Bumetanide – Maths Test ✔✔✔ Clinical trial ✖✖✖

 

Memantine, Arbaclofen and now Bumetanide stumble in clinical trials

(also the less well known Balovaptan, which Roche dropped in 2020).

Place your bets on Suramin, anyone?

 

Plus ça change, plus c'est la même chose

The more things change, the more they stay the same

The first week of the school year brought two big surprises. 

Monty, aged 18 with autism, came top of the class in the math test.  This is a big win for bumetanide treatment, because 9 years ago Monty was effectively innumerate.  With a huge effort by his Assistant, he had learnt how to read and write, but even the most basic maths was beyond him.  That all changed in 2012 thanks to Professor Ben-Ari’s published research on Bumetanide in autism.

The sad news that week was that the Phase 3 clinical trial of Bumetanide for autism had been terminated early.  

Servier and Neurochlore announce the main results of the two phase 3 clinical studies assessing bumetanide in the treatment of Autism Spectrum Disorders in children and adolescents

Paris, 7 September 2021 – Servier and Neurochlore announce that no sign of effectiveness was observed in their two phase 3 clinical studies assessing bumetanide versus placebo in the treatment of Autism Spectrum Disorders (ASD) in children and adolescents. As a consequence, Servier and Neurochlore have decided, by mutual agreement, on an early termination of the two clinical studies in progress.

“The results of the phase 3 clinical studies are a major disappointment,” declares Professor Yehezkel Ben-Ari, President of Neurochlore. “Neurochlore’s teams will now analyze in detail the results of the studies and potentially explore new approaches based on artificial intelligence, which may enable us to identify sub-populations of people suffering from Autism Spectrum Disorders, for whom bumetanide could be effective.

 

Bumetanide also did not pass the NEMO clinical trial, as a treatment for neonatal seizures back in 2015.  This then made it a bit awkward to suggest that children with severe autism might lower their risk of developing epilepsy by taking bumetanide. Since this is a blog, I can speculate.  I would imagine children with severe autism, who are bumetanide-responders, and who are treated from early childhood through to adulthood with this drug, will have a low incidence of developing seizures. Seizures develop in about 30% of those with severe autism (DSM3 autism) and are the leading cause of their early death.  

 A Poorly Constructed Trial?

If such an effective therapy shows no benefit in a trial with 400 participants, something has gone seriously wrong.

I did ask one researcher friend, who just replied bluntly that the trial must have been poorly constructed.  I thought that was a bit brutal, even by my standards.

 

Be honest and admit your limitations

Monty, aged 18, came top in maths among 15 neurotypical 16 year olds.  But the 45 pupils in the year had been split into sub-groups. Two groups of 15 taking extended maths and one group of 15 taking core maths.  For some reason, because Monty has autism they put him in the lower group.

Not to worry, after his coming top in the math test, the school agreed that he can move to one of the upper groups taking the wider math curriculum.

So Monty is no maths genius, he came top among the weakest group of typical kids.  That is the whole truth, which is different to the partial truth.

In a similar way, autism researchers need to accept that there may never be a unifying therapy for autism, one that benefits everyone.

Concentrate on the responders to your treatment and forget the rest.  If you over-sell your therapy, you will fail.

As I have said in this blog many times, most people with an autism diagnosis are not bumetanide-responders.  However, a significant minority of those with severe autism are responders to bumetanide and they will experience a transformative benefit.

Going from a basket case to a Maths Whizz even?

 

Apply common sense and don’t outsource everything

In previous clinical trials of bumetanide, critics said it was all a placebo effect because the parents knew when they were giving bumetanide rather than a placebo.  The bumetanide pill causes the diuresis and placebo does not.

Why can you not use a different diuretic as the placebo?  Answer that one!

Many people using bumetanide give up because of the diuresis.  With schoolkids, the parents will receive complaints from school about excessive toilet breaks.  There will be wetting of trousers, car seats etc.  There will be anxiety caused by urgently needing a toilet, when none is nearby.

So you need a strategy in advance of how to deal with the diuresis.

I was told that people in the one trial centre I know about, were told nothing about the diuresis and how to cope with it.  I was even told the clinician basically told the parents that it was a stupid trial.  Not a good way to ensure compliance with the trial protocol.

So what happens? Some parents will decide to stop giving the diuretic drug, at least on school days.  Maybe they think that a “double-dose” at the weekend will make up the difference.

Clinical trials are a business these days and are outsourced to companies that do this and nothing else.  Don't outsource the most critical part of your work, or at least supervise it.

 

Why, oh why, oh why?

I was contacted by a mother from the southern hemisphere who managed to get Bumetanide prescribed by a pediatrician, based on Ben-Ari's earlier publications.  The diuresis is proving a problem for her family, but the positive effects are clear, for example her son now uses the word “Mummy”, but only while taking Bumetanide.  If you are a Mum/Mom, that is a big deal.  He also now responds to his own name and is "more present", the hallmark sign of a bumetanide-responder.

She saw me on YouTube and sent me a long email, including the “why, oh why, oh why?” are more people not giving bumetanide to their child with severe autism.  There is no good answer.

This Mum, now realizing she is not alone, plans to continue Bumetanide therapy.

Good for her!

 

Who dares wins, or at least stands a chance

I was recently sent an email version of an old post I had written on myelination. The sender had read it and convinced her doctor to prescribe her son Clemastine.

Her son has a single gene autism that is known to feature impaired myelination.

I pointed out that in my blog there are many references to therapies shown to benefit different aspects of the myelination process, clemastine is just one.  Some of these therapies are OTC, like alpha lipoic acid (ALA) and the N-Acetyl glucosamine (NAG), that Tyler brought to everyone’s attention.

Is the young man in question going to improve in function taking one or all of these 3 therapies? At least the mother in question is going to give them all a good shot.

Good for her.

 

Conclusion

I have received quite a few comments and messages about the Bumetanide trial failure.  Many are along the lines of “what do we do now?” and “how long will we have to wait?”

It looks like it pays to be an early adopter, rather than having faith that clinical trials will be structured and implemented properly. 

It has been suggested in the research that a large, 10g, daily dose of the OTC supplement TMG (trimethylglycine) may have an equivalent chloride lowering effect to bumetanide.  There is only anecdotal evidence to support this, but it seems to work for our reader Nancy's adult son - good job Nancy!  The other potentially chloride lowering drugs are more difficult to obtain than bumetanide itself.

There likely will never be a single unifying therapy for autism, just like there can never be for cancer.  In both conditions it is all about specific sub-types.

You would think that the previous trial failures in autism would have caused people to learn this important lesson.  

Hopefully, in the future Suramin clinical trials, where two competing companies are using the same therapy, it will not be assumed that everyone must be a responder for the therapy to be valid.  From the data, it does look like Suramin improves symptoms in a significant percentage of those with severe autism; but the same can also be said of Bumetanide, based on the earlier trials

In December Monty will commence his 10th year of Bumetanide therapy. We have made short breaks periodically to check it is still needed. For our case of autism, Professor Ben-Ari clearly got the science right and transformed a little boy's future life, something Ben-Ari can always be proud of. 

Core vs extended Maths? An unexpected dilemma. And yet they say “Autism is untreatable and you should not try to treat it”. Plus Lego

 

This time the “Professor” wears the Dunce’s cap

I had a surprise last month, talking to my son’s 1:1 assistant, this time about maths (or math in US English).

Normally I am trying to simplify school academics, and so if something really is not important, like argumentative writing, I am all for skipping over it.  The idea is that Monty, aged 17 with autism, should focus on useful learning that he has a chance of mastering.

Monty’s international school follows an English curriculum and in that model you have a choice in some subjects of studying the core or the extended version. So a typical child who wants to become a doctor, or an engineer, will have to follow the extended version of all their subjects, but someone who is going to shift boxes in a warehouse might opt for the core/simplified versions. Most people lie somewhere in between.

People with severe autism would not normally follow any of these academic curricula, because it is all way above their heads.  Their school is about life skills and providing day-care, while the parents are out at work, or having some respite. Realistically, “graduation” is often just a photo opportunity - things could and should be better.

There is very little published about literacy and numeracy in severe autism.

I thought an ambitious target for Monty would be to try and sit exams, aged 18, in five subjects, but at the easy level where possible, the so-called “core” version.  These exams are normally taken at the age of 16, which is the minimum school leaving age in the UK.

The maths teacher has been thinking about which of her students should be aiming at core or extended.  She thinks five pupils should be aiming for extended and the others should settle for core.  Monty is one of the group of five.

The assistant was almost apologetic, because she did not want to change my plans for Monty. He is now "too good" for core maths.

I do know Monty’s mathematical abilities very well, because I teach him maths at the weekend.  He is no maths savant, but he works extremely hard and now has a good understanding of what they learn at school. I am just amazed at the other kids, with no disability, who do not keep up with him. Prior to pharmacological autism treatment, starting at the age of nine, Monty could not subtract single digit numbers, like 9 – 2 = 7.

Even more recently Monty’s school assistant proudly announced his results in the half year maths test. He got 68%, making him 3^rd out of the 15 people in class.  68% certainly does not make you an “A student”, but given he was a “basket case” at maths not many years ago, it is truly remarkable. The teacher even told the whole class his score, which you might think would lead to resentment, but the others are actually very supportive. They have seen his progress over the years. They are currently involved in helping him to reliably tell the time. For some people solving algebra is easier than telling the time – who would have thought that?

The other day I skimmed through an article about some Professor who was quoted as saying “Autism is untreatable and you should not try to treat it”. What a fool - more of a dunce than a Professor. 

Literacy and Numeracy Rates in Autism

People rarely talk about literacy or numeracy in autism. I think it is another issue that people do not want to discuss. We would rather hear about people with savant skills, or characters from those TV shows like the Good Doctor, with trivial autism.

It is clear that many people with severe autism currently cannot read or write, so I suppose they are also innumerate.

You can be non-verbal but literate and numerate; there are specific teaching methods.

I was recently asked to present at an autism conference in Russia. I did click on the organisation’s website and I was pleased to see on the first page its message to Russian parents that you can teach people with autism to read and write and indeed that non-verbal kids belong in school. I agree with them, but it may seem like a Herculean task at times.

My last conference presentation was very simple and not controversial, at the request of the US organizer.  Russians like science and they have asked for a long presentation, so they will get the real deal. A big job for the person who has to translate and then dub it into Russian!

 

 Any human brain can be taught to read, write, count

 

One to one teaching, as above in Russia, is the only way to teach those with severe autism.

Reading and writing do matter. Look at the literacy rates by country and guess where you find countries like Afghanistan, Ethiopia, Sudan and Nigeria?

In Afghanistan the male literacy rate is 55% and for females it is 30%.

Even India has 25% illiterate and they tell us it is the world’s largest democracy. In India literacy ranges from about 66% in Andhra Pradesh in the South East to over 95% in Kerala in the South West. In China illiteracy is just 3% and it shows.

In the US 4% are non-literate and the average American adult reads at the 7^th- to 8^th-grade level, i.e. like a 13 year old child; plenty of room for improvement.  The problem is the large group at the bottom who drag down the overall results. This is why countries like Finland do so well in skill assessments; they do not have a forgotten underclass.

  

Why bother with Mathematics?

It is certainly worthwhile reconsidering what to teach people with severe autism. If you cannot cut your own fingernails, or tie your own shoelaces, why do you need to know any maths?

Maths is all about following instructions/rules. If you can follow instructions, you can do maths. Daily living skills are also all about following instructions; before emptying the dishwasher, check the dishes are actually clean! Monty has learnt that lesson.

What do you do when the toothpaste has run out? Find some more and if that does not work, ask for help.

Learning to follow instructions is extremely important to those with learning difficulties; just like practising motor skills helps them overcome their initial challenges with fine and gross motor skills.  In the end, the problems just fade away.

Lego is a great way to combine following instructions with improving fine motor skills. It is a perfect therapy for autism; at the very beginning you can use large bricks to get a young child to replicate simple colour patterns (so-called “block imitation”) by stacking bricks. You can use Lego to develop team skills; one person locates the next bricks, while the other assembles them.

We have a lot of Lego at home, but until recently it was mainly the simple models of planes and helicopters that were of interest to Monty. People would give complicated (expensive) models for birthday presents, when actually what you want are the cheaper, simple ones.

We have now progressed to the point where Monty has completed a model that was intended for people older than himself. All the Lego sets have an age recommendation on them. Yes, Lego has some very complicated Star Wars models meant for those 18 and over.  A Christmas present from big brother, it did have a ridiculous number of pieces (several hundred) and some mistakes were made. 

Monty actually calls it “doing the instructions”, rather than making Lego.

The key seems to be to leave him entirely alone and let him make the occasional mistake.  If a later part does not fit, he asks for help and you then intervene, find the earlier mistake and correct it.  If you hover behind him to prevent any mistake being made, then you are not achieving much.

 

Conclusion

You definitely can treat severe autism, meaning raise IQ and/or improve quality of life.  The evidence is overwhelming and is sitting there in the peer-reviewed science.

It looks like you can avoid/prevent some autism by taking certain steps prior to conception and during pregnancy. This is quite clever.

After birth, can you “cure” severe autism? I think this will only be possible in rare cases, for example correcting an in-born error of metabolism at an extremely young age. One example in this blog was the young Greek boy with biotinidase deficiency, that responds to high dose biotin. Our reader Roger is a rare example of an adult whose central folate deficiency was only treated in adulthood.

You can minimize many troubling features of autism at any age; this applies to Aspies and those with more severe autism.

Learning maths develops much broader skills than might be initially apparent.

Lego is a great activity and a fun therapy.  You can of course re-use it, particularly the most basic sets, which you can use over and over.