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121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA)
BACKGROUND: Current Phase 2a methods in tuberculosis (TB) drug development are severely limited in capturing a drug candidate’s sterilizing activity (ability to prevent TB relapse). We hypothesize that sputum-based measurements of current methods fail to capture drug activity in deep TB lesion compa...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252863/ http://dx.doi.org/10.1093/ofid/ofy209.012 |
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author | Xie, Yingda Via, Laura Chen, Ray Dodd, Lori Cai, Ying Paripati, Paveen Goldfeder, Lisa Winter, Jill Arora, Kriti Wang, Jing De Jagar, Veronique Malherbe, Stephanus Song, Taeksun Walzl, Gerhard Diacon, Andreas III, Clifton Barry |
author_facet | Xie, Yingda Via, Laura Chen, Ray Dodd, Lori Cai, Ying Paripati, Paveen Goldfeder, Lisa Winter, Jill Arora, Kriti Wang, Jing De Jagar, Veronique Malherbe, Stephanus Song, Taeksun Walzl, Gerhard Diacon, Andreas III, Clifton Barry |
author_sort | Xie, Yingda |
collection | PubMed |
description | BACKGROUND: Current Phase 2a methods in tuberculosis (TB) drug development are severely limited in capturing a drug candidate’s sterilizing activity (ability to prevent TB relapse). We hypothesize that sputum-based measurements of current methods fail to capture drug activity in deep TB lesion compartments, where recalcitrant TB populations are sequestered. In our recent marmoset study, we found complementary 14-day PET/CT delta signatures across different TB lesion compartments that distinguish drugs with long-term sterilizing activity (e.g., rifampin and pyrazinamide) versus drugs with primarily early bactericidal activity (e.g., isoniazid) (Figure 1). We proceeded to evaluate this novel PET/CT Phase 2a approach among TB patients, benchmarked by drugs that are well-characterized clinically and pharmacokinetically. METHODS: HIV-negative patients with smear-positive pulmonary tuberculosis from Cape Town, South Africa were enrolled and randomized to receive a single drug [isoniazid (H), rifampin (R), pyrazinamide (Z), moxifloxacin (M)], a 2-drug regimen (HZ, RZ), or a 4-drug regimen (HRZE, MRZE) for 14 days in an inpatient facility. Primary data points were PET/CT scans evaluated at pretreatment baseline and treatment day 14 (and day 28 in the HRZE arm), and daily overnight sputum for early bactericidal activity measurements. RESULTS: From December 2015 to September 2017, 160 participants completed the study, from whom 340 PET/CT scans and 2,238 overnight sputum samples were collected. PET/CT scans from participants demonstrate diversity of lesion architecture and inter-individual variation in PET/CT changes over 14 days of treatment (Figure 2). A preliminary computational algorithm and first- and second-order PET/CT statistics have been developed for initial segmentation and TB lesion categorization of all study scans. Derivation of radiologic signatures by analysis of 14-day PET/CT changes across each lesion type is ongoing; blinded prediction of each participant’s treatment arm based on these signatures is expected by third-quarter 2018. CONCLUSION: If successful, these signatures may be applied within a 14-day Phase 2a framework to evaluate new TB drug candidates and construct TB drug regimens with complementary lesion pharmacokinetics. [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures. |
format | Online Article Text |
id | pubmed-6252863 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62528632018-11-28 121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA) Xie, Yingda Via, Laura Chen, Ray Dodd, Lori Cai, Ying Paripati, Paveen Goldfeder, Lisa Winter, Jill Arora, Kriti Wang, Jing De Jagar, Veronique Malherbe, Stephanus Song, Taeksun Walzl, Gerhard Diacon, Andreas III, Clifton Barry Open Forum Infect Dis Abstracts BACKGROUND: Current Phase 2a methods in tuberculosis (TB) drug development are severely limited in capturing a drug candidate’s sterilizing activity (ability to prevent TB relapse). We hypothesize that sputum-based measurements of current methods fail to capture drug activity in deep TB lesion compartments, where recalcitrant TB populations are sequestered. In our recent marmoset study, we found complementary 14-day PET/CT delta signatures across different TB lesion compartments that distinguish drugs with long-term sterilizing activity (e.g., rifampin and pyrazinamide) versus drugs with primarily early bactericidal activity (e.g., isoniazid) (Figure 1). We proceeded to evaluate this novel PET/CT Phase 2a approach among TB patients, benchmarked by drugs that are well-characterized clinically and pharmacokinetically. METHODS: HIV-negative patients with smear-positive pulmonary tuberculosis from Cape Town, South Africa were enrolled and randomized to receive a single drug [isoniazid (H), rifampin (R), pyrazinamide (Z), moxifloxacin (M)], a 2-drug regimen (HZ, RZ), or a 4-drug regimen (HRZE, MRZE) for 14 days in an inpatient facility. Primary data points were PET/CT scans evaluated at pretreatment baseline and treatment day 14 (and day 28 in the HRZE arm), and daily overnight sputum for early bactericidal activity measurements. RESULTS: From December 2015 to September 2017, 160 participants completed the study, from whom 340 PET/CT scans and 2,238 overnight sputum samples were collected. PET/CT scans from participants demonstrate diversity of lesion architecture and inter-individual variation in PET/CT changes over 14 days of treatment (Figure 2). A preliminary computational algorithm and first- and second-order PET/CT statistics have been developed for initial segmentation and TB lesion categorization of all study scans. Derivation of radiologic signatures by analysis of 14-day PET/CT changes across each lesion type is ongoing; blinded prediction of each participant’s treatment arm based on these signatures is expected by third-quarter 2018. CONCLUSION: If successful, these signatures may be applied within a 14-day Phase 2a framework to evaluate new TB drug candidates and construct TB drug regimens with complementary lesion pharmacokinetics. [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures. Oxford University Press 2018-11-26 /pmc/articles/PMC6252863/ http://dx.doi.org/10.1093/ofid/ofy209.012 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Abstracts Xie, Yingda Via, Laura Chen, Ray Dodd, Lori Cai, Ying Paripati, Paveen Goldfeder, Lisa Winter, Jill Arora, Kriti Wang, Jing De Jagar, Veronique Malherbe, Stephanus Song, Taeksun Walzl, Gerhard Diacon, Andreas III, Clifton Barry 121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA) |
title | 121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA) |
title_full | 121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA) |
title_fullStr | 121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA) |
title_full_unstemmed | 121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA) |
title_short | 121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA) |
title_sort | 121. improving predictive value of phase 2a tb drug development models through pet/ct imaging (nexgen eba) |
topic | Abstracts |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252863/ http://dx.doi.org/10.1093/ofid/ofy209.012 |
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