 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.

  PMID: 35996282 DERIVED

• 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.

  PMID: 30373800 DERIVED

• 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.

  PMID: 30012767 DERIVED

• 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.

  PMID: 29178937 DERIVED

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Interventions

Levofloxacin; Ofloxacin

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Charles R Horsburgh, MD
• Organization: Boston University School of Public Health

rhorsbu@bu.edu

617-414-1282

Study Officials

• Charles R Horsburgh, MD

  Boston University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Epidemiology

Study Record Dates

• First Submitted: August 5, 2013
• First Posted: August 7, 2013
• Study Start: January 1, 2015
• Primary Completion: March 29, 2022
• Study Completion: March 29, 2022
• Last Updated: May 24, 2023
• Results First Posted: May 24, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

PE (2); ZA (1)