A Phase 2 Trial to Evaluate the Efficacy and Safety of Linezolid in Tuberculosis Patients. (LIN-CL001)

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02279875
• Date of registration: 28/10/2014
• Prospective Registration: Yes
• Primary sponsor: Global Alliance for TB Drug Development
• Public title: A Phase 2 Trial to Evaluate the Efficacy and Safety of Linezolid in Tuberculosis Patients. (LIN-CL001)
• Scientific title: A Phase 2 Dose-ranging Trial to Evaluate the Bactericidal Activity, Safety, Tolerability and Pharmacokinetics of Linezolid in Adult Subjects With Newly Diagnosed Drug-Sensitive, Smear-Positive Pulmonary Tuberculosis.
• Date of first enrolment: November 2014
• Target sample size: 113
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02279875
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

South Africa

Contacts

• Name: Rod Dawson
• Affiliation: University of Cape Town Lung Institute (Pty) Ltd

• Name: Christo van Niekerk
• Affiliation: Global Alliance for TB Drug Development

• Name: Adreas Diacon
• Affiliation: Task Clinical Research Centre

Key inclusion & exclusion criteria

Inclusion Criteria:

Subjects are required to meet all of the following inclusion criteria in order to be
randomized.

1. Provide written, informed consent prior to all trial-related procedures.

2. Male or female, aged between 18 and 75 years inclusive.

3. Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.

4. Drug-sensitive pulmonary Tuberculosis (TB) determined by testing at the trial
appointed laboratory: M.tb positive and rifampicin sensitive on molecular test (e.g.
GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for
acid-fast bacilli (at least 1+ on the IUATLD/WHO scale).

1. either newly diagnosed OR

2. untreated for at least 3 years after cure from a previous episode (Subject can
give a history of cure and previous treatment); AND

3. Previous TB treatment must be discontinued as per exclusion criteria 17.

5. A chest X-Ray which in the opinion of the Investigator is consistent with TB.

6. Ability to produce an adequate volume of sputum as estimated from a screening Coached
Spot Sputum Sample assessment (estimated 10 ml or more overnight production).

7. Be of non-childbearing potential or using effective methods of birth control, as
defined below:

Non-childbearing potential:

1. Subject - not heterosexually active or practices sexual abstinence; OR

2. Female Subject/sexual partner - bilateral oophorectomy, bilateral tubal ligation
and/or hysterectomy or has been postmenopausal with a history of no menses for at
least 12 consecutive months; OR

3. Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy
minimally three months prior to screening;

Effective birth control methods:

A double contraceptive method should be used as follows:

1. Double barrier method which can include any 2 of the following: a male condom,
diaphragm, cervical cap, or female condom (male and female condoms should not be used
together); OR

2. Barrier method (one of the above) combined with hormone-based contraceptives or an
intra-uterine device for the female Subject/partner; AND

3. Are willing to continue practicing one of the above mentioned birth control methods
throughout treatment and for 1 month (both male and female Subjects) after the last
dose of study medication or discontinuation from study medication in case of premature
discontinuation.

Exclusion Criteria:

Subjects will be excluded from participation if they meet any of the following criteria.

Medical Criteria

1. Evidence of clinically significant (as judged by the Investigator), metabolic,
gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary,
neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities
(other than the indication being studied) including malaria.

A rapid test for malaria may be carried out if indicated.

2. Poor general condition where any delay in treatment cannot be tolerated per discretion
of the Investigator.

3. Clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB,
urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.

4. History of allergy or hypersensitivity to any of the study Investigational Medicinal
Products or related substances.

5. Known or suspected current alcohol and/or drug abuse (positive urine drug screen) or
history thereof within the past 2 years that is, in the opinion of the Investigator,
sufficient to compromise the safety and/or cooperation of the Subject.

6. A history of seizures or risk factors for seizures.

7. For HIV infected Subjects:

1. having a CD4+ count <250 cells/µL;

2. with an AIDS-defining opportunistic infection or malignancies (except pulmonary
TB);

3. OR having received antiretroviral therapy medication within the last 90 days

4. OR having received oral or intravenous antifungal medication within the last 90
days.

8. Having participated in other clinical study/ies with investigational agent/s within 8
weeks prior to trial start.

9. Significant cardiac arrhythmia requiring medication or QT interval on ECG >500msec on
screening ECG.

10. Subjects with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis

11. Females who are pregnant or breast-feeding, or planning to conceive a child during the
study or within 1 month of cessation of treatment

12. Diabetes Mellitus

Specific Treatments

13. Previously received treatment with linezolid.

14. Known allergy or intolerance to linezolid.

15. Concomitant use of monoamine oxidase inhibitors (MAOIs) or prior use within 1 month of
screening.

16. Concomitant use of serotonergic agents including SSRI/SNRI antidepressants or prior
use within 3 days of screening should be avoided if possible as subjects on these
agents and linezolid are at risk for serotonin syndrome.

17. Treatment with any drug active against M.tb within 3 months prior to Day 1 (including
but not limited to isoniazid, ethambutol, amikacin, bedaquiline, clofazimine,
cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin,
para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin,
thioamides, metronidazole).

Based on Laboratory Abnormalities:

18. Subjects with the following toxicities at screening as defined by the enhanced
Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November
2007):

1. creatinine grade 2 or greater [>1.5 x Upper Limit of Normal (ULN)];

2. hemoglobin level of <8.0 gm/dL;

3. platelet count <80,000/mm3;

4. absolute neutrophil count <1000/mm3

5. serum potassium, serum magnesium and calcium (corrected for albumin) levels less
than the lower limit of normal for the laboratory;

6. aspartate aminotransferase (AST) grade 3 or greater (=3.0 x ULN) to be excluded;

7. alanine aminotransferase (ALT) grade 3 or greater (=3.0 x ULN) to be excluded;

8. alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (=3.0 -
8.0 x ULN) must be discussed with and approved by the Sponsor Medical Monitor;

9. total bilirubin grade 3 or greater (=2.0 x ULN, or =1.50 x ULN when accompanied
by any increase in other liver function test) to be exclude


Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Tuberculosis

Intervention(s)

Drug: Linezolid

Drug: HRZE (isoniazid rifampicin,pyrazinamide,ethambutol)

Primary Outcome(s)

Bactericidal Activity (Time to Positivity) Days 0 - 14 [BA(TTP)] [Time Frame: Days -2, -1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]

Secondary Outcome(s)

The Bactericidal Activity (Time to Positivity) Days 0 - 2 [BA(TTP)](0-2), and Bactericidal Activity (Time to Positivity) Days 7 - 14 [BA(TTP)](7-14) [Time Frame: Day -2, -1, 1, 2, 7, 8, 9, 10, 11, 12, 13, 14]

The Bactericidal Activity Colony Forming Unit (BACFU)(0-14), BACFU(0-2) and BACFU(7-14) [Time Frame: Day 1, 2, 3, 4, 5, 6, 7, 8, 8, 9, 10, 11, 12, 13, 14]

Time over minimum inhibitory concentration (MIC) will be calculated for each subject in the linezolid arms individually and for each of the linezolid arms as a group, based on the MIC determined at baseline. [Time Frame: Baseline (Day -2 to -1), Day 12 (1200 mg three times per week), Day 14 (all other experimental arms)]

Correlation between AUC0-12 and AUC0-inf, Cmax and time over minimum inhibitory concentration and BA (0-2, 0-14 and 7-14) will be determined using both time to positivity and colony forming unit results, for all subjects combined. [Time Frame: Days -2, -1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]

Incidence of Treatment Emergent Adverse Events (TEAEs) presented by severity (DMID Grade), relatedness, and seriousness, leading to early withdrawal and leading to death. [Time Frame: Screening (-9 to -3, -2, -1), Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and Follow-Up (Day 21)]

Pharmacokinetic parameters for subjects (except in the HRZE treatment arm): Cmax, T1/2, AUC 0 - 12 [Time Frame: Day 12 (pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose) for 1200 3X per week, Day 14 (pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose) for 600 mg QD (B), and Day 14 (pre-dose, 0.5, 1, 2, 4, 8, and 12 hours post-dose) for other arms]

Time over concentration that inhibits 50% of mitochondrial protein synthesis (MPS IC50) [Time Frame: Day 12 (1200 mg three times per week), Day 14 (all other experimental arms)]

Secondary ID(s)

LIN-CL001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors