Back to results"Efficacy and Safety of Levofloxacin vs Isoniazid in Latent Tuberculosis Infection in Liver Transplant Patients". (FLISH-ILT)
Primary Purpose
Latent Tuberculosis Infection, Infection in Solid Organ Transplant Recipients
Status
Terminated
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Levofloxacin
Isoniazid
Sponsored by
About this trial
This is an interventional treatment trial for Latent Tuberculosis Infection focused on measuring Prophylaxis, Tuberculosis, Transplant recipients, Transplant waiting list
Eligibility Criteria
Inclusion Criteria:
Liver transplantation candidates with age ≥ 18 years, no clinical or radiological evidence of active tuberculosis and negative pregnancy test (if applicable)who must meet one or more of the following criteria:
- PPD skin test (initial or after a "booster effect") >5 mm. Alternatively, the determination may be made by the interferon gamma (IFN-g) production in PPD-stimulated lymphocytes using the Quantiferon-TB or ELISPOT assays.
- Past history of tuberculosis not properly treated.
- Past history of contact with a patient with active TB.
- Chest x-ray consistent with past untreated TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes or pleural thickening).
The patient must give their written informed consent.
Exclusion Criteria:
- Lack of consent to participate in the study.
- Intolerance or allergy to levofloxacin or to isoniazid.
- Documented contact with tuberculosis resistant to levofloxacin or to isoniazid.
- Treatment in the previous month with drugs with potential activity against Mycobacterium tuberculosis, (especially quinolones).
Sites / Locations
- Complejo Hospitalario de Albacete
- Hospital Infanta Cristina,
- Hospital Clinic
- Hospital Vall d'Hebron
- Hospital de Cruces
- Complejo Hospitalario Universitario
- Hospital Reina Sofía
- Hospital universitario Virgen de las Nieves
- Hospital 12 de Octubre
- Hospital Gregorio Marañón
- Hospital Ramón y Cajal
- Hospital Universitario Puerta de Hierro
- Hospital Virgen de la Arrixaca
- Hospital Universitario Carlos Haya
- Clínica Universitaria de Navarra
- Hospital Marqués de Valdecillas
- Hospital Virgen del Rocío
- Hospital Universitario La Fe
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
levofloxacin
Isoniazid
Arm Description
Levofloxacin 500 mg daily for 9 months starting on the waiting list for liver transplant
Isoniazid 300 mg/day for 9 months beginning after transplantation, when the "liver function is stable" and not before 3 months nor after 6 months
Outcomes
Primary Outcome Measures
Difference in incidence of tuberculosis disease
A patient will be considered as having tuberculosis when Mycobacterium tuberculosis is isolated by culture or M. Tuberculosis DNA is isolated from a representative clinical sample, organ fluid or tissue by polymerase chain reaction. Also cases of histopathologically confirmed tuberculosis (caseating granulomas with/without demonstration of acid-alcohol resistant bacillus [BAAR]) and clinically compatible presentation will be accepted. Tuberculosis will be classified as pulmonary (pulmonary parenchymal involvement), extrapulmonary (involvement of different organs to the lung) or disseminated (involvement of at least two non-contiguous organs). Cases where tuberculosis is diagnosed on the basis of clinical and/or radiology suspicion and for whom the corresponding physician has prescribed a specific treatment will not be accepted.
Secondary Outcome Measures
Mortality
Number of deaths of any cause
Toxicity
Occurrence of grade 3 or 4 toxicities according to the grading (severity) scale of the National Cancer Institute Common Toxicity Criteria Version 4.0, NCI-CTC-AE v 4.0.
Retransplantation
A new liver transplantation during the follow-up
Graft dysfunction
Development of advanced graft fibrosis stages 3 and 4
Transplant rejection
The occurrence of acute rejection or chronic rejection as per conventional definitions during the follow-up.
Full Information
NCT ID
NCT01761201
First Posted
January 3, 2013
Last Updated
August 5, 2014
Sponsor
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Collaborators
Spanish Network for Research in Infectious Diseases
1. Study Identification
Unique Protocol Identification Number
NCT01761201
Brief Title
"Efficacy and Safety of Levofloxacin vs Isoniazid in Latent Tuberculosis Infection in Liver Transplant Patients".
