Brief Bactericidal Activity of Anti-Tuberculosis Drugs

NCT ID: NCT02236078

Last Updated: 2020-10-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-30
• Study Completion Date: 2020-09-30

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.

Conditions

Tuberculosis; Drug-resistant Tuberculosis; Isoniazid Resistant Tuberculosis (Disorder)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

High dose isoniazid

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

Group Type: EXPERIMENTAL

High dose isoniazid

Intervention Type: DRUG

See arm description

Interventions

High dose isoniazid

See arm description

Intervention Type: DRUG

Other Intervention Names

High dose INH

Eligibility Criteria

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

• Minimum Eligible Age: 8 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kenya Medical Research Institute

OTHER

Sponsor Role: collaborator

Centers for Disease Control and Prevention

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sarah E. Smith-Jeffcoat, MPH

Role: PRINCIPAL_INVESTIGATOR

U.S. Centers for Disease Control and Prevention

J. P. Cegielski, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

JP Cegielski Consulting LLC

Locations

National Institute for Research on Tuberculosis

Chennai, Tamil Nadu, India

Countries

India

References

Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Erokhin VV, Ershova J, Gler MT, Kazennyy BY, Kim HJ, Kliiman K, Kurbatova E, Kvasnovsky C, Leimane V, van der Walt M, Via LE, Volchenkov GV, Yagui MA, Kang H; Global PETTS Investigators; Akksilp R, Sitti W, Wattanaamornkiet W, Andreevskaya SN, Chernousova LN, Demikhova OV, Larionova EE, Smirnova TG, Vasilieva IA, Vorobyeva AV, Barry CE 3rd, Cai Y, Shamputa IC, Bayona J, Contreras C, Bonilla C, Jave O, Brand J, Lancaster J, Odendaal R, Chen MP, Diem L, Metchock B, Tan K, Taylor A, Wolfgang M, Cho E, Eum SY, Kwak HK, Lee J, Lee J, Min S, Degtyareva I, Nemtsova ES, Khorosheva T, Kyryanova EV, Egos G, Perez MT, Tupasi T, Hwang SH, Kim CK, Kim SY, Lee HJ, Kuksa L, Norvaisha I, Skenders G, Sture I, Kummik T, Kuznetsova T, Somova T, Levina K, Pariona G, Yale G, Suarez C, Valencia E, Viiklepp P. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 2012 Oct 20;380(9851):1406-17. doi: 10.1016/S0140-6736(12)60734-X. Epub 2012 Aug 30.

Reference Type: BACKGROUND

PMID: 22938757 (View on PubMed)

Other Identifiers

CDC-NCHHSTP-6435

Identifier Type: -

Identifier Source: org_study_id