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

Sponsor

Fundación Pública Andaluza para la gestión de la Investigación en Sevilla (Other)

Overall Status

Terminated

CT.gov ID

NCT01761201

Collaborator

Spanish Network for Research in Infectious Diseases (Other)

Enrollment

Locations

Arms

Duration (Months)

3.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Latent Tuberculosis Infection Infection in Solid Organ Transplant Recipients	Drug: Levofloxacin Drug: Isoniazid	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Feb 1, 2014

Actual Study Completion Date :

Feb 1, 2014

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Difference in incidence of tuberculosis disease [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 Outcome Measures

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

Other Outcome Measures

Safety [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	Country
1	Complejo Hospitalario de Albacete	Albacete	Spain
2	Hospital Infanta Cristina,	Badajoz	Spain
3	Hospital Clinic	Barcelona	Spain
4	Hospital Vall d'Hebron	Barcelona	Spain
5	Hospital de Cruces	Bilbao	Spain
6	Complejo Hospitalario Universitario	Coruña	Spain
7	Hospital Reina Sofía	Córdoba	Spain
8	Hospital universitario Virgen de las Nieves	Granada	Spain
9	Hospital 12 de Octubre	Madrid	Spain
10	Hospital Gregorio Marañón	Madrid	Spain
11	Hospital Ramón y Cajal	Madrid	Spain
12	Hospital Universitario Puerta de Hierro	Madrid	Spain
13	Hospital Virgen de la Arrixaca	Murcia	Spain
14	Hospital Universitario Carlos Haya	Málaga	Spain
15	Clínica Universitaria de Navarra	Pamplona	Spain
16	Hospital Marqués de Valdecillas	Santander	Spain
17	Hospital Virgen del Rocío	Seville	Spain
18	Hospital Universitario La Fe	Valencia	Spain

Sponsors and Collaborators

Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
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