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.

Parental Placebo Effect in Autism

I have not met that many parents of kids with ASD; from those that I have met it, is clear that often the therapies applied are limited by the more skeptical parent.  There really are no therapies that everyone agrees on.

So it is no surprise that sometimes my wife doubts the value of the therapies I am sharing in this blog.  She would far rather have a homeopathic wonder cure, than use drugs or ABA.  I saw today as an opportunity.  Monty, aged 10 with ASD, had been up half of the night with a virus and his Mum said "don't give him any of your medicines"; "OK" I replied.

By 2pm Monty was in an increasingly bad mood, frustrated,  exhibiting obsessive repetitive behaviours and showing warning signs of mild self injury.

So I mixed him up a Peter cocktail (1.2g NAC, 10 mg atorvastatin and 1mg of bumetanide) in orange juice.  Within 10 minutes things started to change.  Facial expression switched from anger to contented and, most telling of all, he sat at the piano and started to play.  I could not have hoped for a better result. 

After an hour I asked Mum, if she noticed the transformation.  Yes she had and agreed it was remarkable.


Placebo Effect

It is clear that the more involved the parent becomes, the greater is the risk of seeing what you want to see, rather than what is there.  This why nobody generally listens to parents and indeed why doctors are not supposed to treat their children.

It is always good to have a reality check.

I can now move forward to my serotonin and acetylcholine interventions, in the knowledge that previous interventions have past their critical test.

Placebo Effect in Autism

 

Placebo effect in autism - Parent/Child Matrix      

A big problem in autism research is the placebo effect.  It could be because the child found the therapy fun and liked all the attention and so showed improved behaviors; or it could be that the parents so desperately wanted to see an improvement, that they imagined it.

In good research, half of the kids receives the trial drug and the other half receive a placebo.  But what happens when both groups show an improvement?  Well if both groups show equal improvement then the therapy has no value.  In almost all the research I have seen, the placebo group shows an improvement.  In one study the placebo group improved 70% on the behaviour rating scale.

We need to conclude several things:-

• Good studies rely on assessment by clinicians, not parents
• If the therapy was fun and included lots of 1:1 attention, then the kid's behavior will improve, regardless of the medical value of the therapy.
• Do not reject a study because the placebo group improve moderately
• Always focus on the relative improvement of the group on the trial therapy vs the control group on the placebo.

Behavioural rating scales

In autism there are many different behavioural rating scales, including :-

• CGI (clinical global impression) Physician and Parental version 
• ABC (abherrant behaviours checklist)
• CARS (Childhood Autism Rating Scale)
• ADOS (Autism Diagnostic Observation Schedule)

Researchers can pick and choose which scale to use and which scale to emphasize.  All these scales are highly subjective.  Different people assessing the same child will get a slightly different answer.  The same person assessing the same child a week later will also get a slightly different answer. 

Tiny Studies and Not so Objective Researchers

Many studies in autism have a tiny number of subjects, sometimes fewer than ten. Often researchers have a vested interest in the research, this is not always a bad thing. As a result it is best to focus on research that has been frequently cited by other researchers, this should mean that they buy into it.

Example - Secretin Research

In a 2003 study of the hormone secretin, 62 children participated. At that time there were stories that secretin was a "wonder cure" for autism. Half received a one-off injection of secretin, the other half received a placebo. The clinicians' tests showed that there was no behavioral improvement in either group; the parents however saw things differently. The parents of 48 children saw an improvement. When asked to guess whether their child had received the placebo or the secretin, 27 guessed correctly and 27 guessed wrong. Six families would not guess and two families dropped out.