Comparing some Alzheimer's treament numbers

Lane Simonian

Most of these trials lacked a placebo although some had a comparator (such as low dose or compared to acetylcholinesterase treatment).  Most of these trials were for early Alzheimer's disesae (the Chinese herb study also included a moderate Alzheimer's group).  Some of the numbers were taken off of charts so they are not perfectly precise.  These are averages so some people do better and others worse on these types of treatments, which is why you should be careful with individual accounts.  An account of great response may likely be true, but the person may be an outlier.

The three measures--Mini-Mental State Examimation, Alzheimer's Disease Assessment Scale-Clinical Subscale, and Clinical Dementia Rating-scale Sum of the Boxes--can more or less be converted between each other (seen in following link).

http://adni.loni.usc.edu/adni-publications/Balsis_2015_ClinNeuropsych.pdf

No treatment for two years: 4.5 point decline from baseline (MMSE)

Conventional Therapy (including acetycholinesterase inhibitors and Namenda) for two years: 4.0 point decline from baseline (MMSE)

Placebo group in Biogen's aducanumab trial at 78 weeks 1.74 point decline from baseline (CDR-SB)

Aducanumab ("successful" trial) at 78 weeks: 1.35 point decline from baseline (CDR-SB)

https://investors.biogen.com/static-files/ccb1c817-6d20-4987-b9dc-bcfa96829691

Chinese herbs in conjunction with conventional therapies at two years: 1.5 point decline from baseline (MMSE)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729264/

Anavex 2-73 (blarcamesine) at 57 weeks: 2 point improvment from baseline (MMSE)

https://finance.yahoo.com/news/anavex-life-sciences-reports-anavex-110000049.html

Anavex 2-73 (blarcamesine) at 148 weeks: 2 point decline from baseline (MMSE)

https://www.anavex.com/wp-content/uploads/2019/03/ANAVEX2-73_CTAD_2018_Presentation.pdf

 Korean Red Ginseng (Panax Ginseng) at 96 weeks: 10.2 improvement from baseline 
 (ADAS-cog)

Korean Red Ginseng (Panax Ginseng) at 96 weeks: 1.7 point improvement from baseline (MMSE)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

A slight slowing down of progression should not be the standard for the treatment of Alzheimer's disease.  The gold standard (for now at least) is stopping or nearly stopping the progression of the disease.

Crushed

You are conflating two different concepts.  One is scientific  significance and the other is Clinical significance.  Alexander Fleming's 1929 discovery of Penicillin  was of enormous Scientific significance but Clinical significance had to await the the 1939 work of Howard Florey and Ernst Chain who figured out how to produce  clinical quantities.

The key to scientific significance in Alzheimer's therapeutics is not the size of the effect but confidence that it actually exists and is not due to chance.    That requires very large and carefully designed studies of relatively long duration e/g/ thousands of patients for a number of years.   Small, short time , poorly controlled studies are scientifically worthless. 

Such studies are a huge difference from traditional pharmaceuticals, where thereputic effect could be shown from a handful of patients.    Only after establishing scientific significance can we move to clinical significance.

I fully agree that the Karolinska study is of  limited Clinical value.   Its value is scientific.

Lane Simonian

Here is where I will disagree.  When you have large-scale studies on drugs that show a very minimal slowing down of the progression of Alzheimer's disease over long periods of time that is scientifically significant, but not in a positive sense. 

There is also the case of drugs that may be barely statistically significant but not clinically significant.  Or they may have some effect on certain populations (ApoE4 carriers) but not on others (non-ApoE4 carriers).  If aducanumab follows the pattern of other anti-amyloid drugs, the results will be the following--almost no slowing of the progression of the disease in non-ApoE4 carriers, on the cusp of being statistically significant for those with one copy of the gene, and on the cusp of being clinically significant for those with two copies of the gene (who also are at greatest risk for side effects).

So when it comes to anti-amyloid drugs, acetylcholinesterase inhibitors, and Namenda basically what you have is large numbers of trials and large numbers of participants showing very little benefit.

Then you have a series of small trials, often without placebos, in which there defnitely appears to be a benefit.  These trials are of sufficient duration but not of sufficient size to say that these treatments are conclusively beneficial.  So which would you (meaning anyone) continue to pursue?

Crushed

Small or uncontrolled Alzheimer's studies are by any definition WORTHLESS

The result can simply be chance.  (Aleatory uncertainty)

Large, long,  well controlled or  double blind studies reduce aleatory uncertianty

However Scientific significance is just a starting point.  All scientific knowledge is dependent  on our level of epistemic uncertainty. We can have incredibly good data but without a correct covering law we don't actually know anything.

Sometimes we get lucky, and find a useful clinical treatment with limited scientific understanding.   But the converse is far more common  poorly controlled studies are used to drive clinical practice and only later do we realize  it's worthless or harmful   

Heart Stents Are Useless for Most Stable Patients. They’re Still Widely Used.

Why are so many people agreeing to an expensive procedure — and putting themselves at risk — for a placebo effect?  https://www.nytimes.com/2018/02/12/upshot/heart-stents-are-useless-for-most-stable-patients-theyre-still-widely-used.html

 

  

Lane Simonian

Agreed, Crushed.  There are things we think are effective that turn out not to be effective or worse.

I am not a big fan of analogies, but this is how I look at the current status of Alzheimer's treatments.  Say a person has ten pimples on their face and after two years they develop ten more.  Now, if you treat a 1,000 people with a particular medication, and over the course of those two years they only develop 8 more pimples that is not due to chance.  But only developing two fewer pimples is not not likely clinically significant.  The person is still suffering as much physically and pyschologically as the person who now has twenty pimples.

But if you give 40 people another acne medication and they develop no more pimples or only one or two more pimples over two years, that is clinically significant (for sake of this argument).  It may be that those 40 people were never going to get more pimples or that there was some change they made in their diet that led to them not getting any more pimples.  And it is possible that this happens with cognition, too.  But reasonably (not in a statistical sense) people with Alzheimer's disease are going to decline (albeit at different rates) within a two year period (whether on a placebo or not).  The results are clinically significant ragardless of the cause but because the numbers are too low to eliminate chance they are not statistically significant.

Crushed

Oh PLEASE YOU CAN COUNT PIMPLES

You know when someone has them you know when they are cured

It's a worthless analogy for Alzheimer's

That's the whole point

Alzheimer's is like evaluating the effectiveness  of "abstinence only" sex education by asking the young peoples parents.   2 months after the course.

We don't have good tools for knowing who has early  Alzheimer's.  We have very poor tools for progression of  Alzheimer's and its a long slow disease

Lane Simonian

But to a certain degree you can measure cognitive decline.  And when you only marginally slow down that decline (anti-amyloid drugs, acetycholinesterase inhibitors, Namenda) you can produce results that are statistically signficant but not clinically significant.  And with that being the case, the statistical significance is meaningless.  

And then you have cases, where the disease has been substantially slowed down and the results are clinically significant but the number of participants is not large enough to produce statistsical significance.  Which is the more important result?

Michael Ellenbogen

I believe that is false. “But to a certain degree you can measure cognitive decline”    They only can get a bassline once they do a first test with you. What if you were supper smart or super dumb? You would not know anything on the person until the second test and by then its to late. And being smart is not all about IQ.

Michael Ellenbogen

Also I can take the same test and score 5 point difference based on environment, time of day and who is giving it. So what dam good is the test when it is so close in numbers. It is useless.  New tools are needed.

Crushed

with small studies you can't exclude chance

There is also selection bias for for studies that produce the desired result. 

Publication bias is a type of bias that occurs in published academic research. It occurs when the outcome of an experiment or research study influences the decision whether to publish or otherwise distribute it. Publishing only results that show a significant finding disturbs the balance of findings, and inserts bias in favor of positive results.[1] The study of publication bias is an important topic in metascience.

