Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Patrick P. J.  Phillips; Carl M.  Mendel; Divan A.  Burger; Angela  Crook; Andrew J.  Nunn; Rodney Dawson; Andreas H. Diacon; Stephen Henry Gillespie

doi:10.1186/s12916-016-0565-y

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Patrick P. J. Phillips, Carl M. Mendel, Divan A. Burger, Angela Crook, Andrew J. Nunn, Rodney Dawson, Andreas H. Diacon, Stephen Henry Gillespie

Research output: Contribution to journal › Article › peer-review

Abstract

Background
Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials.

Methods
Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome.

Results
Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP.

Conclusions
Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.

Original language	English
Article number	19
Number of pages	11
Journal	BMC Medicine
Volume	14
DOIs	https://doi.org/10.1186/s12916-016-0565-y
Publication status	Published - 4 Feb 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Tuberculosis
Clinical trials
Surrogate endpoints
Moxifloxacin

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10.1186/s12916-016-0565-yLicence: CC BY

Gillespie_2016_LimitedRole_BMCMed_CC
© 2016 Phillips et al. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Final published version, 2.04 MBLicence: CC BY

Cite this

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title = "Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials",

abstract = "Background Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.",

keywords = "Tuberculosis, Clinical trials, Surrogate endpoints, Moxifloxacin",

author = "Phillips, \{Patrick P. J.\} and Mendel, \{Carl M.\} and Burger, \{Divan A.\} and Angela Crook and Nunn, \{Andrew J.\} and Rodney Dawson and Diacon, \{Andreas H.\} and Gillespie, \{Stephen Henry\}",

note = "Supported by the European and Developing Country Clinical Trials Partnership (grant IP.2007.32011.011) and the Global Alliance for TB Drug Development, with support from the Bill \& Melinda Gates Foundation, US Agency for International Development, UK Department for International Development, Directorate-General for International Cooperation of the Netherlands, Irish Aid and Australian Department of Foreign Affairs and Trade.",

year = "2016",

month = feb,

day = "4",

doi = "10.1186/s12916-016-0565-y",

language = "English",

volume = "14",

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T1 - Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

AU - Phillips, Patrick P. J.

AU - Mendel, Carl M.

AU - Burger, Divan A.

AU - Crook, Angela

AU - Nunn, Andrew J.

AU - Dawson, Rodney

AU - Diacon, Andreas H.

AU - Gillespie, Stephen Henry

N1 - Supported by the European and Developing Country Clinical Trials Partnership (grant IP.2007.32011.011) and the Global Alliance for TB Drug Development, with support from the Bill & Melinda Gates Foundation, US Agency for International Development, UK Department for International Development, Directorate-General for International Cooperation of the Netherlands, Irish Aid and Australian Department of Foreign Affairs and Trade.

PY - 2016/2/4

Y1 - 2016/2/4

N2 - Background Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.

AB - Background Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.

KW - Tuberculosis

KW - Clinical trials

KW - Surrogate endpoints

KW - Moxifloxacin

UR - https://www.scopus.com/pages/publications/84961059451

U2 - 10.1186/s12916-016-0565-y

DO - 10.1186/s12916-016-0565-y

M3 - Article

SN - 1741-7015

VL - 14

JO - BMC Medicine

JF - BMC Medicine

M1 - 19

ER -

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Abstract

UN SDGs

Keywords

Access to Document

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Stephen Gillespie

Shorter moxifloxacin-based regimens for drug-sensitive tuberculosis

The relationship between Mycobacterium tuberculosis MGIT time to positivity and cfu in sputum samples demonstrates changing bacterial phenotypes potentially reflecting the impact of chemotherapy on critical sub-populations

Cite this

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Profiles

Stephen Gillespie

Research output

Shorter moxifloxacin-based regimens for drug-sensitive tuberculosis

The relationship between Mycobacterium tuberculosis MGIT time to positivity and cfu in sputum samples demonstrates changing bacterial phenotypes potentially reflecting the impact of chemotherapy on critical sub-populations

Cite this