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I would like to add some additional information to the previously presented analysis on the dropout rate after 5 years. Though the number of remaing subjects in the Phase2a OLE and Humanitarian Extension is rather imprecise as Dr. Missling put it between 21 and 10, I used as reference paper titled
Variability in Annual Mini-Mental State Examination Score in Patients With Probable Alzheimer DiseaseA Clinical Perspective of Data From the Consortium to Establish a Registry for Alzheimer’s Disease
Christopher M. Clark, MD; Lianne Sheppard, PhD; Gerda G. Fillenbaum, PhD; et alDouglas Galasko, MD; John C. Morris, MD; Elizabeth Koss, PhD; Richard Mohs, PhD; Albert Heyman, MD; and the CERAD Investigators
Complex Picture of Age, Comorbidity, MMSE Test Sensitivity and Dispersion of Test Results
The paper contains an interesting graph as it represents the MMSE scores difference for patients at the end of the last year of given patient in the study. The line through the distribution of scores is the average decline per year.
What conclutions I draw from this graph?
First Year: The dispersion is the highest, most are scoring well below the initial scores and minority showing miraclously improvement. This was confirmed on the patients map for Phase2a as low to medium concentration cohorts followed this pattern of dispersion and the average rate of decline.
On subsequent years the dispersion tightens as well as the rate of average decline approaches with years = -3.4 +/-2.8. Also the frequency of miraculous test scores above initial scores falls precipitously. By year 5 there is nobody who scores above the initial score. There is also dying out of the patients as median age is 71 years old and average MMSE initial score was ~ 20. So the least healthy, both cognitevely and physically either die out or drop out. Age had a definitive influence on the average decline for given starting age. Quotation from the paper:
The MMSE score declined by an average of 3.41 points per year (P<.001) at age 71 years. Age had a statistically significant impact, with a 0.06-point-per-year (P<.001) additional decline for every year greater than 71 or a corresponding reduction in the rate of decline for every year less than 71. Sex had no significant effect (P=.43).
So on average if subject is 55 of age the anual decline is =-2.4, but at age 85 it is = -4.2. It seems as the older subjects die out the younger stay in the study.
I have been thinking how to measure the performance of Blarcamesine in this complex situation, where age, inital score, dropouts due to comorbidity and dropouts due to low MMSE scores can not be fully untangled or separated from the picture painted by the given data. Add to that a small sample size and you have gotten more than you can chew. I think that I found an alternative measure.
The paper had two cohorts. One was the people with probable Alzheimer’s diagnosis and the other was a control group of the same composition but cognitively healthy. Figure 1 shows the dwindling number of both groups over time.
Nothing is perfect in this picture, but it seems that by that measure Blarcamesine brings the morbidity very close to the background morbidity and disability experienced by the healthy controls. This is in some sense comparable as the study in the paper had recruited people from age 50 and up and average age being 71. Anavex recruited from ages 55 to 85, and used score from 14 to 24, if I am correct. The above study scored ranged from 10 to 24 MMSE.
Due to the advanced age of the subjects this comparison makes more sence than just looking at absolute numbers of survivors. In the study we can not separate death from disability due to very low MMSE scores, as both produced droping out of the study. I hope that similar situation was present in the Phase2a trial.
I do not know wwhether my analysis has any validity. The voices which want the dosing to be moved toward less progressed patients might indeed bring the morbidity of those who succumb to Alzheimer’s near those experienced by the cognitively healthy.
Now, give me a beer……
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