Studies with significant results can be of the same standard as studies with a null result with respect to quality of execution and design.[2] However, statistically significant results are three times more likely to be published than papers with null results.[3] A consequence of this is that researchers are unduly motivated to manipulate their practices to ensure that a statistically significant result is reported.[4]  https://en.wikipedia.org/wiki/Publication_bias

Discontinuation and non publication of interventional clinical trials conducted in patients with mild cognitive impairment and Alzheimer’s disease 

Results:A total of 744 studies were identified, of which 502 (67%) were industry-sponsored ones. A total of 127 (17%) were discontinued prematurely. Of the 617 completed trials, 450 (73%) were not published, representing approximately 66,655 participants who incurred the risks of trial participation without subsequently contributing to the medical literature. https://alz-journals.onlinelibrary.wiley.com/doi/pdfdirect/10.1016/j.trci.2018.03.005 

So for every positive study published four others  were never published   that is why you cant rely on crap publication.

Lane Simonian

It is certainly true that Alzheimer's disease tests lack precision.  Good days and bad days, getting better at taking the test, and observational bias can all be problems.  But over a year to two year period, from mulitple clinical trials we know what the average rate of cognitive decline for someone with Alzheimer's disease is going to be.  There are a  handful of drugs and treatments that appear to slow down or almost stabilize the rate of decline for at least a two year period of time and these results while not statistically significant are far superior to any drug currently being used to treat Alzheimer's disease or any of the anti-amyloid drug now being studied for Alzheimer's disease.

I am actually pleased that some journals will publish non-significant results.  I want to know what seems to be having an impact and what common mechanism these treaments may have. 

Anavex 2-73 now is in phase three trials in Austraila, parts of Europe, and Canada.  GV-971 (a compound derived from brown algae) has gained conditional approval in China and now is being trialed in other parts of the world including the United States (the improvment in ADAS-cog scores at 36 weeks was 2.7, which is not quite clinically significant).  We will have answers in the next few years about the effectiveness of these drugs (perhaps as early as next year for Anavex 2-73).

  

ElaineD

Re: Stents

In 1999 at Emory Hospital a nuclear stress test followed by an angiogram  revealed that my Left Anterior Descending Coronary Artery was 95% blocked. Two other coronary arteries were blocked, as well. The blocked LADC is known as the 'Widow Maker'.

I was tested at Emory because I had disabling pain on exertion, and pain woke me up in the middle of the night, as well.  I had severe unstable angina. I was being treated for heartburn!

I was 57 years old.

After three angioplasties and two stents were placed in my heart the pain stopped immediately.  I did not have a heart attack, thank goodness.

In the almost 22 years since my stents stopped the pain, I have had no coronary incidents.  No matter where we lived I have been attended by outstanding cardiologists.     

Would I have had a heart attack without the stents?  Who knows. I do know that without the stents I would have been an invalid.  

Elaine

Crushed

Sorry Lane you are promoting the Dog Poop fallacy

if you do 10 small studies of rubbing dog poop on Alzheimers patients BY CHANCE  1 or Two will show positive results

You then publish it in the J  of Dog Poop Research

and the illiterati go crazy for it.   SMALL STUDIES ARE TOTALLY WORTHLESS

Crushed

ElaineD wrote:

Would I have had a heart attack without the stents?  Who knows. I do know that without the stents I would have been an invalid.  

The people who die due to a treatment don't write letters.I's called survivor bias.

That is why we do research

 

 

Strictly for Humor It took us 4 years for DW to get pregnant, but I don't think anyone want to repeat the strategy  that worked 

Post Hoc is not Propter hoc

  

Crushed

Lane Simonian wrote:

Anavex 2-73 now is in phase three trials in Austraila, parts of Europe, and Canada.  GV-971 (a compound derived from brown algae) has gained conditional approval in China and now is being trialed in other parts of the world including the United States (the improvment in ADAS-cog scores at 36 weeks was 2.7, which is not quite clinically significant).  We will have answers in the next few years about the effectiveness of these drugs (perhaps as early as next year for Anavex 2-73). 

