PK Study of Anti-TB Drugs

• ClinicalTrials.gov Identifier: NCT02457208
• Recruitment Status: Completed
• First Posted: May 29, 2015
• Last Update Posted: October 3, 2018
• Sponsor: University of Oxford
• Information provided by (Responsible Party): University of Oxford

Tracking Information

• First Submitted Date: April 22, 2015
• First Posted Date: May 29, 2015
• Last Update Posted Date: October 3, 2018
• Actual Study Start Date: July 7, 2015
• Actual Primary Completion Date: January 14, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 26, 2015)

• Plasma drug levels of Rifampicin [ Time Frame: 6 Months ]
  Rifampicin, Isoniazid, Pyrazinamide and Ethambutol in different study groups
• Plasma drug levels of Isoniazid [ Time Frame: 6 Months ]
• Plasma drug levels of Pyrazinamide [ Time Frame: 6 Months ]
• Plasma drug levels of Ethambutol [ Time Frame: 6 Month ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 26, 2015)

• Time to negativity of M. tuberculosis [ Time Frame: 6 Months ]
  Time to negativity of M. tuberculosis in relation to drug
• 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: PK Study of Anti-TB Drugs
• 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
• 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.

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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Tuberculosis

Intervention

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

Study Arms

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.

Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 1, 2018): 61
• Original Estimated Enrollment (submitted: May 26, 2015): 60
• Actual Study Completion Date: January 14, 2018
• Actual Primary Completion Date: January 14, 2018 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Thailand

Administrative Information

• NCT Number: NCT02457208
• Other Study ID Numbers: SMRU1407
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University of Oxford
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Oxford
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University of Oxford
• Verification Date: October 2018