Let’s Break it Down-4

dutch-tallship-1245672Well! If the last section was a stormy sea of up and down graphs and whirlpools of numbers, I think we’re in for some smoother sailing now! In the last post, three of the five measurements used in this trial were discussed. So, on to the last two and some clarification on the RSBQ (Rett Syndrome Behavior Questionnaire)


*disclaimer: unless otherwise noted, these are my opinions only.

Other core efficacy measures
The other two core efficacy measures, MBA and Top 3, both showed improvement from baseline in the 200mg/kg group that was larger than placebo (MBA: -2.9 versus -2.6 and Top 3: -18.54 versus -12.52), but the differences were not statistically significant or clinically meaningful.  As an efficacy measure the MBA did not appear to be sensitive to change in this younger population and therefore Neuren intends to use the RSBQ as the primary efficacy measure in a future pivotal trial.  There is evidence that the MBA may be more appropriate as a measure for older age groups.  The MBA instrument was designed and has mainly been used as a measure for long-term observational studies rather than to measure change in short-term clinical trials.

The MBA is Motor Behavior Assessment (MBA), a rating scale in which the clinician rates the subject’s current level of function. This is where the Natural History Study comes in handy, so thank you to everyone who participates in that. It appears from what I read on clinicaltrials.gov that this MBA is actually the Rett syndrome Natural History Motor Behavior Assessment. I found this article: Developmental Delay in Rett syndrome: data from the Natural History Study. The whole article is really interesting, but if you scroll down to tables 1-4 you will see the motor function that was evaluated.

The “Top 3” simply means the top three concerns of the primary caregiver/s.

Basically, both of these measurements showed some improvement at the 200mg/kg dose, but not enough to be considered significant. The Motor Behavior Assessment scale seems to be more suited  to the older group and not sensitive enough for the younger children, especially given that it is usually used in long-term observation studies and not such short trials. Therefore, Neuren intends to use the RSBQ (Rett syndrome Behavior Questionnaire) as the primary efficacy measurement in the Phase 3 Pivotal trial (A pivotal trial is a clinical trial or study intended to provide evidence for a drug marketing approval, e.g. by the United States Food and Drug Administration-from Wikipedia).

Now, finally we get to the Rett syndrome Behavior Questionnaire aka RSBQ.

RSBQ – further information and detailed results 
The RSBQ is a well-validated instrument that has been used in other Rett syndrome clinical trials.  It has been correlated with quality of life outcomes and has been characterized and validated in peer-reviewed publications.  The RSBQ is designed to measure the frequency of 45 neurobehavioral items, reflecting the severity of the syndrome.  The items are rated from 0 to 2, with a score of zero indicating the item is not true for an individual; 1 meaning the item is somewhat or sometimes true in the individual; and 2 meaning that the item is often or very true in the individual.  The items are organized into eight subscales: General Mood, Breathing Problems, Hand Behaviors, Repetitive Face Movements, Body Rocking and Expressionless Face, Night-time Behaviors, Fear/Anxiety, and Walking/Standing.  In this trial the high dose of trofinetide showed a positive effect on many of the items and across these subscales…

What we have here is a detailed list of the things that make our children’s lives and ours a living hell at times. 45 “items”, like they’re just things, like objects in your house. Except chairs and tables don’t make you want to cry almost every day, they don’t scream for hours, they don’t cause you to go without sleep for days. A very euphemistic term, “items”. I think it should be called a list of 45 child stealing thieves, but that’s just me.

I think the above paragraph is pretty self explanatory as far as how the “child stealing thieves” are rated; here’s the graph of the 8 subscales. When you look at it a dot to the left means improvement with Trofinetide, the further to the left the greater the improvement. A dot to the right means improvement on placebo. Now, before people start questioning the last measurement “standing/walking”, I don’t know the answer to your inevitable questions, but it is important to remember NO ONE GOT WORSE IN ANY WAY being on Trofinetide.


Each of these subscales have several questions in each and you can see the breakdown in the full report on page 6. I am going to note some of the things that showed significant improvement, though, because I think these will bring comfort to a lot of parents.

The number one improved symptom was “screaming for no apparent reason at night.” Other significant improvements were seen in screaming overall, breath holding and the ability to grasp among many others. This is really tremendous given the short duration of the trial.  And, before anyone asks about speaking, pointing etc. those are items covered on the Motor Behavior Assessment. Whether those items in particular showed any improvement is not specified in this report, just a general observation that there was some improvement overall, but not clinically significant as mentioned above. That doesn’t mean it wasn’t seen, but that for the younger girls this isn’t a sensitive enough scale and not meant for such a short trial. Don’t get discouraged because talking isn’t in this report, Trofinetide is working to repair the brain and the brain is so complex that it’s incredible that in six weeks any improvement was seen and not just a little improvement but significant improvement.

Dr Kaufmann commented on the RSBQ: “The recent improvements in the care of individuals with Rett syndrome has made evident that affected girls and women display a variety of neurobehavioral problems, and that these symptoms affect their quality of life.  At present, the Rett Syndrome Behaviour Questionnaire (RSBQ), is the only available instrument for evaluating the wide range of abnormal behaviors in Rett syndrome.  An open label trial of IGF-1 demonstrated mild improvements in anxiety and mood, as measured by the RSBQ and another behavior rating scale, supporting use of the RSBQ for detecting improvements in clinical trials.”

Just putting it out there, Katie and I LOVE Dr. Kaufmann. He’s a big fan of Fox!

So, what can we take from this statement? First, the RSBQ is the only available standard for evaluating the abnormal behaviors in Rett syndrome. Secondly, IGF-1 helped, demonstrating improvements in anxiety and mood. Why is that significant? Because Trofinetide is a modified portion of the IGF-1 protein. To me, this reinforces the premise behind the use and effectiveness of Trofinetide. Lastly, Dr. Kaufmann agrees that the RSBQ is an appropriate measurement in clinical trials. And, damn the man is SMART!

Coming into the harbor now. Just one more installment of Breaking it Down to go!



This entry was posted in anxiety in Rett syndrome, Communication, cure, Dr. Walter Kaufmann, hand clasping in Rett syndrome, Neuren Pharmaceuticals, Rett Research, Rett Syndrome, Talking, Trail to a Texas Trial, Trofinetide, Trofinetide Pediatric trial and tagged , , , , , . Bookmark the permalink.

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