 

 It's an open label study

   ANAVEX®2-73-AD-004 clinical study is a Phase 2b/3 double-blind, randomized, placebo-controlled, 48-week safety and efficacy trial of ANAVEX®2-73 for the treatment of early Alzheimer’s disease. The Phase 2b/3 study is expected to enroll approximately 450 patients, randomized 1:1:1 to two different ANAVEX®2-73 doses or placebo. The ANAVEX®2-73 Phase 2b/3 study design includes genomic precision medicine biomarkers identified in the previous ANAVEX®2-73 Phase 2a study (ANAVEX2-73-002, NCT02244541). Primary and secondary endpoints will assess safety and both cognitive and functional efficacy, measured through ADAS-Cog, ADCS-ADL and CDR-SB. ANAVEX®2-73 Phase 2a Alzheimer’s disease study previously demonstrated dose dependent improvement in exploratory endpoints of cognition (MMSE) and function (ADCS-ADL).4 ANAVEX®2-73-AD-EP-004 is the 96-week open label extension of the placebo-controlled Phase 2b/3 ANAVEX®2-73 study.  Published: Mar 31, 2021

 It's an open label study

  

jfkoc

Post hoc ergo propter hoc....but with out a correlation would one even look for causation?

Lane Simonian

No one with Alzheimer's disease improves over a two year period without some kind of intervention.  Some people may decline more slowly than others, but to one degree or another they will all sadly decline.

The first part of the current Anavex 2-73 trial is placebo-controlled.  

The ongoing placebo-controlled 450-patient Phase 2b/3 ANAVEX®2-73 clinical study in patients with Alzheimer's disease is presently over 92% enrolled and includes prespecified SIGMAR1 gene expression as endpoints using ADAS-Cog (cognition) and ADCS-ADL (activities of daily living and function) as primary endpoints.

Michael Ellenbogen

Sorry Lane thatThis  is FALSE.  

No one with Alzheimer's disease improves over a two year period without some kind of intervention.  Some people may decline more slowly than others, but to one degree or another they will all sadly decline.

Crushed

Lane Simonian wrote:

The first part of the current Anavex 2-73 trial is placebo-controlled.  

The ongoing placebo-controlled 450-patient Phase 2b/3 ANAVEX®2-73 clinical study in patients with Alzheimer's disease is presently over 92% enrolled and includes prespecified SIGMAR1 gene expression as endpoints using ADAS-Cog (cognition) and ADCS-ADL (activities of daily living and function) as primary endpoints.

Placebo control simply means the patients with Dementia don't know what drug they get BUT THE INVESTIGATORS KNOW EXACTLY WHO IS GETTING EACH DRUG

The question is WHY.  

Michael Ellenbogen

Crushed what is the difference with what you said and double blind.

Lane Simonian

The Anavex 2-73 trial is double-blinded: neither the participants nor the investigators know who is getting the high dose of the drug, the low dose of the drug, or the placebo:

Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases including Alzheimer’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced that the Company has received approval by the Australian Human Research Ethics Committee to initiate its Phase 2b/3 double-blind, randomized, placebo-controlled, 48-week safety and efficacy trial of ANAVEX®2-73 for the treatment of early Alzheimer’s disease. The Phase 2b/3 study is scheduled to initiate enrollment of approximately 450 patients, randomized 1:1:1 to two different ANAVEX®2-73 doses or placebo within the next month. As part of the planned international study, North American sites will be added.

Anavex 2-73 and Aricept (donepezil) are both sigma-1 receptor agonists, the effect of which is to limit intracellular calcium release and the breakdown of acteylcholine under conditions of oxidative stress (which is a common feature of many neurological diseases and conditions).  They also both limit further oxidative stress.  There is not a synergestic effect between the two drugs, however.  In addition, Anavex 2-73 appears to work better than Aricept.  Whether this is because Anavex 2-73 is a better agonist of sigma-1 receptors or because it is a direct antioxidant or neither or both has yet to be determined.

https://www.neurologylive.com/view/sigma1-agonists-offer-combination-approach-to-dementia-symptoms

Crushed

 There are Two different studies . 

  ANAVEX®2-73-AD-EP-004 is the 96-week open label extension of the placebo-controlled Phase 2b/3 ANAVEX®2-73 study.  Published: Mar 31, 2021