Extensively Drug Resistant Tuberculosis, Multi-drug Resistant Tuberculosis
Conditions
Keywords
Linezolid, Zyvox, Peripheral Neuropathy, Optic Neuropathy, Anemia, Thrombocytopenia
Brief summary
This study evaluated the safety and tolerability of low-dose linezolid (600 mg once daily) administered for 16 weeks as part of an optimized background regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB).
Detailed description
Tuberculosis Trials Consortium (TBTC) Study 30 was a randomized, double-blind, placebo-controlled Phase I/II clinical trial conducted to evaluate the safety and tolerability of low-dose linezolid when added to an optimized background regimen for the treatment of multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis. Participants received either linezolid 600 mg orally once daily or matching placebo for 16 weeks in addition to background therapy consisting of at least four drugs with presumed activity against Mycobacterium tuberculosis. The primary objectives were to assess tolerability, defined as the proportion of participants completing at least 80% of planned doses within 18 weeks, and safety, assessed by the occurrence of serious adverse events during treatment and a 4-week follow-up period. Secondary assessments included adverse event profiles, laboratory safety parameters, and time to sputum culture conversion. The study was conducted in Durban, South Africa, among adults with confirmed MDR or XDR tuberculosis.
Interventions
DRUGLinezolid
600 mg po daily for 112 doses (16 weeks)
DRUGPlacebo
Placebo given daily for 112 doses (16 weeks)
Sponsors
Centers for Disease Control and Prevention
University of KwaZulu
Columbia University
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pulmonary tuberculosis with or without extrapulmonary TB with a M. tuberculosis isolate that is confirmed to be resistant to at least rifampin and isoniazid (without regard to prior treatment for TB). 2. A documented positive sputum culture result for M. tuberculosis from a sputum obtained in the four months prior to enrollment. 3. Willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 6 months prior to enrollment. 4. Residence within the Durban Functional Region (Durban Metropolitan Area) or Tugela Ferry, Msinga District, KZN, RSA. 5. Age ≥ 18 years. 6. Karnofsky score of \> 50 (see section 18.1) 7. Willingness by the patient to attend scheduled follow-up visits and undergo study assessments. 8. Women with child-bearing potential must agree to practice an adequate method of birth control or to abstain from heterosexual intercourse during study therapy. (Standard birth control measures are provided free of charge by public health institutions) 9. Laboratory parameters done within 14 days prior to screening: 1. Serum creatinine level \< 2 times upper limit of normal 2. Hemoglobin level ≥ 9.0 g/dL 3. Platelet count of ≥ 80,000/mm3 4. Absolute neutrophil count (ANC) \> 1000/ mm3 5. Negative pregnancy test (for women of childbearing potential) 10. Able to provide informed consent or legally authorized representative able to do so if decisionally impaired.
Exclusion criteria
1. Currently breast-feeding or pregnant. 2. Known allergy or intolerance to linezolid. 3. Planned therapy during the intensive phase of tuberculosis treatment using drugs having unacceptable interactions with linezolid, including dopamine, selective serotonin uptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), amitriptyline, bupropion, mirtazepine, levodopa, carbidopa, sinemet, or herbal medications. 4. Significant peripheral neuropathy as evidenced by \< 5 seconds of vibratory sense to a 128 Hz tuning fork on either big toe 5. Pain, aching or burning of the feet that interfere with walking or sleep. 6. In the judgment of the physician the patient is not expected to survive for more than 4 weeks. 7. Anticipated surgical intervention for the treatment of pulmonary tuberculosis 8. Visual acuity of 20/200 (6/60 meters) best corrected vision or less. 9. Poor color vision as evidenced by incorrect answers on \> four of 12 screening Ishihara plates 10. Participation in another drug trial. 11. The patient has received second line TB drugs for \> 7 days immediately prior to enrollment (note: use of first line drugs such as INH, Rifampin, PZA, or ethambutol for \> 7 days immediately prior to enrollment is allowed)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Completing at Least 80% (≥90 of 112) of Assigned Study Drug Doses Within 18 Weeks | 18 weeks | Proportion of participants who completed at least 80% (≥90 of 112 doses) of directly observed study drug within 18 weeks of treatment initiation. |
| Number of Serious Adverse Events During Study Drug Therapy and 4 Weeks Post-Therapy | 20 weeks | Number of serious adverse events occurring during study drug therapy and the 4 weeks after completion of study therapy. |
Countries
South Africa
Contacts
PRINCIPAL_INVESTIGATORJussi Saukkonen, MD
Boston University
PRINCIPAL_INVESTIGATORWaffa El-Sadr, MD
Columbia University
PRINCIPAL_INVESTIGATORNesri Padayachin, MBChB
University of Kwa-Zulu Natal
Participant flow
Pre-assignment details
Thirty-six participants were enrolled and randomized. Two participants were not included in the participant flow analysis population: one participant withdrew before receiving any study drug, and one participant was determined to be ineligible after enrollment and was withdrawn from the study. Therefore, 34 participants received at least one dose of study drug and are included in the Participant Flow module.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 36 years |
| HIV Status HIV Negative | 3 participants |
| HIV Status HIV Positive | 15 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 10 / 16 | 11 / 18 |
| serious Total, serious adverse events | 0 / 16 | 1 / 18 |
Outcome results
None listed