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Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment (PODrtb)

28 kwietnia 2021 zaktualizowane przez: Helen Margaret McIlleron, University of Cape Town

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.

Przegląd badań

Status

Zakończony

Warunki

Szczegółowy opis

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.

Typ studiów

Obserwacyjny

Zapisy (Rzeczywisty)

142

Kontakty i lokalizacje

Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.

Lokalizacje studiów

  • Afryka Południowa
    • Western Cape
      • Cape Town, Western Cape, Afryka Południowa, 7725
        • Brooklyn Chest Hospital
      • Cape Town, Western Cape, Afryka Południowa, 7725
        • DP Marias Hospital

Kryteria uczestnictwa

Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.

Kryteria kwalifikacji

Wiek uprawniający do nauki

18 lat i starsze (Dorosły, Starszy dorosły)

Akceptuje zdrowych ochotników

Nie

Płeć kwalifikująca się do nauki

Wszystko

Metoda próbkowania

Próbka prawdopodobieństwa

Badana populacja

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.

Opis

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.

-

Plan studiów

Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.

Jak projektuje się badanie?

Szczegóły projektu

  • Modele obserwacyjne: Kohorta
  • Perspektywy czasowe: Z mocą wsteczną

Co mierzy badanie?

Podstawowe miary wyniku

Miara wyniku
Opis środka
Ramy czasowe
To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients.
Ramy czasowe: 2 years

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

Miary wyników drugorzędnych

Miara wyniku
Opis środka
Ramy czasowe
To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
Ramy czasowe: 2 years

To describe the individual susceptibility and MIC distributions of the infecting strains of Mtb in the study population.

• Determine moxifloxacin, kanamycin, ethionamide, isoniazid, cycloserine and pyrazinamide MICs in baseline culture isolates in each patient and in positive 8-week cultures
2 years

Inne miary wyników

Miara wyniku
Opis środka
Ramy czasowe
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.
Ramy czasowe: 2 years

Using TTP data from serial MGIT cultures taken weekly during the first 12 weeks of treatment, to develop a nonlinear mixed effects model describing the population response to standard MDR-TB treatment.

• Individual model parameter estimates will be obtained from the model
2 years
To describe the key drivers of treatment response in the standard multi-drug regimen for MDR-TB
Ramy czasowe: 2 years
  • Quantify the effects of PK exposure and MIC on key treatment response parameters
  • Identify key PK thresholds for treatment response
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.
Ramy czasowe: 2 years
2 years

Współpracownicy i badacze

Tutaj znajdziesz osoby i organizacje zaangażowane w to badanie.

Sponsor

University of Cape Town

Współpracownicy

Baylor Research Institute

Daty zapisu na studia

Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.

Główne daty studiów

Rozpoczęcie studiów (Rzeczywisty)

30 lipca 2015

Zakończenie podstawowe (Rzeczywisty)

30 stycznia 2021

Ukończenie studiów (Rzeczywisty)

30 stycznia 2021

Daty rejestracji na studia

Pierwszy przesłany

29 marca 2016

Pierwszy przesłany, który spełnia kryteria kontroli jakości

29 marca 2016

Pierwszy wysłany (Oszacować)

4 kwietnia 2016

Aktualizacje rekordów badań

Ostatnia wysłana aktualizacja (Rzeczywisty)

29 kwietnia 2021

Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości

28 kwietnia 2021

Ostatnia weryfikacja

1 kwietnia 2021

Więcej informacji

Terminy związane z tym badaniem

Słowa kluczowe

Dodatkowe istotne warunki MeSH

Inne numery identyfikacyjne badania

  • PODrtb

Plan dla danych uczestnika indywidualnego (IPD)

Planujesz udostępniać dane poszczególnych uczestników (IPD)?

TAk

Opis planu IPD

The investigators listed on the protocol comprise the study management group and are the custodians of the data generated from the study. All manuscripts arising from the data generated as a result of this study are to be approved by this group before submission for publication. Manuscripts arising from the trial will be submitted to peer-reviewed journals. In accordance with NIH public access policy the final peer-reviewed journal manuscripts will be submitted NIH Manuscript Submission System (NIHMS) upon acceptance for publication, and be made publicly available on PubMed Central no later than 12 months after the official date of publication. All presentations and publications will acknowledge the trial's funding sources. Authorship will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) and the study management group will resolve any problems of authorship and maintain the quality of publications

Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .

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