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| ID | Type | Description | Link |
|---|---|---|---|
| 1U01AI100805-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
| Centers for Disease Control and Prevention | FED |
| Macleods Pharmaceuticals Ltd | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dose 1 | Active Comparator | Levofloxacin 11mg/kg daily + Optimized Background Regimen (OBR) |
|
| Dose 2 | Experimental | Levofloxacin 14mg/kg daily + Optimized Background Regimen (OBR) |
|
| Dose 3 | Experimental | Levofloxacin 17mg/kg daily + Optimized Background Regimen (OBR) |
|
| Dose 4 | Experimental | Levofloxacin 20mg/kg daily + Optimized Background Regimen (OBR) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 24 weeks |
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Inclusion Criteria:
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):
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:
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| Name | Affiliation | Role |
|---|---|---|
| Charles R Horsburgh, MD | Boston University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Partners in Health | Lima | Peru | ||||
| University of Cayetana Heredia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40080768 | Derived | 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. | |
| 35996282 | Derived |
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| ID | Title | Description |
|---|---|---|
| FG000 | Dose 1 | Levofloxacin 11mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| FG001 | Dose 2 | Levofloxacin 14mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| FG002 | Dose 3 | Levofloxacin 17mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| FG003 | Dose 4 | Levofloxacin 20mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Dose 1 | Levofloxacin 11mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | A modified intention to treat (MITT) population n=98 was analyzed. | Posted | Median | Inter-Quartile Range | weeks | 28 weeks |
|
Adverse events were collected from the signing of consent form to the final visit. For a typical participant that would be 28 weeks.
The definitions do not differ from the clinicaltrials.gov definitions.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dose 1 | Levofloxacin 11mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute psychosis | Psychiatric disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Blood uric acid increased | Investigations | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Charles R Horsburgh, MD | Boston University School of Public Health | 617-414-1282 | rhorsbu@bu.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 7, 2017 | Jan 26, 2023 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D018088 | Tuberculosis, Multidrug-Resistant |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
Not provided
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| ID | Term |
|---|---|
| D064704 | Levofloxacin |
| D015242 | Ofloxacin |
| ID | Term |
|---|---|
| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
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|
|
| 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. |
|
| Lima |
| Peru |
| Stellenbosch University | Cape Town | South Africa |
| 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. |
| 30373800 | 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. |
| 30012767 | 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. |
| 29178937 | 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. |
| Adverse Event |
|
| Lack of compliance |
|
| Pregnancy |
|
| Rifampin susceptible |
|
| Treatment failure |
|
| Withdrawal by Subject |
|
| XDR at baseline |
|
| Lost to Follow-up |
|
| Increased QTc |
|
| Death |
|
| Involved in another investigative trial |
|
| BG001 | Dose 2 | Levofloxacin 14mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| BG002 | Dose 3 | Levofloxacin 17mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| BG003 | Dose 4 | Levofloxacin 20mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | Dose 2 | Levofloxacin 14mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| OG002 | Dose 3 | Levofloxacin 17mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
| OG003 | Dose 4 | Levofloxacin 20mg/kg daily + Optimized Background Regimen (OBR) 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. 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. |
|
|
| Primary | 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. | Intention to treat analysis based on the number of participants that completed treatment (n=108). | Posted | Number | Events | 28 weeks | Events | Events |
|
|
|
| Secondary | 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). | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| 0 |
| 25 |
| 2 |
| 25 |
| 24 |
| 25 |
| EG001 | Dose 2 | Levofloxacin 14mg/kg daily + Optimized Background Regimen (OBR) 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. 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. | 0 | 28 | 1 | 28 | 28 | 28 |
| EG002 | Dose 3 | Levofloxacin 17mg/kg daily + Optimized Background Regimen (OBR) 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. 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. | 1 | 28 | 4 | 28 | 28 | 28 |
| EG003 | Dose 4 | Levofloxacin 20mg/kg daily + Optimized Background Regimen (OBR) 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. 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. | 0 | 27 | 3 | 27 | 27 | 27 |
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Chronic Obstructive Pulmonary disease | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Delirium | Psychiatric disorders | Non-systematic Assessment |
|
| Gastroenteritis | Infections and infestations | Non-systematic Assessment |
|
| Hepatic function abnormal | Hepatobiliary disorders | Systematic Assessment |
|
| Immune reconstitution inflammatory syndrome | Immune system disorders | Non-systematic Assessment |
|
| Ischaemic Stroke | Nervous system disorders | Non-systematic Assessment |
|
| Oedema peripheral | General disorders | Non-systematic Assessment |
|
| Pain in extremily | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary fistula | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Weight decreased | Investigations | Systematic Assessment |
|
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Deafness | Ear and labyrinth disorders | Non-systematic Assessment |
|
| Eosinophilia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Hepatic function abnormal | Hepatobiliary disorders | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Chest pain | General disorders | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Disseminated tuberculosis | Infections and infestations | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Drug induced liver injury | Hepatobiliary disorders | Systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | Systematic Assessment |
|
| Hyperuricaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Meningitis Tuberculosis | Infections and infestations | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Neuropathy peripheral | Nervous system disorders | Non-systematic Assessment |
|
| Oedema peripheral | General disorders | Non-systematic Assessment |
|
| Ototoxicity | Ear and labyrinth disorders | Non-systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | Non-systematic Assessment |
|
| Hepatic Function Abnormal | Hepatobiliary disorders | Systematic Assessment |
|
| Eosinophilia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Acariasis | Infections and infestations | Systematic Assessment |
|
| Acarodermatitis | Infections and infestations | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Adjustment disorder | Psychiatric disorders | Systematic Assessment |
|
| Affect Lability | Psychiatric disorders | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Anorectal disease | Gastrointestinal disorders | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | Systematic Assessment |
|
| Arrhythmia | Cardiac disorders | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Aspartate Aminostransferase Increased | Investigations | Systematic Assessment |
|
| Asthenia | General disorders | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Bicytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Blister | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | Systematic Assessment |
|
| Blood folate decreased | Investigations | Systematic Assessment |
|
| Blood glucose increased | Investigations | Systematic Assessment |
|
| Body Tinia | Infections and infestations | Systematic Assessment |
|
| Bradycardia | Cardiac disorders | Systematic Assessment |
|
| Breast pain | Reproductive system and breast disorders | Systematic Assessment |
|
| Breath sounds abnormal | Investigations | Systematic Assessment |
|
| Bronchitis | Infections and infestations | Systematic Assessment |
|
| Bulimia Nervosa | Psychiatric disorders | Systematic Assessment |
|
| Chronic Obstructive Pulmonary Disease | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Conjunctivitis Allergic | Eye disorders | Systematic Assessment |
|
| Conjunctivitis bacterial | Infections and infestations | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | Systematic Assessment |
|
| costochondritis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Creatinine Renal Clearance | Investigations | Systematic Assessment |
|
| Dental Caries | Gastrointestinal disorders | Systematic Assessment |
|
| Dental Discomfort | Gastrointestinal disorders | Systematic Assessment |
|
| Depression | Psychiatric disorders | Systematic Assessment |
|
| Dermatitis Acneiform | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Diabetes Mellitus | Endocrine disorders | Systematic Assessment |
|
| Diarrrhoea | Gastrointestinal disorders | Systematic Assessment |
|
| Diplopia | Eye disorders | Systematic Assessment |
|
| Dry eye | Eye disorders | Systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Dysuria | Renal and urinary disorders | Systematic Assessment |
|
| Ear Discomfort | Ear and labyrinth disorders | Systematic Assessment |
|
| Ear Pain | Ear and labyrinth disorders | Systematic Assessment |
|
| Eosinophil Count Increase | Investigations | Systematic Assessment |
|
| Erectile Dysfunction | Reproductive system and breast disorders | Systematic Assessment |
|
| Exoriation | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Eye Pruritis | Eye disorders | Systematic Assessment |
|
| Eye Swelling | Eye disorders | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Fibroadenoma of breast | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | Systematic Assessment |
|
| Fungal Infection | Infections and infestations | Systematic Assessment |
|
| Gastric Disorder | Gastrointestinal disorders | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | Systematic Assessment |
|
| Gastroenteritis | Gastrointestinal disorders | Systematic Assessment |
|
| Gastrooesophageal reflux | Gastrointestinal disorders | Systematic Assessment |
|
| Gingival Pain | Gastrointestinal disorders | Systematic Assessment |
|
| Grip strength decreased | Investigations | Systematic Assessment |
|
| Gynaecomastia | Reproductive system and breast disorders | Systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | Systematic Assessment |
|
| Hallucinations, mixed | Psychiatric disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Hearing impaired | Ear and labyrinth disorders | Systematic Assessment |
|
| Heat rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Herpes simplex | Infections and infestations | Systematic Assessment |
|
| Herpes virus infection | Infections and infestations | Systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hyperkeratosis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hypersensitivity | Immune system disorders | Systematic Assessment |
|
| Hypoacusis | Ear and labyrinth disorders | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | Systematic Assessment |
|
| Hypoaesthesia oral | Gastrointestinal disorders | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypothyroidism | Endocrine disorders | Systematic Assessment |
|
| Incision site pain | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Influenza like illness | General disorders | Systematic Assessment |
|
| Injection site haematoma | General disorders | Systematic Assessment |
|
| Injection site pain | General disorders | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | Systematic Assessment |
|
| Jaundice | Hepatobiliary disorders | Systematic Assessment |
|
| Joint effusion | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Joint injury | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Joint instability | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Joint swelling | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Laceration | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Libido increased | Psychiatric disorders | Systematic Assessment |
