| Title | 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. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Wilcock GK [1], Gauthier S [2], Frisoni GB [3], Jia J [4], Hardlund JH [5], Moebius HJ [6], Bentham P [7], Kook KA [8], Schelter BO [9], Wischik DJ [10], Davis CS [11], Staff RT [12], Vuksanovic V [13], Ahearn T [14], Bracoud L [15], Shamsi K [16], Marek K [17], Seibyl J [18], Riedel G [19], Storey JMD [20], Harrington CR [21], Wischik CM [22] |
| Journal | J Alzheimers Dis |
| Volume | 61 |
| Issue | 1 |
| Pagination | 435-457 |
| Date Published | 2018 |
| ISSN | 1875-8908 |
| 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. |
| DOI | 10.3233/JAD-170560 [23] |
| Alternate Journal | J. Alzheimers Dis. |
| PubMed ID | 29154277 [24] |
| PubMed Central ID | PMC5734125 |
