Clinical Trials – Bumetanide and Memantine & Making Sense of it all in a Single Book

This week I received a message: -

“Your Bumetanide treatment is on trial among 25 teenagers here and parents are loving it”

My reply, brief as usual (unlike my blog posts)

“Great!”

I did not mention that in the first phase of the trial 50% of the teenagers are going to be on the placebo.  It is Dr Ben-Ari’s treatment.

A clinician told me that all the parents of children, to whom she has prescribed bumetanide, think their children are responders and is wondering how to deal with the parental placebo effect.

I had another clinician telling me, “I guess from your experience with the blog, most people are not responders to Bumetanide”.  Then came an analysis of the recent tiny study in China that showed on average there was a measurable improvement on the CARS scale (Childhood Autism Rating Scale), but the question arose was “is this response large enough for parents to notice?”

Memantine (Namenda)

A few years ago, Memantine was also trialled at the University Hospital where we live, the same one that is part of the current Bumetanide study.

Memantine was subject to a rigorous multi-center study of nearly one thousand children a few years ago.  The FDA did not like all the off-label prescribing of Memantine for autism and asked the producer to carry out a serious clinical trial.

The first phase of the trial was to identify the responders, those responders then were to be enrolled to two follow-on trials to collect additional useful data.  The trial was terminated after the first phase was completed because in the subsequent trials the placebo produced as good results as Memantine.

So, we should assume memantine is no good for autism?

Or

In spite of spending millions of dollars and liaising with the FDA on the detailed structure of the trial, the producer did not know how to organize an autism trial properly?

I was just writing a part of my autism book that reviews all the drugs trialed to date in autism and I noted that Antonio Hardan (for me, Dr NAC from Stanford) has published a review of data from those expensive Memantine trials.

Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies

… the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

I think that is Hardan-speak for “I think Memantine can be a useful therapy, for some people”.  I am not totally sure and I can see why Barney Rubble might be left scratching his head. 

Hardan is about to become Stanford's Dr Nexium, as he runs a clinical trial of the acid lowering drug esomeprazole (Nexium).  I am not sure why he thinks this will improve autism.  I think it will make some people's autism worse, because over time it will cause intestinal dysbiosis.

https://stanfordhealthcare.org/trials/a/NCT03866668.html

Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use

Autism for Dummies?

Writing a comprehensive book about autism is quite a task.  If it is too complicated nobody will read it, but if you do not go into the how and why of autism, you have not contributed very much.

My elder son has suggested calling it “Autism for Dummies”; but that was not helpful suggestion.  We probably all count as Dummies, when it comes to autism, even Dr Naviaux, who I think knows the most.

I like the book written by a US Academic who treated his "untreatable" brain cancer (Gioblastoma, life expectancy 14 months), by reading the research and applying off-label therapies, using cheap generic drugs.  He has lived long enough to publish a second edition.  The first edition has a cover that looks like a medical textbook; he learned his lesson and the second edition looks more like a cookery book.

Before using pharmaceuticals to treat autism, we used a Peter-created, ABA-inspired, home therapy program.  Amongst many resources, we had two old, but excellent books - they were published nearly 40 years ago.  One was blue and one was yellow (code named by me and therapists as the yellow and blue books), one was about increasing good behaviors and the other was about reducing bad behaviors.  I could not leave them lying around at home, because in the tittle of these use cute looking books was in large print “SEVERE RETARDATION”.  The books are great and of course they should have been combined into a single book. 

I am not a fan of giving a nice name to somethings that is bad.

To me, intellectual disability sounds like not being very good at playing chess.

Accept bad news and move on.

Peter’s Book

I decided to have three sections in my book and have a nice cookery book style cheerful cover, so nobody can be embarrassed.  I will not be citing endless complicated research papers. 

I start with all the general issues that are relevant to understanding autism, that do not relate to complicated science.  I finish with a section on how autism can be treated based on applying the research findings to date, what ideas I came up with myself and other people’s ideas shared on this blog. 

Sandwiched in between easy reading section 1 and practical section 3, is a more heavy-going section 2; it is a simplified review of the biology and chemistry that is relevant to autism.  These are things you need to know to make any sense of those tens of thousands of published autism papers, that most people do not know exist.

Section 2 is not going to be a favourite for Roger, but I think he will like sections 1 and 3.  To really judge what to do in the therapy part (section 3), understanding at least part of section 2 is advisable and that is why it has to be there.

It is just like fixing your car, it does help to know a little bit about how it works, before you start tinkering with it.  Even the mechanic at the dealership does not know everything about how it works, but hopefully he knows enough.

If the mechanic cannot fix your car, you just sell it. You may feel a pain in your wallet, but no long-term guilt.

The autism is equivalent is putting your child into an institution, or group home.  You either feel guilty at this point, or later on when something goes terribly wrong. 

I am forever having to fix things - from cars to computers, to solar panels, air conditioners, blocked drains, a leaking swimming pool etc.  Once you realize the "experts" are often not so expert, you engage yourself to solve the problems; or at least tell the expert what you want him to do, like “I found the leak, here it is, now fix it like this”.

Don’t skip section 2, invest time to learn some biology.