Linezolid to Treat Extensively-Drug Resistant Tuberculosis
Condition: Pulmonary Tuberculosis; Multidrug Resistant Tuberculosis; Extensively Drug Resistant Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis
Intervention: Immediate Start Linezolid; Delayed Start Linezolid
Intervention MeSH terms: Linezolid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: XDR-TB; Linezolid; Drug Resistance; Computed Tomography; Pharmacokinetics; Tuberculosis; Drug Resistance Tuberculosis; MDR-TB

Summary:

      This study, conducted in Masan and Seoul, South Korea, investigated the effectiveness of
      linezolid (LZD) in treating patients with extensively drug resistant tuberculosis (XDR TB).
      Because regular medicines do not work well against XDR TB, many more people die from it than
      from regular TB, which can be successfully treated by taking TB medication for 6 months.
      Linezolid has been used to treat other kinds of infections, but has not been well studied for
      TB. This study examined the side effects and effectiveness of prolonged treatment with
      linezolid at two different doses.

      People 20 years of age and older who have XDR TB were eligible for this 3-year study.

      Participants underwent the following tests and procedures:

        -  LZD treatment: Patients were randomly assigned to one of two study groups. Group 1
           patients were observed for 2 months before starting LZD, while group 2 patients begin
           taking LZD right away. Both groups began with a 600 mg daily dose of LZD. After patients
           stopped coughing up TB germs (or after 4 months on LZD) they were randomly assigned
           either to continue taking 600 mg of LZD for the rest of the study or to take a decreased
           dose of 300 mg. In addition to LZD, patients continued to take their currently
           prescribed TB medications.

        -  Medical history.

        -  Physical examinations each month during treatment.

        -  Sputum collections once a week or more until 3 weeks after the patient was no longer
           contagious.

        -  Blood draws every week for 16 to 24 weeks and then once a month.

        -  Urine collections at several time points.

        -  Nerve and eye examinations before starting treatment and then monthly to look for
           possible LZD side effects.

        -  CT scans of the lungs three to four times the first year and once more later in the
           study. For this test the patient lay on a table within the doughnut-shaped CT scanner
           while special X-ray pictures are taken.

      Patients who participated in a substudy had PET scans instead of the CT scans. For this test,
      the patient was given an injection into a vein of a radioactive chemical that can be detected
      by a special camera and viewed on a screen. The patient lay on a table within the
      doughnut-shaped scanner while pictures were taken.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Males and females age 20 and above

        Documented pulmonary tuberculosis at screening

        Radiographic evidence of tuberculous disease of the lung(s)

        History of chronic, AFB positive sputum smears and culture positive TB

        Mycobacterium species identification as Mycobacterium tuberculosis

        Confirmed resistance to INH, RIF, kanamycin, ofloxacin, and moxifloxacin by genotypic or
        phenotypic testing OR subjects with documented failure to respond to treatment despite DST
        susceptibility

        Failure to respond (after at least 6 months) to a anti-TB drug regimen including any known
        active agents

        Willingness to be an inpatient until 2 consecutive AFB-negative sputum smears

        When an outpatient, willing to come back for weekly tests and scheduled follow-up visits

        Willingness to have samples stored

        Ability and willingness to give written or oral informed consent

        EXCLUSION CRITERIA:

        Subjects below 20 years of age

        Subjects who have previously been on LZD

        Women of childbearing potential, who are pregnant, breast feeding, or unwilling to avoid
        pregnancy (i.e., the use of appropriate contraception including oral and subcutaneous
        implantable hormonal contraceptives, condoms, diaphragm, intrauterine device (IUD), or
        abstinence from sexual intercourse). [Note: Prospective female participants of childbearing
        potential must have negative pregnancy test (urine) within 48 hours prior to study entry.]

        Men who are unwilling to use contraceptives or practice abstinence

        People with any of the following in their current medical assessments:

        Absolute neutrophil count less than 1000 cells/mL

        White blood cell count (WBC) less than 3.0 X 10(3)/microL

        Hemoglobin less than 7.0 g/dL

        Platelet count less than 75,000 cells/mm(3)

        Serum creatinine greater than 2.0 mg/dL

        Aspartate aminotransferase (AST or SGOT) greater than 100 IU/L

        Alanine aminotransferase (ALT or SGPT) greater than 100 IU/L

        Total bilirubin greater than 2.0 mg/dL

        Moderate or severe peripheral or optical neuropathy (or a history of)

        HIV-1 or HIV-2 infection

        Systemic lupus erythematosus, rheumatoid arthritis, or other connective tissue disease

        Patients who, in the investigator's judgment, are too ill to participate in the study

        History of allergy or serious adverse reaction to the LZD formulation used in this study

        Patients with anticipated surgical intervention

        The use of any of the following drugs within 30 days prior to study or anticipated use of
        these drugs within the next 60 days: (Please not, bronchodilators and cough syrup (or
        similar cough medicines) are allowed before and during the study if blood pressure is
        monitored regularly, per Contraindications, p.12, of the Zyvox Package Insert.)

        Selective serotonin reuptake inhibitors (SSRIs)

        Monoamine oxidase inhibitors (MAOIs)

        Systemic cancer chemotherapy

        Systemic corticosteroids

        Systemic investigational agents

        Antiretroviral medications

        Growth factors

        HIV vaccines

        Immune globulin

        Interleukins

        Interferons

        The need for ongoing therapy with antidepressants (SSRI, MAOI), hydroxyzine, dopaminergic
        agents (such as Sinemet, dopamine, and dobutamine), lithium, cyclosporine, tacrolimus,
        sirolimus, and levodopa (such as sinemet) while on study drug

        Any other serious systemic illness requiring treatment and/or hospitalization until subject
        either completes therapy or is clinically stable on therapy for at least 14 days prior to
        study entry

        Patients who the physician has reason to believe may have been non-compliant in the
        previous 12 months of treatment

        SUBSTUDY ELIGIBILITY CRITERIA

        INCLUSION CRITERIA:

        Subjects who meet the inclusion criteria for main study are eligible for the substudy.

        EXCLUSION CRITERIA:

        Exclusion criteria for main study apply to the substudy with the exception that subjects
        with uncontrolled diabetes mellitus will be excluded from the substudy. The study physician
        may decide that a patient is healthy enough to participate in the main study but not the
        sub-study.