Acronym
FLISH-ILT
Official Title
"A Prospective, Randomized, Comparative Clinical Trial of the Efficacy and Safety of Levofloxacin Versus Isoniazid in the Treatment of Latent Tuberculosis Infection in Liver Transplant Patients".
Study Type
Interventional
2. Study Status
Record Verification Date
August 2014
Overall Recruitment Status
Terminated
Why Stopped
Recruitment rythm not sufficent to reach the simple size needed.
Study Start Date
January 2012 (undefined)
Primary Completion Date
February 2014 (Actual)
Study Completion Date
February 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Collaborators
Spanish Network for Research in Infectious Diseases
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
A multicenter, prospective, non-inferiority, randomized and open clinical trial comparing levofloxacin with isoniazid in the treatment of latent tuberculosis infection in patients eligible for liver transplantation.
Patients over 18 years of age on the waiting list for liver transplantation.
Sample size: n=870 patients.
HYPOTHESIS
Levofloxacin treatment of latent tuberculosis infection, begun while on the waiting list for liver transplantation, is safer and not less effective than isoniazid treatment begun after transplantation when liver function is stable.
Detailed Description
Primary Objective
To demonstrate that the incidence of tuberculosis in patients with latent tuberculosis infection and treated with levofloxacin is not higher than that observed in patients treated with isoniazid.
Secondary Objective
To demonstrate that the efficacy of levofloxacin is not limited by adverse effects, paying particular attention to hepatotoxicity.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Latent Tuberculosis Infection, Infection in Solid Organ Transplant Recipients
Keywords
Prophylaxis, Tuberculosis, Transplant recipients, Transplant waiting list
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
68 (Actual)
8. Arms, Groups, and Interventions
Arm Title
levofloxacin
Arm Type
Experimental
Arm Description
Levofloxacin 500 mg daily for 9 months starting on the waiting list for liver transplant
Arm Title
Isoniazid
Arm Type
Active Comparator
Arm Description
Isoniazid 300 mg/day for 9 months beginning after transplantation, when the "liver function is stable" and not before 3 months nor after 6 months
Intervention Type
Drug
Intervention Name(s)
Levofloxacin
Other Intervention Name(s)
Generic name: Levofloxacin, ATC Code: J01MA., Pharmaceutical form: Levofloxacin 500 mg film-coated tablets
Intervention Description
Levofloxacin
Intervention Type
Drug
Intervention Name(s)
Isoniazid
Other Intervention Name(s)
Generic name: Isoniazid., ATC Code: J04AC, Pharmaceutical form: tablets.
Intervention Description
300 mg/day for 9 months beginning after transplantation, when the "liver function is stable" and not before 3 months nor after 6 months.
Primary Outcome Measure Information:
Title
Difference in incidence of tuberculosis disease
Description
A patient will be considered as having tuberculosis when Mycobacterium tuberculosis is isolated by culture or M. Tuberculosis DNA is isolated from a representative clinical sample, organ fluid or tissue by polymerase chain reaction. Also cases of histopathologically confirmed tuberculosis (caseating granulomas with/without demonstration of acid-alcohol resistant bacillus [BAAR]) and clinically compatible presentation will be accepted. Tuberculosis will be classified as pulmonary (pulmonary parenchymal involvement), extrapulmonary (involvement of different organs to the lung) or disseminated (involvement of at least two non-contiguous organs). Cases where tuberculosis is diagnosed on the basis of clinical and/or radiology suspicion and for whom the corresponding physician has prescribed a specific treatment will not be accepted.
Time Frame
18 months of follow-up
Secondary Outcome Measure Information:
Title
Mortality
Description
Number of deaths of any cause
Time Frame
18 months
Title
Toxicity
Description
Occurrence of grade 3 or 4 toxicities according to the grading (severity) scale of the National Cancer Institute Common Toxicity Criteria Version 4.0, NCI-CTC-AE v 4.0.
Time Frame
During all the 18 months of follow-up
Title
Retransplantation
Description
A new liver transplantation during the follow-up
Time Frame
18 months
Title
Graft dysfunction
Description
Development of advanced graft fibrosis stages 3 and 4
Time Frame
18 months
Title
Transplant rejection
Description
The occurrence of acute rejection or chronic rejection as per conventional definitions during the follow-up.
