PK Study of Anti-TB Drugs

Study Description

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Brief Summary:

This is a prospective descriptive and pharmacokinetic study will be conducted among newly diagnosed patients registered in the two SMRU TB clinics located on the Thai-Myanmar border. This study aims to recruit (1) 30 adults with HIV co-infection and (2) 30 adults without HIV co-infection in one year. Patients will be given the standard 6 month anti-TB drugs as per WHO guidelines.

Condition or disease	Intervention/treatment	Phase
Tuberculosis	Drug: Isoniazid (H); Drug: Rifampicin (R); Drug: Pyrazinamide (Z); Drug: Ethambutol (E)	Phase 1

Detailed Description:

The threat of tuberculosis and HIV remains as major public health issues all over the world. Multi-drug resistant tuberculosis (MDR TB) is also a rising public health issue. Currently available standardized TB treatment is 6 months in duration. Previous pharmacokinetic and pharmacodynamic (PK/PD) studies of anti-TB drugs have shown that a number of factors such as HIV status, diabetes, malnutrition, age, sex, race, genetics (e.g. NAT2 polymorphisms), drug- drug interactions and food interactions may cause variation of the PK and/or the treatment outcome. But the findings are not persistent from one study to another, for example Chideya S. et al's study in Botswana showed that lower Cmax of anti-TB drugs frequently occurred in TB/HIV coinfected patients and low Cmax of pyrazinamide was related to poor treatment outcomes. On the other hand Requena-Méndez A. et al's study showed the variation of rifampin Cmax was not related to HIV. Large between-patient variability in PK parameters was recently shown to be strongly associated with TB treatment failures and possibly the emergence of drug resistant TB.

The primary objective of this study aims to describe the plasma drug levels of the first-line anti- tuberculosis drugs in two different pulmonary TB patient groups: (1) adults with HIV co-infection and (2) adults without HIV co-infection. The secondary objectives are to investigate the clinical, microbiological and immunological outcomes of the study participants in relation to the plasma drug level and to conduct full genome sequencing and spoligotyping of MTB strains.

Plasma drug levels from venous blood will be measured densely 13 times per day at two occasions: after the first dose on Day 1 and 6 weeks after treatment. Thereafter plasma drug levels will be measured at six hours post-dose on months 2, 3, 4, 5 and 6.

Clinical, microbiological and immunological parameters such as liver and renal function, CRP and LTA4G and sputum examination (smear microscopy, RNA PCR, culture) to monitor clinical progress will also be measured.

The analysis on the plasma drug level in relation to the clinical and microbiological outcomes will be carried out in order to describe the PK/PD of anti-TB drugs and clinical, microbiogical and immunological outcomes in consideration of any possible factors that would influence the relationship between them.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Studying the Blood Levels of First-line Anti-tuberculosis Drugs in Relation to Treatment Outcomes Among Newly Diagnosed Adults With Pulmonary Tuberculosis on the Thai-Myanmar Border
Actual Study Start Date :	July 7, 2015
Estimated Primary Completion Date :	February 2018
Estimated Study Completion Date :	February 2018

Arms and Interventions

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Arm

Intervention/treatment

Experimental: 2HRZE/4HR; 2HRZE/4HR; Intensive phase: 2 months HRZE - once daily; Continuation phase: 4 months HR - once daily Adults will be treated with fixed dose combination (FDC) tablets containing: Intensive phase (content per tablet) Isoniazid -75 mg, Rifampicin - 150 mg, Pyrazinamide - 400 mg, Ethambutol - 275 mg Continuation phase (content per tablet) Isoniazid 150 mg Rifampicin 300 mg *Drug dosing will be adjusted by patient body weight.

Drug: Isoniazid (H) Drug: Rifampicin (R) Drug: Pyrazinamide (Z) Drug: Ethambutol (E)

Outcome Measures

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Primary Outcome Measures :

1. Plasma drug levels of Rifampicin [ Time Frame: 6 Months ]
   Rifampicin, Isoniazid, Pyrazinamide and Ethambutol in different study groups
2. Plasma drug levels of Isoniazid [ Time Frame: 6 Months ]
3. Plasma drug levels of Pyrazinamide [ Time Frame: 6 Months ]
4. Plasma drug levels of Ethambutol [ Time Frame: 6 Month ]

Secondary Outcome Measures :

1. Time to negativity of M. tuberculosis [ Time Frame: 6 Months ]
   Time to negativity of M. tuberculosis in relation to drug
2. Genotyping MTB strains [ Time Frame: 6 Months ]
   Genotyping MTB strains in order to see any infection with new wild MTB or mutant strain in the study population

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

1. Clinical and microbiogical diagnosis of pulmonary TB
2. Males and females aged >18 years old
3. Willing to comply with study procedures including residing in the TB centre or nearby for six months
4. Written informed consent provided by participant

Exclusion Criteria:

1. TB treatment in the past
2. Known or suspected pregnancy
3. Enrolled for TB treatment at one of the study sites
4. Known hypersensitivity/intolerance to one or more of anti-TB drugs
5. The MTB strain that shown resistant to Rifampicin, which is the precursor marker of MDR TB detected by a MTB/Rif Xpert Assay

6. Biochemistry test result:

   1. Creatinine > 3 x upper limit of normal (ULN)
   2. bilirubin > 2.5 x ULN
   3. AST and/or ALT > 5 x ULN
7. Refuse to take HIV testing
8. The diagnosed TB patients who choose to take the treatment at a Thai hospital or a hospital in Myanmar
9. The proven non-TB patients by clinical and microbiological diagnosis.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Dr. Thomas Pouplin, PhD	66 2 203 6333	thomas@tropmedres.ac
Contact: Professor Francois Nosten, MD, PhD	+66 5 554 5021	francois@tropmedres.ac

Locations

Thailand
Shoklo Malaria Research Unit	Recruiting
Mae Sot, Tak, Thailand, 63110
Contact: Francois Nosten, MD,PhD

Sponsors and Collaborators

University of Oxford

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	University of Oxford
ClinicalTrials.gov Identifier:	NCT02457208 History of Changes
Other Study ID Numbers:	SMRU1407
First Posted:	May 29, 2015
Last Update Posted:	October 10, 2017
Last Verified:	October 2017

Keywords provided by University of Oxford:

pharmacokinetics

Additional relevant MeSH terms:

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Leprostatic Agents

Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP3A Inducers; Fatty Acid Synthesis Inhibitors; Hypolipidemic Agents; Antimetabolites; Lipid Regulating Agents