Friday, 10 July 2015

Clinical Investigation vs Off-Label Treatment for Autism

Antonio Hardan, the psychiatrist at the Stanford School of Medicine, has published another paper.  Hardan is interesting, he is a clinician rather than a rocket scientist, but he gets involved in a very wide variety of clinical trials, usually of existing drugs that might be effective in autism.

In his latest paper, this time about Glutamatergic Dysfunction in Autism, he highlights the problems with clinical trials:-

·        Heterogeneity of autism

·        Subjective rating scales rather than biological measures.

In other words there is no single autism and there is no good way to reliably measure the efficacy of any drug tested on it.  Consider what that really means.

Hardan really should know about this, just look at the clinical trials he has been involved in:-

So why bother with Clinical Trials?

This may sound like a very unscientific question, but perhaps it is not.  A couple of years ago Roche pulled the plug on Arbaclofen, because it “failed” in its autism clinical trial.  Many parents thought it worked.  Now the Simons Foundation has acquired the rights to the drug and is restarting trials.  How many other trial drugs were prematurely brushed aside?

Many years ago the hormone secretin was put forward as a therapy for autism, particularly for people with GI problems.  Several expensive clinical trials later, it was determined to be ineffective.  But some people continued to rave about it.  Where they all deluded?

The very expensive IVIG therapy has also been put forward as a wonder therapy for autism.  The critics highlight that in studies 90% of people do not benefit and therefore the therapy has little value.  But what if you are in 10% that do respond very well?

Intravenous immunoglobulin treatment of children with autism.


Since autism has been associated with immunologic abnormalities suggesting an autoimmune cause of autistic symptoms in a subset of patients, this study was undertaken to investigate whether intravenous immunoglobulin (i.v.Ig) would improve autistic symptoms. Ten autistic children with immunologic abnormalities, demonstrated on blood tests, were enrolled in this study. Their ages ranged from 4 to 17 years, with two girls and eight boys. Eight children (1 female and 7 male) historically had undergone autistic regression. Intravenous immunoglobulin, 200 to 400 mg/kg, was administered every 6 weeks for an intended treatment program of four infusions. In five children, there was no detectable change in behavior during the treatment program. In four children, there was a mild improvement noted in attention span and hyperactivity. In none of these children did the parents feel that the improvement was sufficient to warrant further continuation of the infusions beyond the termination of the program. Only in one child was there a very significant improvement, with almost total amelioration of autistic symptoms over the time period of the four infusions. Once the treatment program was completed, this child gradually deteriorated over a 5-month time period and fully reverted to his previous autistic state. In this treatment program, five children had no response to intravenous immunoglobulin. In the four children who showed mild improvements, those improvements may simply have been due to nonspecific effects of physician intervention and parental expectation (ie, placebo effect). However, in one child there was a very significant amelioration of autistic symptoms. There were no distinguishing historic or laboratory features in this child who improved. Given a positive response rate of only 10% in this study, along with the high economic costs of the immunologic evaluations and the intravenous immunoglobulin treatments, the use of intravenous immunoglobulin to treat autistic children should be undertaken only with great caution, and only under formal research protocols.

Just in this blog, which is amateur and not intended as a rigorous scientific review, we have seen numerous “rare” conditions that lead to “autism” that are actually treatable.

If you add up all these “rare” conditions you get a sizeable proportion of all the autism, diagnosed in those under four years old (i.e. more severe autism).

Clinical Investigations

If you accept that the initial autism diagnosis really tells very little, then you are left, like Hardan, testing all sorts of clever ideas on a trial group of kids who may have one to several, of thousands of discrete dysfunctions (CNVs etc.).

Then if you get a 10% response rate, you are doing great.

If you target something like oxidative stress, that is caused by hundreds of those thousands of discrete dysfunctions (CNVs etc.), then your odds of success shoot up.  This was the case in Hardan’s trial of N-acetyl cysteine.

Hardan is now going to trial oxytocin on kids with autism, but this idea has already been well and truly “trashed” by highly respected mainstream doctors.  They do this because they think autism is something easy to define and measure like high blood pressure.  If it is therapeutic in 10% of cases, that is great.

Quacks, Off-label and Clinical Investigations

I think it is great that Hardan can try all these drugs at Stanford and nobody even thinks of calling him a quack.  The same applies to a small number of inquisitive doctors at Johns Hopkins and Boston Children’s Hospital.

It would be interesting to know how Hardan treats his patients with ASD, who are not enrolled in a clinical trial.  Does he prescribe off-label? 

