Metronidazole for Pulmonary Tuberculosis (South Korea)

NCT00425113 | Completed Phase 2 Results DMC

• 2 other identifiers: 99990704107-I-N041
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 2

Brief Summary

This study will evaluate the effect of adding metronidazole to standard second-line therapy for tuberculosis in patients who have multi-drug resistant tuberculosis (MDR-TB) of the lungs. It will evaluate the safety and tolerability of metronidazole in combination with antituberculosis agents. Metronidazole is a drug widely used to treat bacterial and parasitic infections occurring in environments with very little oxygen such as the human colon. Nine million new cases of sputum-positive tuberculosis are diagnosed worldwide each year. Patients ages 20 and older who have symptoms of TB, who have been treated for tuberculosis but whose disease is multi-drug resistant, and who are not pregnant or breast feeding may be eligible for this study. They will be recruited in the National Masan Tuberculosis Hospital (NMTH), Masan, Republic of Korea. Patients will undergo the following tests and procedures:

• Collection of sputum for counting of bacteria.
• Drawing of blood for routine blood chemistry analysis; for measuring levels of metronidazole; TB lipid analysis; and for testing levels of T-cells, which are part of an immune response.
• Two targeted positron emission tomography (PET) scans, each with a computed tomography (CT) scan, and five high-resolution CT scans. Patients will receive either an 8-week course of standard second-line agents plus placebo (sugar pill) or an 8-week course of standard agents plus metronidazole. The subjects, doctors and researchers will not know which patients are taking the metronidazole until after the first 2 years of the trial. A total of 60 patients will be assigned to two cohorts of 30 patients each. After 8 weeks, all patients will return to the standard of care chemotherapy, according to normal procedures at NMTH. Side effects of metronidazole commonly reported are vaginal discharge, symptoms of Candida cervicitis and vaginitis, headache, nausea and vomiting, and dizziness. Peripheral neuropathy, an abnormal condition of the nerves, may also be a side effect. The precise incidence of neuropathy is unknown but is usually related to the duration of metronidazole use. It can almost always be reversed when the drug is discontinued. Serious side effects, though rare, may include leukopenia and thrombocytopenia (disorders in the blood), seizures and other central nervous system problems, and hepatitis. This study may or may not have a direct benefit for participants. However, it is possible that patients' drug-resistant disease may be more effectively treated as a result of metronidazole. The study may help identify new methods for measuring drug effectiveness during TB studies.

Conditions

Tuberculosis; Multi-Drug Resistant Tuberculosis

Keywords

Mycobacterium Tuberculosis; Anaerobic; FDG-PET-HRCT; HRCT; Lesion Matrix; Tuberculosis; TB

Outcome Measures

Primary Outcomes (1)

• Changes in TB Lesion Sizes Using High Resolution Computed Tomography (HRCT).

  Lesions were defined as nodules (\<2 mm, 2-\<4 mm, and 4-10 mm), consolidations, collapse, cavities, fibrosis, bronchial thickening, tree-in-bud opacities, and ground glass opacities. Each CT was divided into six zones (upper, middle, and lower zones of the right and left lungs) and independently scored for the above lesions by three separate radiologists blinded to treatment arm. A fourth radiologist adjudicated any scores that were widely discrepant among the initial three radiologists. The HRCT score was determined by visually estimating the extent of the above lesions in each lung zone as follows: 0=0% involvement; 1= 1-25% involvement; 2=26-50% involvement; 3=51-75% involvement; and 4=76-100% involvement. A composite score for each lesion was calculated by adding the score for each specific abnormality in the 6 lung zones and dividing by 6, with the change in composite score measured at 2 and 6 months compared to baseline. Composite sums of all 10 composite scores are reported.

  6 months.

Secondary Outcomes (1)

• Time to Sputum Culture Conversion to Negative on Solid Medium

  2 months

Study Arms (2)

Metronidazole

EXPERIMENTAL

Metronidazole added to background TB treatment regimen during initial 2 months

Drug: Metronidazole; Procedure: Blood Draw; Procedure: CT Scan; Procedure: PET Scan

Placebo

PLACEBO COMPARATOR

Placebo added to background TB treatment regimen during initial 2 months

Procedure: Blood Draw; Procedure: CT Scan; Procedure: PET Scan

Interventions

Metronidazole DRUG

Metronidazole

Blood Draw PROCEDURE

Metronidazole; Placebo

CT Scan PROCEDURE

Metronidazole; Placebo

PET Scan PROCEDURE

Metronidazole; Placebo

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and females age 20 and above
• Signs or symptoms of tuberculosis (i.e., cough that has lasted 3 weeks or longer, hemoptysis, chest pain, fatigue, weight loss, night sweats)
• Subjects with documented AFB smear-positive pulmonary tuberculosis at screening to NMTH
• Radiographic evidence of tuberculous disease of the lung(s)
• TB isolate resistant to at least isoniazid and rifampicin
• Drug Susceptibility Testing (DST) results known for ofloxacin (can be either sensitive or resistant)
• Ability and willingness to give written or oral informed consent
• Willingness to be an inpatient at NMTH for, at minimum, the duration of study drug/placebo treatment
• Willingness to have samples stored
• Available for follow-up visits

You may not qualify if:

• People who are unwilling or unable to abstain from alcohol consumption for the study drug treatment duration (8 weeks)
• Women of childbearing potential, who are pregnant, breast feeding, or unwilling to avoid pregnancy by the use of appropriate contraception including oral and subcutaneous implantable hormonal contraceptives, condoms, diaphragm, intrauterine device (IUD), or abstinence from sexual intercourse at study screening and during the study drug/placebo treatment (two months with allowed stops) (Note: Prospective female participants of childbearing potential must have negative pregnancy test (urine) within 48 hours prior to study entry.)
• Subjects with pan resistant isolates
• Presently taking 2nd -line agents started more than 14 days prior to initial FDG-PET scan
• People with any of the following in their current medical assessment:
• Absolute neutrophil count less than 1000 cells/mL
• White Blood Cell count (WBC) less than 3.0 X 10(3)/microliter
• Hemoglobin less than 7.0 g/dL
• Platelet count less than 75,000 cells/mm(3)
• Serum creatinine greater than 2.0 mg/dL
• Aspartate aminotransferase (AST or SGOT) greater than 100 IU/L
• Alanine aminotransferase (ALT or SGPT) greater than 100 IU/L
• Total bilirubin greater than 2 mg/dL
• Moderate or severe peripheral neuropathy
• HIV-1 or HIV-2 infection

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (2)

National Masan Tuberculosis Hospital

Masan, South Korea

Location

Yonsei University College of Medicine

Seoul, South Korea

Location

Related Publications (3)

• Andreu J, Caceres J, Pallisa E, Martinez-Rodriguez M. Radiological manifestations of pulmonary tuberculosis. Eur J Radiol. 2004 Aug;51(2):139-49. doi: 10.1016/j.ejrad.2004.03.009.

  PMID: 15246519 BACKGROUND

• Brooks JV, Furney SK, Orme IM. Metronidazole therapy in mice infected with tuberculosis. Antimicrob Agents Chemother. 1999 May;43(5):1285-8. doi: 10.1128/AAC.43.5.1285.

  PMID: 10223954 BACKGROUND

• Carrara S, Vincenti D, Petrosillo N, Amicosante M, Girardi E, Goletti D. Use of a T cell-based assay for monitoring efficacy of antituberculosis therapy. Clin Infect Dis. 2004 Mar 1;38(5):754-6. doi: 10.1086/381754. Epub 2004 Feb 17.

  PMID: 14986262 BACKGROUND

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Multidrug-Resistant

Interventions

Metronidazole; Blood Specimen Collection; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Limitations and Caveats

Major limitation of our study was the small sample size. Planned enrollment was 80 subjects but DSMB recommended closing the study to new enrollment after 35 subjects due to increased peripheral neuropathy in the metronidazole arm.

Results Point of Contact

• Title: Ray Chen
• Organization: National Institute of Allergy and Infectious Diseases

ray.chen@nih.gov

301-443-5816

Study Officials

• Clifton E Barry, Ph.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 19, 2007
• First Posted: January 22, 2007
• Study Start: December 1, 2006
• Primary Completion: October 1, 2012
• Study Completion: February 1, 2013
• Last Updated: July 10, 2013
• Results First Posted: July 10, 2013

Record last verified: 2013-05

Locations

KR (2)