BBA: Brief Bactericidal Activity of Anti-Tuberculosis Drugs

Sponsor

Centers for Disease Control and Prevention (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT02236078

Collaborator

Kenya Medical Research Institute (Other)

Enrollment

Location

Arm

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators will determine the bactericidal activity of high-dose isoniazid against M. tuberculosis isolates that are (1) susceptible to isoniazid at 2.0 mcg/ml but resistant at 0.1 and 0.4 mcg/ml or (2) susceptible at 0.4 mcg/ml but resistant at 0.1 mcg/ml when tested in the BD MGIT 960 system. Further, the investigators will investigate the molecular genetic determinants of these differences in susceptibility.

To achieve these objectives the investigators will carry out an innovative variation on early bactericidal activity (EBA) study methodology. Patients at risk for drug-resistant TB will be screened for INH resistance using approved molecular assays. In those with INH-resistant TB, the investigators will quickly perform phenotypic DSTs using the direct method in the Bactec Mycobacterium Growth Indicator Tube (MGIT) 960 system, so results will be available within 7 days. If the DST results show the susceptibility patterns noted above, patients will receive 900 mg/d INH (600 mg if <45kg), and assess its effect with serial quantitative sputum cultures for 6 days. If the concentration of viable bacteria decreases significantly, the investigators will interpret this to mean the drug is having an effect. If not, the drug is ineffective. After 6 days, the patients will resume treatment according to national guidelines.

In case the investigators identify drugs that are effective under these conditions, the investigators will sequence known and putative genes associated with the action of these drugs for the mycobacterial isolates from these patients.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis Drug-resistant Tuberculosis Isoniazid Resistant Tuberculosis (Disorder)	Drug: High dose isoniazid	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Brief Bactericidal Activity of Anti-Tuberculosis Drugs in Drug-Resistant Tuberculosis

Study Start Date :

Nov 1, 2015

Actual Primary Completion Date :

Sep 30, 2020

Actual Study Completion Date :

Sep 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High dose isoniazid INH 900 mg daily to be administered orally for 6 days (600 mg for patients weighing <45 kg)	Drug: High dose isoniazid See arm description Other Names: High dose INH

Arm

Intervention/Treatment

Experimental: High dose isoniazid

INH 900 mg daily to be administered orally for 6 days (600 mg for patients weighing <45 kg)

Drug: High dose isoniazid

See arm description

Other Names:

High dose INH

Outcome Measures

Primary Outcome Measures

Delta CFU/ml/day [6 days]
Change in colony forming units per ml of sputum over 6 days

Secondary Outcome Measures

Time-to-detection (TTD) [6 days]
Interval in hours from culture inoculation to detection of mycobacterial growth in MGIT 960

Other Outcome Measures

Acquired isoniazid resistance [2 months]
Increased level of resistance to isoniazid

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent
INH resistance by approved molecular genetic test
Phenotypic drug susceptibility test results match one of the required patterns
Sputum microscopy positive for acid fast bacilli

Exclusion Criteria:

Ineligible for MDR TB treatment according to national guidelines
HIV infection with CD4 count less than 50
Pregnancy
Incarceration
Too sick to participate (Karnofsky score <60, arterial pO2<90, respiratory rate repeatedly >25/min, clinician's judgment)
Hepatic enzymes >3x normal
Estimated glomerular filtration rate <60 mL/min/1.73 m2
Unable to provide adequate sputum specimen

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institute for Research on Tuberculosis	Chennai	Tamil Nadu	India

Sponsors and Collaborators

Centers for Disease Control and Prevention
Kenya Medical Research Institute

Investigators

Principal Investigator: Sarah E. Smith-Jeffcoat, MPH, U.S. Centers for Disease Control and Prevention
Principal Investigator: J. P. Cegielski, MD, MPH, JP Cegielski Consulting LLC