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

• ClinicalTrials.gov Identifier: NCT01761201
• Recruitment Status: Terminated
• First Posted: January 4, 2013
• Last Update Posted: August 6, 2014
• Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Collaborator: Spanish Network for Research in Infectious Diseases
• Information provided by (Responsible Party): Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Tracking Information

• First Submitted Date: January 3, 2013
• First Posted Date: January 4, 2013
• Last Update Posted Date: August 6, 2014
• Study Start Date: January 2012
• Actual Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 3, 2013)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 3, 2013)

• 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.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: January 3, 2013)

Safety [ Time Frame: 18 months ]

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.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: "Efficacy and Safety of Levofloxacin vs Isoniazid in Latent Tuberculosis Infection in Liver Transplant Patients".
• 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".

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

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Latent Tuberculosis Infection
• Infection in Solid Organ Transplant Recipients

Intervention

• Drug: Levofloxacin
  Levofloxacin
  Other Names:

  • Generic name: Levofloxacin
  • ATC Code: J01MA.
  • Pharmaceutical form: Levofloxacin 500 mg film-coated tablets
• 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.

Study Arms

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

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, 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 5, 2014): 68
• Original Estimated Enrollment (submitted: January 3, 2013): 870
• Actual Study Completion Date: February 2014
• Actual Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT01761201
• Other Study ID Numbers: FLISH-ILT; 2010-022302-41 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Study 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

• PRS Account: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Verification Date: August 2014