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Trial record 51 of 76 for:    "Bacterial Infectious Disease" | "Polyestradiol phosphate"

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
Sponsor:
Collaborator:
Kenya Medical Research Institute
Information provided by (Responsible Party):
Centers for Disease Control and Prevention

Brief Summary:

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:

  1. The bactericidal activity of RBT in patients whose baseline DST results demonstrate susceptibility to RBT and resistance to RMP.
  2. 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.
  3. 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.
  4. The bactericidal activity of moxifloxacin in patients whose baseline DST results demonstrate susceptibility to moxifloxacin and resistance to ofloxacin.
  5. 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.
  6. 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: CAP-susceptible/KAN-resistant
Capreomycin 1 gm to be administered intramuscularly daily for 10 days
Drug: Capreomycin
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
Drug: Rifampicin
see arm description

Experimental: RBT-susceptible/RMP-resistant
Rifabutin 300 mg daily to be administered orally for 10 days
Drug: Rifabutin
see arm description

Experimental: MOX-susceptible/OFL-resistant
Moxifloxacin 400 mg daily to be administered orally for 6 days
Drug: Moxifloxacin
see arm description




Primary Outcome Measures :
  1. Decrease in colony forming units per ml of sputum [ Time Frame: 10 days ]

Secondary Outcome Measures :
  1. Acquired drug resistance to the assigned drug [ Time Frame: 2 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • RMP and/or 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

Information from the National Library of Medicine

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


Contacts
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Contact: J. Peter Cegielski, MD, MPH +1-404-639-5329 pcegielski@cdc.gov

Locations
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Kenya
Kenya Medical Research Institute Recruiting
Kisumu, Nyanza Province, Kenya
Contact: Kevin P Cain, MD    +254-710-602-786    kcain@cdc.gov   
Sponsors and Collaborators
Centers for Disease Control and Prevention
Kenya Medical Research Institute
Investigators
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Principal Investigator: J. Peter Cegielski, MD, MPH U.S. Centers for Disease Control and Prevention

Publications:
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Responsible Party: Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier: NCT02236078     History of Changes
Other Study ID Numbers: CDC-NCHHSTP-6435
First Posted: September 10, 2014    Key Record Dates
Last Update Posted: July 26, 2016
Last Verified: July 2016

Additional relevant MeSH terms:
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Gram-Positive Bacterial Infections
Bacterial Infections
Norgestimate, ethinyl estradiol drug combination
Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Moxifloxacin
Rifampin
Isoniazid
Rifabutin
Capreomycin
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antibiotics, Antitubercular
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers