Measurement of Anti-TB Drugs in Lung Tissue From Patients Having Surgery to Treat Tuberculosis

NCT00816426 | Completed Phase 1

• 2 other identifiers: 99990906109-I-N061
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 3

Brief Summary

This study, conducted jointly by researchers at the National Masan TB Hospital, Asan and Samsung Medical Centers in Seoul, Republic of Korea, and the Yonsei University and the NIH in the United States, will examine why some patients with tuberculosis (TB) develop disease that is harder to treat than most cases. TB is an infection of the lung that usually can be successfully treated with anti-TB drugs. However, some people get a more serious kind of disease (called multi-drug resistant TB or extensively drug-resistant TB) that is very difficult to treat and may not be cured by the regular medicines available. This study will try to find out if some of the common TB drugs are getting to the place where the TB bacteria are. It will also look at how current anti-TB drugs might be used more effectively and how better drugs might be developed. People 20 years of age and older with hard-to-treat TB who have elected to undergo surgical removal of part of their lung at the National Masan Tuberculosis Hospital, Masan, the Asan Medical Center, and the Samsung Medical Center, may be eligible for this study. Participants undergo the following procedures:

• Medical history and physical examination, including sputum sample.
• Blood tests at various times during the study.
• Drug administration. Subjects are given one dose each of five common TB drugs rifampicin, isoniazid, pyrazinamide, kanamycin and moxifloxacin before they undergo surgery to remove part of their lung. After surgery, some of the lung tissue and fluid around the lungs that was removed during surgery will be examined to determine the regions where the TB bacteria live and analyze the lung tissue itself.
• Dynamic MRI (magnetic resonance imaging) scan. This type of scan uses a magnetic field and radio waves to produce pictures of the lung. Subjects lie very still on a table inside the cylindrical scanner with their head on a soft cradle and their hands over their head. Several images are obtained for less than 5 minutes at a time.

Conditions

Tuberculosis

Keywords

Tuberculosis; Lesions; Pharmacokinetics; Maldistribution; Histopathology

Outcome Measures

Primary Outcomes (1)

• Comparison between the relative permeability coefficients of RIF and KM in pathologically defined large caseous necrotic nodules.

  Dosing given 24 hours- 2 hours before surgery

Secondary Outcomes (3)

• The comparison between the relative permeability coefficients of RIF, KM, INH, PZA and MXF in caseous necrotic nodules versus open cavities

  Dosing given 24 hours -2 hours before surgery, then endpoint assessed from time of surgery.

• The comparison between the absolute permeability coefficients of each of the five drugs in uninvolved lung and in closed necrotic lesions

  Dosing given 24 hours -2 hours before surgery, then endpoint assessed from time of surgery.

• The comparison between the exposure ratio or ratio between the Area Under the Curve (AUC0-24) in lesions (AUClesion), uninvolved lung (AUClung) and plasma (AUCplasma) for RIF and KM in large caseous necrotic nodules

  Dosing given 24 hours -2 hours before surgery, then endpoint assessed from time of surgery.

Study Arms (5)

1

OTHER

Dosing 2 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Kanamycin; Drug: Moxifloxacin

2

OTHER

Dosing 4 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Kanamycin; Drug: Moxifloxacin

3

OTHER

Dosing 8 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Kanamycin; Drug: Moxifloxacin

4

OTHER

Dosing 12 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Kanamycin; Drug: Moxifloxacin

5

OTHER

Dosing 24 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Kanamycin; Drug: Moxifloxacin

Interventions

Rifampicin DRUG

Rifampicin or rifampin (RIF) is a semi-synthetic compound derived from Amycolatopsis rifamycinica. It is mostly used in combination to treat TB, while other disease indications include brucellosis, leprosy, legionnaire's disease and problematic drug-resistant staphylococcal infections. RIF inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA. Its MIC against replicating TB bacilli is 0.1 g/ml and its minimum bactericidal activity (MBC) is 0.5 g/mL. It is one of the rare anti-TB drugs with some activity against nonreplicating cells.

1; 2; 3; 4; 5

Isoniazid DRUG

Isoniazid (INH) is a first-line antituberculous medication discovered in 1952 and used in the prevention (alone) and treatment (in combination) of tuberculosis. Isoniazid is a prodrug and must be activated by a bacterial catalase to inhibit the synthesis of mycolic acids in the mycobacterial cell wall. Consequently, INH is bactericidal to rapidly-dividing mycobacteria, with an MIC of 0.05 g/ml and an MBC of 1 g/ml, but is inactive if the mycobacterium is nonreplicating or slow-growing.

1; 2; 3; 4; 5

Pyrazinamide DRUG

Pyrazinamide (PZA) is a synthetic derivative of nicotinamide requiring ctivation by the mycobacterial enzyme pyrazinamidase, only active under acidic conditions which are thought to be found within the phagolysosomal compartment of macrophages. The conversion product, pyrazinoic acid, inhibits fatty acid synthetase I, required by the bacterium to synthesize fatty acids, though this has been disputed. It has an MIC of 6 g/ml and is not cidal under in vitro conditions. Overall, its mechanism of action and reasons for good sterilizing activity in vivo are poorly understood. It is part of the 4-drug combination recommended by the WHO to treat drugsensitive tuberculosis and is also included in most econd-line regimens.

