“Efficacy and Safety of Levofloxacin vs Isoniazid in Latent Tuberculosis Infection in Liver Transplant Patients”.

Overview

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.

Full Title of Study: “”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

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: February 2014

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.

Interventions

  • Drug: Levofloxacin
    • Levofloxacin
  • 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.

Arms, Groups and Cohorts

  • Experimental: levofloxacin
    • Levofloxacin 500 mg daily for 9 months starting on the waiting list for liver transplant
  • 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

Clinical Trial Outcome Measures

Primary Measures

  • Difference in incidence of tuberculosis disease
    • Time Frame: 18 months of follow-up
    • 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 Measures

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

Participating in This Clinical Trial

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).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
  • Collaborator
    • Spanish Network for Research in Infectious Diseases
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Julián de la Torre Cisneros, MD, Principal Investigator, Hospital Universitario Reina Sofía, Córdoba, Spain
    • José M. Aguado, MD, PhD, Study Chair, Hospital Universitario 12 de Octubre, Madrid

References

Torre-Cisneros J, Doblas A, Aguado JM, San Juan R, Blanes M, Montejo M, Cervera C, Len O, Carratala J, Cisneros JM, Bou G, Muñoz P, Ramos A, Gurgui M, Borrell N, Fortún 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, Gavaldá J, Torre-Cisneros J, Blanes M, Rufí G, Moreno A, Gurguí 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. Review. Erratum in: Transplantation 1997 Sep 27;64(6):942.

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