|
| Ligament sprain | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Limb discomfort | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Limb injury | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Lip swelling | Gastrointestinal disorders | Systematic Assessment |
|
| Lower respiratory tract infection | Infections and infestations | Systematic Assessment |
|
| Lymphadenopathy | Blood and lymphatic system disorders | Systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Major depression | Psychiatric disorders | Systematic Assessment |
|
| Mood altered | Psychiatric disorders | Systematic Assessment |
|
| Muscle atrophy | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Musculoskeletal discomfort | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Myopia | Eye disorders | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Nasal discomfort | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | Systematic Assessment |
|
| Neck Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Neuritis | Nervous system disorders | Systematic Assessment |
|
| Neurodermatitis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Night sweats | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Nightmare | Psychiatric disorders | Systematic Assessment |
|
| Odynophagia | Gastrointestinal disorders | Systematic Assessment |
|
| Oral Candidiasis | Infections and infestations | Systematic Assessment |
|
| Oral disorder | Gastrointestinal disorders | Systematic Assessment |
|
| Oral Herpes | Infections and infestations | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Otitis Externa | Infections and infestations | Systematic Assessment |
|
| Otitis Media | Infections and infestations | Systematic Assessment |
|
| Pain | General disorders | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pallor | Vascular disorders | Systematic Assessment |
|
| Palpitations | Cardiac disorders | Systematic Assessment |
|
| Papule | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | Systematic Assessment |
|
| Paronychia | Infections and infestations | Systematic Assessment |
|
| Pelvic pain | Reproductive system and breast disorders | Systematic Assessment |
|
| Peripheral sensory neuropathy | Nervous system disorders | Systematic Assessment |
|
| Personality disorder | Psychiatric disorders | Systematic Assessment |
|
| Pharyngitis | Infections and infestations | Systematic Assessment |
|
| Pharyngitis bacterial | Infections and infestations | Systematic Assessment |
|
| Pharyngotonsillitis | Infections and infestations | Systematic Assessment |
|
| Photosensitivity reaction | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Physical assault | Social circumstances | Systematic Assessment |
|
| Pityriasis alba | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pleuritic pain | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | Systematic Assessment |
|
| Polyarthritis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Polycythaemia vera | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Polydipsia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Polyuria | Renal and urinary disorders | Systematic Assessment |
|
| Post herpetic Neuralgia | Nervous system disorders | Systematic Assessment |
|
| Post inflammatory pigment change | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Presyncope | Nervous system disorders | Systematic Assessment |
|
| Proctalgia | Gastrointestinal disorders | Systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pruritus genital | Reproductive system and breast disorders | Systematic Assessment |
|
| Psoas Abscess | Infections and infestations | Systematic Assessment |
|
| Psychotic disorder | Psychiatric disorders | Systematic Assessment |
|
| Pyrexia | General disorders | Systematic Assessment |
|
| Rales | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Rash pustular | Infections and infestations | Systematic Assessment |
|
| Renal impairment | Renal and urinary disorders | Systematic Assessment |
|
| Rhinitis | Infections and infestations | Systematic Assessment |
|
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Sensory loss | Nervous system disorders | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | Systematic Assessment |
|
| Skin exfoliation | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Skin hyperpigmentation | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Skin hypopigmentation | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Skin lesion | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Skin papilloma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Sneezing | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Somnolence | Nervous system disorders | Systematic Assessment |
|
| Subcutaneous abscess | Infections and infestations | Systematic Assessment |
|
| Syncope | Nervous system disorders | Systematic Assessment |
|
| Synovial cyst | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | Systematic Assessment |
|
| Tendon pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Tenosynovitis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Throat irritation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | Systematic Assessment |
|
| Tooth abscess | Infections and infestations | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | Systematic Assessment |
|
| Transaminases increased | Investigations | Systematic Assessment |
|
| Tremor | Nervous system disorders | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Urine analysis abnormal | Investigations | Systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Vaginal discharge | Reproductive system and breast disorders | Systematic Assessment |
|
| Vessel puncture site bruise | General disorders | Systematic Assessment |
|
| Viral pharyngitis | Infections and infestations | Systematic Assessment |
|
| Vision blurred | Eye disorders | Systematic Assessment |
|
| Visual acuity reduced | Eye disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Vulvovaginitis | Infections and infestations | Systematic Assessment |
|
| Weight decreased | Investigations | Systematic Assessment |
|
| Xeroderma | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Xerosis | General disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| Events |
|