Clinical trial NCT02236078: Brief Bactericidal Activity of Anti-Tuberculosis Drugs
Official title: Brief Bactericidal Activity of Anti-Tuberculosis Drugs in Drug-Resistant Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Tuberculosis
Drug-resistant Tuberculosis
Isoniazid Resistant Tuberculosis (Disorder)
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: Kenya Medical Research Institute
First posted: 2014-09-10
Enrollment: 18
Sex: ALL
Minimum age (years): 8
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Delta CFU/ml/day
timeFrame: 6 days
Secondary outcomes:
measure: Time-to-detection (TTD)
timeFrame: 6 days
Other outcomes:
measure: Acquired isoniazid resistance
timeFrame: 2 months
Locations:
city: Chennai
country: India
facility: National Institute for Research on Tuberculosis
state: Tamil Nadu
Study officials:
affiliation: U.S. Centers for Disease Control and Prevention
name: Sarah E. Smith-Jeffcoat, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: JP Cegielski Consulting LLC
name: J. P. Cegielski, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.