"Efficacy and Safety of Levofloxacin vs Isoniazid in Latent Tuberculosis Infection in Liver Transplant Patients". (FLISH-ILT)

"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".

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.

Study Overview

• Status: Terminated
• Conditions: Infection in Solid Organ Transplant Recipients; Latent Tuberculosis Infection
• Intervention / Treatment: Drug: Levofloxacin; Drug: Isoniazid

Detailed Description

Primary Objective

1. 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

2. To demonstrate that the efficacy of levofloxacin is not limited by adverse effects, paying particular attention to hepatotoxicity.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Albacete, Spain
    • Complejo Hospitalario de Albacete
  • Badajoz, Spain
    • Hospital Infanta Cristina,
  • Barcelona, Spain
    • Hospital Vall d'Hebron
  • Barcelona, Spain
    • Hospital Clínic
  • Bilbao, Spain
    • Hospital de Cruces
  • Coruña, Spain
    • Complejo Hospitalario Universitario
  • Córdoba, Spain
    • Hospital Reina Sofia
  • Granada, Spain
    • Hospital Universitario Virgen de las Nieves
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Madrid, Spain
    • Hospital Gregorio Marañón
  • Madrid, Spain
    • Hospital Universitario Puerta de Hierro
  • Murcia, Spain
    • Hospital Virgen de la Arrixaca
  • Málaga, Spain
    • Hospital Universitario Carlos Haya
  • Pamplona, Spain
    • Clinica Universitaria de Navarra
  • Santander, Spain
    • Hospital Marqués de Valdecillas
  • Seville, Spain
    • Hospital Virgen Del Rocio
  • Valencia, Spain
    • Hospital Universitario La Fe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: levofloxacin; Levofloxacin 500 mg daily for 9 months starting on the waiting list for liver transplant	Drug: Levofloxacin; Levofloxacin; Other Names: Generic name: Levofloxacin; ATC Code: J01MA.; Pharmaceutical form: Levofloxacin 500 mg film-coated tablets
Active Comparator: Isoniazid; 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	Drug: 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.; Other Names: Generic name: Isoniazid.; ATC Code: J04AC; Pharmaceutical form: tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	18 months of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Number of deaths of any cause	18 months
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.	During all the 18 months of follow-up
Retransplantation	A new liver transplantation during the follow-up	18 months
Graft dysfunction	Development of advanced graft fibrosis stages 3 and 4	18 months
Transplant rejection	The occurrence of acute rejection or chronic rejection as per conventional definitions during the follow-up.	18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	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.	18 months

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Collaborators: Spanish Network for Research in Infectious Diseases
• Investigators: Principal Investigator: Julián de la Torre Cisneros, MD, Hospital Universitario Reina Sofía, Córdoba, Spain; Study Chair: José M. Aguado, MD, PhD, Hospital Universitario 12 de Octubre, Madrid

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• official web site for the Spanish Infectious Disease Network

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: January 3, 2013
• First Submitted That Met QC Criteria: January 3, 2013
• First Posted (Estimate): January 4, 2013

Study Record Updates

• Last Update Posted (Estimate): August 6, 2014
• Last Update Submitted That Met QC Criteria: August 5, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Tuberculosis; Prophylaxis; Transplant recipients; Transplant waiting list
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Infections; Communicable Diseases; Tuberculosis; Latent Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Antitubercular Agents; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Fatty Acid Synthesis Inhibitors; Levofloxacin; Ofloxacin; Isoniazid
• Other Study ID Numbers: FLISH-ILT; 2010-022302-41 (EudraCT Number)