TBTC Study 30: Safety and Tolerability of Low Dose Linezolid in MDR TB

TBTC Study 30: A Phase I/II Pilot Study for Evaluation of Low Dose, Once Daily, Linezolid Plus Optimized Background Therapy (OBT) Versus Placebo Plus OBT for the Treatment of Multi-drug Resistant Tuberculosis

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).

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.

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)