It is clear that most doctors in developed countries will run a mile/kilometer at the idea of treating somebody off label.  They fear being struck off/sued/ridiculed.

We had the UK pediatrician commenting on this blog that Baclofen was effective in 70+% of her/his patients with anxiety plus Asperger’s, but did not feel happy to continue prescribing it without some supporting evidence from elsewhere.  The fact that it was safe and effective was not enough.

Many of the tiny number of off-label doctors really do look like quacks to me, so I can understand the concern of mainstream doctors not to want to be associated with them.

What is the, scientifically well-briefed, parent supposed to do? (if self-treating is not an option)

I think there should be a way where you can enroll your child in a “clinical investigation”, where you accept that all the treatments are experimental and therefore have a higher level of risk than normal.  You waive your right to sue the doctor, or the hospital.  You can opt out of up to 10% of the therapies, based on valid concern.  For example, you might think IVIG is not safe.

You then enter a program in which all your child’s data can be used for research purposes.  So you agree to have to have EEGs, scans, genetic testing, spinal tap/lumbar puncture, blood tests, urine tests, hair tests etc.

The child is completely profiled and material is stored for possible further analysis later.

All known tests are then carried out, even obscure things like biotin deficiency, creatine deficiency and those amino acids we saw that triggered rare autism.

Then you go through all of the therapies known to be effective in some people.  So it includes memantine, IVIG,  donepezil, bumetanide, oxytocin, propranolol, baclofen, arbaclofen, even Zyrtec, NAC, D-Cycloserine, carnosine, carnitine, pancreatic enzymes, probiotic bacteria  etc.

The whole process would take a year.  If you treated 1,000 children you would then have a wealth of data.

You might have individually rare disorders totaling 15% of cases and then several clusters where the same drugs were effective in sizeable groups of children.  Then you would be able to look back in the data for the biomarkers of each cluster.

Then you would write a smartphone app for doctors to treat autism.  They would input the various biomarkers requested and out would come the suggested drug therapy recommendation(s).  So it would be a “guided off-label” approach where the doctor knows that the recommendations are “scientifically supported” but may not be perfect.

We just need the Simons Foundation to sponsor it! 

If you think it might be too expensive, just remember that at the recent international autism conference in Utah, there were 2,000 scientists and researchers in attendance. What exactly have they achieved, in practical terms, in the last 10 years and are likely to achieve in the next 10 years?

It does seem that some view success as diagnosing ever more people with "autism", so that they can receive "services", when they really should be diagnosing specific biological dysfunctions.

It is not an easy task, but you do not need 2,000 researchers.  You just need 20 pragmatic people to review the data and make a decision tree showing how to choose the 5 drugs most likely to help a particular person, based on their specific biomarkers.  

I guess that would leave 1,980 people with not much to do. 


  1. For me its very frustrating to see the lack of consistency and follow up on the research we generally see in autism.
    One way of getting real advances and consistent data would be simply perform the full screening on the respondents to the treatments. This would provide the necessary support the medical community needs for prescription off label, and also allow for improvements on experiment design for future works.

    But going with your suggestion, if you decide to venture the project and go with crowdfunding you have my pledge.

    1. If there was a serious attempt to treat autism much could be achieved, but it looks unlikely. There are so many crank therapies, all interventions are treated as such. To change mindsets you would need 100 percent proof, this is impossible since there are very many types of autism.

  2. It seems that the biggest mindset that needs to be adjusted is that ASD is a singular condition. A 10% success rate may not seem much but it could be that the subset in which a particular approach is effective might only be 10-15% of the ASD population - a huge win for that sector!

    1. Very true. Part of the problem is the use of the word "autism". It is the equivalent of saying you have a headache, it might be a brain tumour or it might be the flu. If you exhibit autism, the next question should be why and is it serious enough to be disabling. If it is disabling, it should be treated as a serious neurological condition and the sub-type established, and treated.

  3. "You waive your right to sue the doctor".

    That's the problem. There's no way of doing that which would inspire confidence in the prescibing doctor! The USA is a litiginous country. It's citizens would find their way round that one whatever they had signed as soon as anything went wrong. The UK is going the same way.

    Also, if something goes wrong, it's not just the family who are entitled to pursue their doctor - if a child dies or suffers harm, the General Medical Council (in the UK) & the equivalent organisation in the USA will be right on the doctor's back, no matter what rights have been waived. Unless there has been a registered randomised controlled trial with all the legalities ticked, or there is a body of evidence that other doctors approve the use of this drug in similar circumstances, that doctor is for the high jump.

    Sad realities, I know. The idea has great appeal otherwise.