1; 2; 3; 4; 5

Kanamycin DRUG

Kanamycin (KM) is an aminoglycoside antibiotic belonging to the same class of drugs as Streptomycin, one of the first drugs used to treat TB in the 50 s. It kills sensitive bacteria by binding to the 30S ribosomal subunit and interfering with protein synthesis. Its MIC and MBC against MTB are 2 and 6 g/mL, respectively, with a remarkably low MBC/MIC ratio. However, KM is only used to treat serious bacterial infections due to severe renal toxicity and ototoxicity. No interaction with the metabolism of other drugs has been reported. The drug is approved by the Korean Ministry of Food and Drug Safety (MFDS) but not the US FDA for use against pulmonary TB.

1; 2; 3; 4; 5

Moxifloxacin DRUG

Moxifloxacin (MXF) is a synthetic fluoroquinolone antibiotic. It inhibits bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, which are essential enzymes playing a crucial role in the replication and repair of bacterial DNA. Its MIC, MBC and intracellular activity against MTB are 0.5, 2 and 1 g/mL, respectively, with again a low MBC/MIC ratio.

1; 2; 3; 4; 5

Eligibility Criteria

• Age: 20 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females age 20 and above
• Selected for lung resection due to anti-tuberculous treatment failure, multidrug resistant disease, or other reason determined by the treating physician
• Radiographic evidence of tuberculous disease of the lung(s)
• If already on an aminoglycoside, ability and willingness to substitute this aminoglycoside with KM for the one study dose
• Willingness to receive MRI scan and marker and Gadolinium injection
• Willingness to have samples stored
• Ability and willingness to give written or oral informed consent

You may not qualify if:

• Subjects less than 20 years of age
• Women of childbearing potential who are pregnant, breast feeding, or unwilling to avoid pregnancy (i.e., the use of appropriate contraception including oral and subcutaneous implantable hormonal contraceptives, condoms, diaphragm, intrauterine device (IUD), or abstinence from sexual intercourse) \[Note: Prospective female participants of childbearing potential must have negative pregnancy test (urine) within 48 hours prior to study entry.\]
• Allergy or hypersensitivity to any of the 5 study drugs, any aminoglycoside, or rifamycin (those allergic to fluoroquinolones will not receive MXF).
• Those with severe gout
• Severe claustrophobia or Gadolinium hypersensitivity (tbc)
• Renal, hepatic, auditory and/or vestibular impairment.
• Serum creatinine greater than 2.0 mg/dL (renal)
• Aspartate aminotransferase (AST or SGOT) greater than 100 IU/L (LFTs)
• Alanine aminotransferase (ALT or SGPT) greater than 100 IU/L (LFTs)
• Total bilirubin greater than 2.0 mg/dL (LFTs)
• The use of any of Rifampicin (RIF), Rifapentine or Rifabutin within 30 days prior to the study
• HIV infection, determined by a positive HIV test performed with the past 6 months
• The use of any of the following drugs within 30 days prior to study:
• Systemic cancer chemotherapy
• Systemic corticosteroids (oral or IV only) with the following

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Korean Center for Disease Control and Prevention: collaborator
• International Tuberculosis Research Center: collaborator
• Novartis Institute for Tropical Medicine: collaborator
• Asian Medical Center: collaborator

Study Sites (3)

Pusan National Unversity Hospital (PNUH)

Busan, South Korea

Location

Asan Medical Center

Seoul, South Korea

Location

National Medical Center

Seoul, South Korea

Location

Related Publications (4)

• Soman A, Honeybourne D, Andrews J, Jevons G, Wise R. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother. 1999 Dec;44(6):835-8. doi: 10.1093/jac/44.6.835.

  PMID: 10590288 BACKGROUND

• Drexler DM, Garrett TJ, Cantone JL, Diters RW, Mitroka JG, Prieto Conaway MC, Adams SP, Yost RA, Sanders M. Utility of imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) on an ion trap mass spectrometer in the analysis of drugs and metabolites in biological tissues. J Pharmacol Toxicol Methods. 2007 May-Jun;55(3):279-88. doi: 10.1016/j.vascn.2006.11.004. Epub 2006 Dec 5.

  PMID: 17222568 BACKGROUND

• Wagner C, Sauermann R, Joukhadar C. Principles of antibiotic penetration into abscess fluid. Pharmacology. 2006;78(1):1-10. doi: 10.1159/000094668. Epub 2006 Jul 19.

  PMID: 16864973 BACKGROUND

• Strydom N, Gupta SV, Fox WS, Via LE, Bang H, Lee M, Eum S, Shim T, Barry CE 3rd, Zimmerman M, Dartois V, Savic RM. Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization. PLoS Med. 2019 Apr 2;16(4):e1002773. doi: 10.1371/journal.pmed.1002773. eCollection 2019 Apr.

  PMID: 30939136 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Rifampin; Isoniazid; Pyrazinamide; Kanamycin; Moxifloxacin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Aminoglycosides; Glycosides; Carbohydrates; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring

Study Officials

• Clifton E Barry, Ph.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 31, 2008
• First Posted: January 1, 2009
• Study Start: December 29, 2008
• Primary Completion: August 26, 2014
• Study Completion: December 29, 2017
• Last Updated: December 9, 2019

Record last verified: 2017-12-29

Locations

KR (3)