Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 435-457 |
| Number of pages | 24 |
| Journal | Journal of Alzheimer's Disease |
| Volume | 61 |
| Issue number | 1 |
| Early online date | 17 Nov 2017 |
| DOIs | |
| Publication status | Published - 28 Nov 2017 |
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Keywords
- ADAS-cog
- Alzheimer’s disease
- amyloid protein
- clinical trial
- cohort study
- methylthioninium
- tau protein
- treatment
Cite this
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 journal › Article
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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 -