Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment

NCT02727582 | Completed

• 1 other identifier: PODrtb
• Study Type: observational
• Target: 142
• Locations: 1 country
• Sites: 2

Brief Summary

Multidrug-resistant (MDR) tuberculosis (TB), defined as simultaneous resistance to isoniazid and rifampin, has been declared a global emergency. Treatment outcomes are poor, driven by toxicity and limited efficacy of the 2nd-line anti-TB drugs. Although there is evidence that both anti-TB activity and most of the toxicity of the key drugs are related to drug exposure, the pharmacokinetic/pharmacodynamic (PK/PD) relationships in patients with MDR-TB are poorly characterized. Moreover potential synergy of drug combinations has not been identified in the context of MDR-TB, dosing has not taken into account the concentrations needed to suppress resistance, and the role of minimum inhibitory concentrations (MICs) in dosing is poorly studied. There are therefore opportunities to optimize drug doses and combinations to improve efficacy, and reduce toxicity. Based on this observational study of patients on standard treatment for MDR-TB, our proposal builds on novel methodologies we have developed, largely for drug sensitive TB:

1. 1.The application of computational analytical techniques to tease out the individual contributions of anti-TB drugs used in combination
2. 2.The development of a treatment response biomarker model based on time-to-positivity in liquid culture of serial sputum samples.
3. 3.The in vitro determination of PK targets for anti-TB activity and the suppression of resistance using the hollow fiber models of Mycobacterium tuberculosis (Mtb) (HFM-TB).

Conditions

Multidrug-resistant Tuberculosis

Keywords

MDR

Outcome Measures

Primary Outcomes (1)

• To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients.

  To describe the population PK of moxifloxacin, terizidone, ethionamide, pyrazinamide and kanamycin in a cohort of 142 South African patients diagnosed with MDR-TB. * Develop LC-MS/MS assays to accurately quantify moxifloxacin, terizidone, ethionamide, pyrazinamide and kanamycin in plasma. * Determine plasma concentrations of the 5 drugs in serial samples (6 samples drawn during a dosing interval) in each patient. * Develop population nonlinear mixed effects models to describe the plasma PK of the 5 drugs in patients with MDR-TB. * Estimate individual PK measures of exposure for each drug. * In those patients who consent to pharmacogenetic evaluation, collect and store a suitable blood sample

  2 years

Secondary Outcomes (1)

• To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.

  2 years

Other Outcomes (3)

• Develop a treatment response model using time to positivity (TTP) in serial MGIT sputum cultures as a surrogate marker to quantify viable mycobacterial burden by time and hence response to treatment during the initial phase of treatment.

  2 years

• To describe the key drivers of treatment response in the standard multi-drug regimen for MDR-TB

  2 years

• Describe the safety and tolerability of standard MDR-TB treatment through serial standardized collection of laboratory results and AE data, and describe PK associations with such toxicity.

  2 years

Eligibility Criteria

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

Study Population

142 Xpert MTB/RIF positive adults (\>18 years of age), with or without HIV, and starting the standard 5-drug regimen for MDR-TB. The MDR-TB regimen also applies to patients who have rifampicin mono-resistant TB so these patients will also be eligible for the study.

You may qualify if:

• Age \> 18 years Current diagnosis of pulmonary MDR-TB or rifampicin-monoresistant TB
• Baseline sputum sample with positive Gene Xpert MTB/RIF test, or confirmed positive Mycobacterium tuberculosis culture displaying resistance to rifampicin with or without isoniazid resistance on standard DST.
• Eligible for standard MDR-TB treatment regimen (see Table 1), or, started on standard MDR-TB regimen within the past 1 month.
• Written confirmation of informed consent to participate.
• Pregnant women satisfying all other eligibility criteria may be enrolled.

You may not qualify if:

• Critically ill or medically unstable\* e.g. organ failure - on ventilator, receiving dialysis for acute renal failure, fulminant hepatitis (\*can be recruited once stabilized if still eligible), or severe haemoptysis.
• Unwilling to participate, or unable to understand the Participant information and provide full informed consent.

Sponsors & Collaborators

• University of Cape Town: lead
• Baylor Research Institute: collaborator

Study Sites (2)

Brooklyn Chest Hospital

Cape Town, Western Cape, 7725, South Africa

Location

DP Marias Hospital

Cape Town, Western Cape, 7725, South Africa

Location

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Research Officer

Study Record Dates

• First Submitted: March 29, 2016
• First Posted: April 4, 2016
• Study Start: July 30, 2015
• Primary Completion: January 30, 2021
• Study Completion: January 30, 2021
• Last Updated: April 29, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share

Locations

ZA (2)