Time Frame
18 months
Other Pre-specified Outcome Measures:
Title
Safety
Description
Drug tolerance will be evaluated by a clinical study interview and periodic analytical determinations which will include levels of transaminases (ALT and AST), alkaline phosphatase and gamma-GT, bilirubin, according to the study visit schedule.
All symptoms and laboratory results will be evaluated for severity according to the grading (severity) scale of the National Cancer Institute Common Toxicity Criteria Version 3.0, NCI-CTC-AE v 3.0.
Time Frame
18 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Liver transplantation candidates with age ≥ 18 years, no clinical or radiological evidence of active tuberculosis and negative pregnancy test (if applicable)who must meet one or more of the following criteria:
PPD skin test (initial or after a "booster effect") >5 mm. Alternatively, the determination may be made by the interferon gamma (IFN-g) production in PPD-stimulated lymphocytes using the Quantiferon-TB or ELISPOT assays.
Past history of tuberculosis not properly treated.
Past history of contact with a patient with active TB.
Chest x-ray consistent with past untreated TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes or pleural thickening).
The patient must give their written informed consent.
Exclusion Criteria:
Lack of consent to participate in the study.
Intolerance or allergy to levofloxacin or to isoniazid.
Documented contact with tuberculosis resistant to levofloxacin or to isoniazid.
Treatment in the previous month with drugs with potential activity against Mycobacterium tuberculosis, (especially quinolones).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Julián de la Torre Cisneros, MD
Organizational Affiliation
Hospital Universitario Reina Sofía, Córdoba, Spain
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
José M. Aguado, MD, PhD
Organizational Affiliation
Hospital Universitario 12 de Octubre, Madrid
Official's Role
Study Chair
Facility Information:
Facility Name
Complejo Hospitalario de Albacete
City
Albacete
Country
Spain
Facility Name
Hospital Infanta Cristina,
City
Badajoz
Country
Spain
Facility Name
Hospital Clinic
City
Barcelona
Country
Spain
Facility Name
Hospital Vall d'Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital de Cruces
City
Bilbao
Country
Spain
Facility Name
Complejo Hospitalario Universitario
City
Coruña
Country
Spain
Facility Name
Hospital Reina Sofía
City
Córdoba
Country
Spain
Facility Name
Hospital universitario Virgen de las Nieves
City
Granada
Country
Spain
Facility Name
Hospital 12 de Octubre
City
Madrid
Country
Spain
Facility Name
Hospital Gregorio Marañón
City
Madrid
Country
Spain
Facility Name
Hospital Ramón y Cajal
City
Madrid
Country
Spain
Facility Name
Hospital Universitario Puerta de Hierro
City
Madrid
Country
Spain
Facility Name
Hospital Virgen de la Arrixaca
City
Murcia
Country
Spain
Facility Name
Hospital Universitario Carlos Haya
City
Málaga
Country
Spain
Facility Name
Clínica Universitaria de Navarra
City
Pamplona
Country
Spain
Facility Name
Hospital Marqués de Valdecillas
City
Santander
Country
Spain
Facility Name
Hospital Virgen del Rocío
City
Seville
Country
Spain
Facility Name
Hospital Universitario La Fe
City
Valencia
Country
Spain
12. IPD Sharing Statement
Citations:
PubMed Identifier
19445585
Citation
Torre-Cisneros J, Doblas A, Aguado JM, San Juan R, Blanes M, Montejo M, Cervera C, Len O, Carratala J, Cisneros JM, Bou G, Munoz P, Ramos A, Gurgui M, Borrell N, Fortun J, Moreno A, Gavalda J; Spanish Network for Research in Infectious Diseases. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis. 2009 Jun 15;48(12):1657-65. doi: 10.1086/599035.
Results Reference
background
PubMed Identifier
9158022
Citation
Aguado JM, Herrero JA, Gavalda J, Torre-Cisneros J, Blanes M, Rufi G, Moreno A, Gurgui M, Hayek M, Lumbreras C, Cantarell C. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation. 1997 May 15;63(9):1278-86. doi: 10.1097/00007890-199705150-00015. Erratum In: Transplantation 1997 Sep 27;64(6):942.
Results Reference
background
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"Efficacy and Safety of Levofloxacin vs Isoniazid in Latent Tuberculosis Infection in Liver Transplant Patients".
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