    1. I was rather shocked how fearful UK doctors are of the GMC. Where i currently live the doctor will prescribe what you want, if you have a good reason for it. I even obtained an orphan drug from Japan by explaining to the Japanese doctor why I thought it would be effective. By contrast my UK doctor sister would not prescribe a particular antihistamine, but i obtained it freely in Italy.

      So I do not expect any innovations in autism to come from the UK, which is a pity.

  4. I just want to applaud you for this post, very well said.

  5. There is a nice case report about off-label Bumetanide treatment in a girl with autism from the Netherlands:

    Published in an official journal of the American Academy of Pediatrics, so it could be another helpful paper for parents or doctors looking for the way to prescribe the drug.

    The authors applied for local ethics committee before starting Bumetanide. One top neurologist in my country successfully treating kids with intractable epilepsy with medical marijuana drugs did not do this and has just been banned from prescribing these drugs in a tertiary center. Neither of his patients experienced any problem and apparently it’s a matter of personal conflict there, but parents say they are left without drugs now as they have no other doctor experienced with this kind of treatment. Luckily, you can’t smoke Bumetanide, so at least there are no such emotions about this...

    I am currently increasing the dose of Bumetanide (turned out that my son needs 1400 mg K daily to reach potassium blood level>4.5). What time do you give the second dose of Bumetanide - in the evening or earlier? I wonder if one need to have a stable level of the drug 24h or it's better to give it during the day only.

    1. I aim to give the second dose about 5.30pm, sometimes a bit later

      The problem is the diuresis, so it is not wise to give it within 2 or 3 hours of bed time. One reader with a child not toilet-trained, stopped using it because of this reason. Ben Ari did tell me that they would like to make an analog of bumetanide that did not cause diuresis, but this would cost many millions of dollar/euros.

      The half life is quite short so you cannot really achieve a stable level. It appears to need a sharp increase to have much effect, rather like the potassium.

      More and more people are telling me that their child responds to bumetanide and even people with extremely rare single gene types of autism.

      If you want another thing to trial to improve cognition, I suggest cinnamon.

    2. Thank you. I’ve read that for more “usual” indications the second dose is recommended 6-8 hours after the first and with 0,5mg I gave it at 2 PM, but it may be too much with higher dose.

      Few months ago my son experienced some problems with bladder control and to my surprise it was increasing the dose of bumetanide that apparently helped then. Maybe with more awareness it was also easier for him to control urination? Of course there can be many reasons for enuresis, so it may not apply to other kids.

      Anyway, diuresis is a nuisance for some kids on bumetanide, so it would be good to have a drug without this effect. Many millions of dollars are already spent on autism....

      My son is free from his headache/channelopathy attacks for last 3 months, so I can now think about new treatments. A bit challenging to add another drug to his 6 (not including K, intranasal antihistamine and broccoli). Cinnamon effects you described are very encouraging, thanks for sharing them. Very surprising about such common thing as cinnamon... just as treating urinary incontinence with a diuretic was a surprise to me. In my son many things point to mitochondrial dysfunction, although he is not typically regressive, so I am also researching this now.

    3. The number of pills does become a challenge. One mother who followed Dr Kelley's therapy for mitochondrial disease just too bothersome, produces her own all in one product.

      Many millions have been spent on autism, but not very wisely in my opinion. It would make sense for a big drug firm to produce and patent the bumetanide analog. Then they can charge a premium over regular bumetanide (which is very cheap where I live) but vigorously promote it worldwide. However, big pharma is actually opposed to what Ben Ari is doing. Very disappointing and more reason to develop your own solution at home..

  6. My sons was admitted to the hospital on his third birthday for ITP. The next day he was given IVIG. That evening he looked me in the eye and sustained eye contact for more than a minute. I'm not used to getting more than a second of eye contact from him. I told the nurses on duty, the doctor, the doctors who "treat" his autism and anyone else who would listen and they just ignored it. There's no way it was just a fluke. Since he regressed at 15 months it's the only time he's given me more than two straight seconds of eye contact. He's eight now...

    1. Here is a study from 2018 that may be of interest to you and your doctors:-

      A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation.

      Significant improvements from baseline to study endpoint were observed in several subscales of the CCC-2, SRS, CGI-I, CGI-S, and ADOS, including Associated Maladaptive Behaviors (P ≤ .043), Reciprocal Social Interaction (P = .015), Communication (P < .001), and Stereotyped Behaviors and Repetitive Interests (P ≤ .013). Statistically significant reductions were also seen in numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation. IVIG was well tolerated.


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