Brief Bactericidal Activity of Anti-Tuberculosis Drugs

Tuberculosis Clinical Trial

— BBA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02236078
• Other study ID #: CDC-NCHHSTP-6435
• Status: Completed
• Phase: Phase 1
• Start date: November 2015
• Est. completion date: September 30, 2020

Study information

• Verified date: January 2020
• Source: Centers for Disease Control and Prevention
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: September 30, 2020
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Drug-resistant Tuberculosis
• Isoniazid Resistant Tuberculosis (Disorder)
• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

Drug:
• High dose isoniazid
See arm description

Locations

Country	Name	City	State
India	National Institute for Research on Tuberculosis	Chennai	Tamil Nadu

Sponsors (2)

Lead Sponsor	Collaborator
Centers for Disease Control and Prevention	Kenya Medical Research Institute

Country where clinical trial is conducted

India, 

References & Publications (1)

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. Erratum in: Lancet. 2012 Oct 20;380(9851):1386. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Acquired isoniazid resistance	Increased level of resistance to isoniazid	2 months
Primary	Delta CFU/ml/day	Change in colony forming units per ml of sputum over 6 days	6 days
Secondary	Time-to-detection (TTD)	Interval in hours from culture inoculation to detection of mycobacterial growth in MGIT 960	6 days