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Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Helen Shiells, Bjoern O. Schelter, Peter Bentham, Thomas C. Baddeley, Christopher M. Rubino, Harish Ganesan, Jeffrey Hammel, Vesna Vuksanovic Orcid Logo, Roger T. Staff, Alison D. Murray, Luc Bracoud, Damon J. Wischik, Gernot Riedel, Serge Gauthier, Jianping Jia, Hans J. Moebius, Jiri Hardlund, Christopher M. Kipps, Karin Kook, John M.D. Storey, Charles R. Harrington, Claude M. Wischik

Journal of Alzheimer's Disease, Volume: 75, Issue: 2, Pages: 501 - 519

Swansea University Author: Vesna Vuksanovic Orcid Logo

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DOI (Published version): 10.3233/jad-191173

Abstract

Background:Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.Objective:To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.Methods:We undertook a 52-week Phase III st...

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Published in: Journal of Alzheimer's Disease
ISSN: 1387-2877 1875-8908
Published: IOS Press 2020
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URI: https://cronfa.swan.ac.uk/Record/cronfa60497
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The principal outcomes were change on the Addenbrookes Cognitive Examination &#x2013; Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.Results:There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3&#x2013;0.6&#x200A;ng/ml at the 8&#x200A;mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8&#x200A;mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346&#x200A;ng/ml with having minimal drug exposure. 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spelling 2022-07-21T14:06:38.0899389 v2 60497 2022-07-14 Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia a1a6e2bd0b6ee99f648abb6201dea474 0000-0003-4655-698X Vesna Vuksanovic Vesna Vuksanovic true false 2022-07-14 HDAT Background:Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.Objective:To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.Methods:We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination – Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.Results:There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3–0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.Conclusions:Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20–60 mg/day. A confirmatory placebo-controlled trial is now planned. Journal Article Journal of Alzheimer's Disease 75 2 501 519 IOS Press 1387-2877 1875-8908 Behavioral variant frontotemporal dementia, clinical trials, hydromethylthionine, leucomethylthioninium, tau protein, TDP-43 19 5 2020 2020-05-19 10.3233/jad-191173 COLLEGE NANME Health Data Science COLLEGE CODE HDAT Swansea University The study was sponsored by TauRx Therapeutics (Singapore). 2022-07-21T14:06:38.0899389 2022-07-14T10:28:48.5925541 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Helen Shiells 1 Bjoern O. Schelter 2 Peter Bentham 3 Thomas C. Baddeley 4 Christopher M. Rubino 5 Harish Ganesan 6 Jeffrey Hammel 7 Vesna Vuksanovic 0000-0003-4655-698X 8 Roger T. Staff 9 Alison D. Murray 10 Luc Bracoud 11 Damon J. Wischik 12 Gernot Riedel 13 Serge Gauthier 14 Jianping Jia 15 Hans J. Moebius 16 Jiri Hardlund 17 Christopher M. Kipps 18 Karin Kook 19 John M.D. Storey 20 Charles R. Harrington 21 Claude M. Wischik 22 60497__24687__4bad8162472d45c9816f57f9673a38b0.pdf 60497_VoR.pdf 2022-07-21T14:04:31.1495824 Output 474195 application/pdf Version of Record true This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia
spellingShingle Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia
Vesna Vuksanovic
title_short Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia
title_full Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia
title_fullStr Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia
title_full_unstemmed Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia
title_sort Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia
author_id_str_mv a1a6e2bd0b6ee99f648abb6201dea474
author_id_fullname_str_mv a1a6e2bd0b6ee99f648abb6201dea474_***_Vesna Vuksanovic
author Vesna Vuksanovic
author2 Helen Shiells
Bjoern O. Schelter
Peter Bentham
Thomas C. Baddeley
Christopher M. Rubino
Harish Ganesan
Jeffrey Hammel
Vesna Vuksanovic
Roger T. Staff
Alison D. Murray
Luc Bracoud
Damon J. Wischik
Gernot Riedel
Serge Gauthier
Jianping Jia
Hans J. Moebius
Jiri Hardlund
Christopher M. Kipps
Karin Kook
John M.D. Storey
Charles R. Harrington
Claude M. Wischik
format Journal article
container_title Journal of Alzheimer's Disease
container_volume 75
container_issue 2
container_start_page 501
publishDate 2020
institution Swansea University
issn 1387-2877
1875-8908
doi_str_mv 10.3233/jad-191173
publisher IOS Press
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Background:Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.Objective:To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.Methods:We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination – Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.Results:There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3–0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.Conclusions:Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20–60 mg/day. A confirmatory placebo-controlled trial is now planned.
published_date 2020-05-19T04:18:39Z
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