Brief Bactericidal Activity of Anti-Tuberculosis Drugs (BBA)
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|ClinicalTrials.gov Identifier: NCT02236078|
Recruitment Status : Unknown
Verified July 2016 by Centers for Disease Control and Prevention.
Recruitment status was: Recruiting
First Posted : September 10, 2014
Last Update Posted : July 26, 2016
Multidrug-resistant (MDR) tuberculosis (TB) must be treated with second-line drugs (SLD) that are less effective, more toxic, and more expensive. Treatment requires at least 20 months with 4 or more effective drugs based on timely drug susceptibility test (DST) results. However, there are many examples of closely related drugs with differing antimicrobial activities.
Labs have found differences in DST results among the rifamycins, rifampin (RMP) and rifabutin (RBT); the fluoroquinolones, ofloxacin and moxifloxacin; and the second-line injectable agents, kanamycin, amikacin, and capreomycin. In a related finding, isolates resistant to 0.2 mcg/ml INH may be susceptible to higher concentrations. In the Preserving Effective Tuberculosis Treatment Study (PETTS), 32% of RMP-resistant isolates were susceptible to RBT, 41% of kanamycin-resistant isolates were susceptible to capreomycin, and 45% of isolates resistant to 0.2 mcg/ml INH were susceptible to 1.0 or 5.0 mcg/ml (1). Other studies have demonstrated differences in DST results between moxifloxacin and ofloxacin. Whether these in vitro results translate into clinical efficacy is completely unknown. Given the severely limited treatment options in MDR TB, it would be exceedingly useful to know whether these in vitro results translate into evidence for clinically meaningful treatment decisions.
The investigators will determine the clinical bactericidal activity of certain antibiotics against M. tb that appear to be effective in vitro even though closely related drugs from the same class are ineffective in vitro. Further, the investigators propose to determine the molecular genetic determinants of these differences.
Specifically, we plan to determine:
- The bactericidal activity of RBT in patients whose baseline DST results demonstrate susceptibility to RBT and resistance to RMP.
- The bactericidal activity of high-dose INH in patients whose baseline DST results demonstrate susceptibility to high concentrations of INH and resistance to low concentrations of INH.
- The bactericidal activity of RMP when an approved molecular assay demonstrates genetic mutations associated with RMP resistance, but the phenotypic testing demonstrates susceptibility to RMP.
- The bactericidal activity of moxifloxacin in patients whose baseline DST results demonstrate susceptibility to moxifloxacin and resistance to ofloxacin.
- The bactericidal activity of amikacin and capreomycin in patients whose baseline DST results demonstrate susceptibility to either of these two drugs and resistance to kanamycin.
- The genetic mutations associated with both in vivo and in vitro drug resistance and bactericidal activity.
To achieve these objectives the investigators propose an innovative variation on early bactericidal activity (EBA) study methodology. Patients at risk for MDR TB will be screened for RMP resistance and INH resistance using molecular assays. In those with RMP-resistant or 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 14-21 days. If the DST results show, for example, RMP resistance but susceptibility to RBT, consenting patients will be treated with RBT by itself for 10 days. The investigators will assess its effect with serial quantitative sputum cultures. 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 10 days, the patients will resume individualized multidrug treatment based on the full set of DST results.
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.
The results would have immediate implications for treatment of MDR TB and for diagnostic mycobacteriology.
|Condition or disease||Intervention/treatment||Phase|
|Tuberculosis Drug-resistant Tuberculosis Multidrug-resistant Tuberculosis||Drug: Capreomycin Drug: High dose isoniazid Drug: Rifampicin Drug: Rifabutin Drug: Moxifloxacin||Not Applicable|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||150 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Brief Bactericidal Activity of Anti-Tuberculosis Drugs in Drug-Resistant Tuberculosis|
|Study Start Date :||November 2015|
|Estimated Primary Completion Date :||September 2017|
|Estimated Study Completion Date :||September 2018|
Capreomycin 1 gm to be administered intramuscularly daily for 10 days
See arm Description
Experimental: High dose isoniazid
INH 900 mg daily to be administered orally for 10 days
Drug: High dose isoniazid
See arm description
Experimental: rpoB mutant/Rifampicin-susceptible
Rifampin 600 mg daily to be administered orally for 10 days
see arm description
Rifabutin 300 mg daily to be administered orally for 10 days
see arm description
Moxifloxacin 400 mg daily to be administered orally for 6 days
see arm description
- Decrease in colony forming units per ml of sputum [ Time Frame: 10 days ]
- Acquired drug resistance to the assigned drug [ Time Frame: 2 months ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02236078
|Contact: J. Peter Cegielski, MD, MPHfirstname.lastname@example.org|
|Kenya Medical Research Institute||Recruiting|
|Kisumu, Nyanza Province, Kenya|
|Contact: Kevin P Cain, MD +254-710-602-786 email@example.com|
|Principal Investigator:||J. Peter Cegielski, MD, MPH||U.S. Centers for Disease Control and Prevention|