Brief Bactericidal Activity of Anti-Tuberculosis Drugs

NCT02236078 | Completed Phase 1

• 1 other identifier: CDC-NCHHSTP-6435
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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)

Outcome Measures

Primary Outcomes (1)

• Delta CFU/ml/day

  Change in colony forming units per ml of sputum over 6 days

  6 days

Secondary Outcomes (1)

• Time-to-detection (TTD)

  6 days

Other Outcomes (1)

• Acquired isoniazid resistance

  2 months

Study Arms (1)

High dose isoniazid

EXPERIMENTAL

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

Drug: High dose isoniazid

Interventions

High dose isoniazid DRUG

See arm description

Also known as: High dose INH

High dose isoniazid

Eligibility Criteria

• Age: 8 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• Kenya Medical Research Institute: collaborator

Study Sites (1)

National Institute for Research on Tuberculosis

Chennai, Tamil Nadu, India

Location

Related 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.

  PMID: 22938757 BACKGROUND

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Multidrug-Resistant

Interventions

Isoniazid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Sarah E. Smith-Jeffcoat, MPH

  U.S. Centers for Disease Control and Prevention

  PRINCIPAL INVESTIGATOR

• J. P. Cegielski, MD, MPH

  JP Cegielski Consulting LLC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2014
• First Posted: September 10, 2014
• Study Start: November 1, 2015
• Primary Completion: September 30, 2020
• Study Completion: September 30, 2020
• Last Updated: October 19, 2020

Record last verified: 2020-01

Locations

IN (1)