Clinical trial NCT02727582: Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment
Official title: Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Multidrug-resistant Tuberculosis
Keywords: MDR
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Baylor Research Institute
First posted: 2016-04-04
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
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.

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. The application of computational analytical techniques to tease out the individual contributions of anti-TB drugs used in combination
2. The development of a treatment response biomarker model based on time-to-positivity in liquid culture of serial sputum samples.
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).

Thus the research will enhance our understanding of current modalities of TB treatment, while contributing research approaches for future regimen optimization.

This protocol describes the clinical research component (points 1\&2).

Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients. The 2nd-line drugs to be examined are those comprising the standardized regimen used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.

Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a quantifiable impact on the rates at which viable Mtb are cleared from the sputum.

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

Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone are linked to drug concentrations.

Detailed description: Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients. The 2nd-line drugs to be examined are those comprising the standardized regimen used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.

Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a quantifiable impact on the rates at which viable Mtb are cleared from the sputum.

Rationale: There is substantial variability in the PK parameters of the 2nd-line drugs between patients, and in the susceptibility of individual Mtb isolates to those drugs. Concentration-dependent activity has been demonstrated for moxifloxacin, pyrazinamide and aminoglycosides, and higher doses of moxifloxacin and pyrazinamide have been proposed. Studies are needed to identify the most important determinants of treatment response and to describe the optimal drug exposures in MDR-TB, taking MICs into account. We will describe the exponential decline of viable Mtb in the sputum of MDR-TB patients in a treatment response model based on time-to-positivity in liquid culture, thus furthering the field of TB biomarker research. We will then define the relationship between PK and the rates of eradication of viable Mtb from the sputum of patients on the standard MDR-TB regimen to identify the more potent drugs driving treatment response, and to identify synergism or antagonism between individual drugs. Examples of specific questions that will be addressed include: What is the impact of pyrazinamide resistance on treatment response?; What is the impact of inhA mutations on the effect of ethionamide?; and, Should a higher doses of moxifloxacin and pyrazinamide be considered?

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

Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone are linked to drug concentrations.

Rationale: Treatment limiting adverse drug effects are common in patients on MDR-TB treatment regimens. Although several common toxicities are linked to specific drugs and are thought to be dose-related, the relationship between PK and toxicity has not been adequately studied. Overlapping toxicity of antiretroviral drugs in HIV-infected patients, amongst other risk factors, may be contributory. Minimum drug concentration thresholds associated with increased toxicity would allow optimization of doses by targeting concentrations below which toxicity is common, but above which there is optimal efficacy.

Eligibility criteria: Inclusion Criteria:

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.

Exclusion Criteria:

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.

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Primary outcomes:
measure: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients.
timeFrame: 2 years
Secondary outcomes:
measure: To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
timeFrame: 2 years
Other outcomes:
measure: 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.
timeFrame: 2 years
measure: To describe the key drivers of treatment response in the standard multi-drug regimen for MDR-TB
timeFrame: 2 years
measure: 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.
timeFrame: 2 years
Locations:
city: Cape Town
country: South Africa
facility: Brooklyn Chest Hospital
state: Western Cape
city: Cape Town
country: South Africa
facility: DP Marias Hospital
state: Western Cape
Study officials:
References: