Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease

Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial

Gordon K Wilcock, Serge Gauthier, Giovanni B Frisoni, Jianping Jia, Jiri H Hardlund, Hans J Moebius, Peter Bentham, Karin A Kook, Bjoern Olaf Schelter, Damon J Wischik, Charles S Davis, Roger T Staff, Vesna Vuksanovic, Trevor Ahearn, Luc Bracoud, Kohkan Shamsi, Ken Marek, John Seibyl, Gernot Riedel, John M. D. Storey & 2 others Charles R Harrington, Claude M Wischik

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Abstract

Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
Original languageEnglish
Pages (from-to)435-457
Number of pages24
JournalJournal of Alzheimer's Disease
Volume61
Issue number1
Early online date17 Nov 2017
DOIs
Publication statusPublished - 28 Nov 2017

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Phase III Clinical Trials
Alzheimer Disease
Cohort Studies
Atrophy
Activities of Daily Living
Therapeutics
Glucose
Brain

Keywords

  • ADAS-cog
  • Alzheimer’s disease
  • amyloid protein
  • clinical trial
  • cohort study
  • methylthioninium
  • tau protein
  • treatment

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Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease : Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. / Wilcock, Gordon K; Gauthier, Serge; Frisoni, Giovanni B; Jia, Jianping ; Hardlund, Jiri H ; Moebius, Hans J; Bentham, Peter; Kook, Karin A; Schelter, Bjoern Olaf; Wischik, Damon J; Davis, Charles S; Staff, Roger T; Vuksanovic, Vesna; Ahearn, Trevor; Bracoud, Luc; Shamsi, Kohkan; Marek, Ken ; Seibyl, John ; Riedel, Gernot; Storey, John M. D.; Harrington, Charles R; Wischik, Claude M.

In: Journal of Alzheimer's Disease, Vol. 61, No. 1, 28.11.2017, p. 435-457.

Research output: Contribution to journalArticle

Wilcock, Gordon K ; Gauthier, Serge ; Frisoni, Giovanni B ; Jia, Jianping ; Hardlund, Jiri H ; Moebius, Hans J ; Bentham, Peter ; Kook, Karin A ; Schelter, Bjoern Olaf ; Wischik, Damon J ; Davis, Charles S ; Staff, Roger T ; Vuksanovic, Vesna ; Ahearn, Trevor ; Bracoud, Luc ; Shamsi, Kohkan ; Marek, Ken ; Seibyl, John ; Riedel, Gernot ; Storey, John M. D. ; Harrington, Charles R ; Wischik, Claude M. / Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease : Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. In: Journal of Alzheimer's Disease. 2017 ; Vol. 61, No. 1. pp. 435-457.
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abstract = "Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.",
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author = "Wilcock, {Gordon K} and Serge Gauthier and Frisoni, {Giovanni B} and Jianping Jia and Hardlund, {Jiri H} and Moebius, {Hans J} and Peter Bentham and Kook, {Karin A} and Schelter, {Bjoern Olaf} and Wischik, {Damon J} and Davis, {Charles S} and Staff, {Roger T} and Vesna Vuksanovic and Trevor Ahearn and Luc Bracoud and Kohkan Shamsi and Ken Marek and John Seibyl and Gernot Riedel and Storey, {John M. D.} and Harrington, {Charles R} and Wischik, {Claude M}",
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TY - JOUR

T1 - Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease

T2 - Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial

AU - Wilcock, Gordon K

AU - Gauthier, Serge

AU - Frisoni, Giovanni B

AU - Jia, Jianping

AU - Hardlund, Jiri H

AU - Moebius, Hans J

AU - Bentham, Peter

AU - Kook, Karin A

AU - Schelter, Bjoern Olaf

AU - Wischik, Damon J

AU - Davis, Charles S

AU - Staff, Roger T

AU - Vuksanovic, Vesna

AU - Ahearn, Trevor

AU - Bracoud, Luc

AU - Shamsi, Kohkan

AU - Marek, Ken

AU - Seibyl, John

AU - Riedel, Gernot

AU - Storey, John M. D.

AU - Harrington, Charles R

AU - Wischik, Claude M

N1 - The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-170560. The study was sponsored by TauRx Therapeutics (Singapore). We thank Lon Schneider and Howard Feldman for their contribution to the Scientific Advisory Board. We gratefully acknowledge study investigators and the generosity of study participants. Authors’ disclosures available online (http://j-alz.com/manuscript disclosures/17-0560r3).

PY - 2017/11/28

Y1 - 2017/11/28

N2 - Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

AB - Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

KW - ADAS-cog

KW - Alzheimer’s disease

KW - amyloid protein

KW - clinical trial

KW - cohort study

KW - methylthioninium

KW - tau protein

KW - treatment

U2 - 10.3233/JAD-170560

DO - 10.3233/JAD-170560

M3 - Article

VL - 61

SP - 435

EP - 457

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 1

ER -