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.

rsbq

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!

 

 

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 | Tagged , , , , , | Leave a comment

Let’s Break it Down-3 (Tipping the Scales)

So, here we go. I struggled with this section because of the graphs and numbers. There may be many of you who go…”What’s the big deal, so easy to understand!” Me, to say I’m good at math would be stretch and I wanted to be sure that I understood. So, I went to a researcher, sweet man gave me SO much more credit of possibly understanding his answer than I deserved. Thank you, you know who you are! Not wanting to bother him again (or show my severe lack of understanding to someone I respect)  next, I tried a statistic’s teacher that I did a trial presentation for, no answer. Undeterred, I went straight to the UCLA Statistics Dept. and after some back and forth with Dr. Li, Assistant Professor Applied Statistics and Statistical Modeling, as well as their interface with Statistical Genomics, Bioinformatics, and Computational Biology, I came to have a very basic understanding, but one she said was correct! So, now on to Part 3!

Key outcomes from the trial:
82 subjects were randomized into the following groups: 24 to placebo BID, 27 to 200mg/kg BID, 16 to 100mg/kg BID and 15 to 50mg/kg BID.  The mean and median age, weight and BMI did not differ significantly between the four groups.
The pre-specified efficacy analyses prioritized 5 core syndrome-specific measures:

1. The RSBQ, a rating scale in which the subject’s caregiver rates the frequency of symptoms.

 2. The CGI-I, in which the clinician rates how much the subject’s overall illness has improved or worsened, relative to baseline. 

3. The RTT-DSC, in which the clinician assesses on a visual analog scale the severity of concerns identified for each subject on an individual basis. 

4. The Motor Behavior Assessment (MBA), a rating scale in which the clinician rates the subject’s current level of function.   

5. The Caregiver Top 3 Concerns (Top 3), in which the subject’s caregiver assesses on a visual analog scale the severity of concerns identified for each subject on an individual basis.

The first three of these measures each demonstrated improvement for the highest dose, compared with placebo, which was both statistically significant and clinically meaningful.  The improvement increased throughout the course of treatment right through to the time that treatment ceased.  This suggests that further benefit may be achieved with even longer treatment duration.  Some regression of benefit was observed after treatment ceased.  These results are illustrated in the following charts, in which a downward movement represents an improvement from day 14 baseline:  (graphs should be here, but I think they would just confuse the issue and I couldn’t get them to transfer over, but you can view them on page 3-4 of Neuren’s announcement)

22% of subjects in the 200mg/kg dose group received a CGI-I score of 2 (“much improved”) compared with 4% of subjects in the placebo group.

The mean (lsmean) improvements at day 54 for the 200mg/kg and placebo groups were, respectively, 16% and 6% of the day 14 baseline.

(Only the first three core measures will be discussed in this post) So, here we go…
82 subjects were randomized into the following groups: 24 to placebo BID, 27 to 200mg/kg BID, 16 to 100mg/kg BID and 15 to 50mg/kg BID.  The mean and median age, weight and BMI did not differ significantly between the four groups.

Easy! Of 82 participants-24 got the placebo twice a day; 27 got 200mg/kg (200mg per kilogram a kilogram being 2.2 lbs) twice a day; 16 got 100mg/kg twice a day and 15 got 50mg/kg twice a day. The rest means that if you averaged in age, weight, and BMI (Body Mass Index) it didn’t really favor one group over the other.

The pre-specified efficacy analyses prioritized 5 core syndrome-specific measures:

Pre-specified efficacy means that before the trial even started they set goals which, if reached, would show efficacy.

1. The RSBQ, a rating scale in which the subject’s caregiver rates the frequency of symptoms.

The Rett Syndrome Behavior Questionnaire is a recognized standard of 45 questions rated by the parent.

 2. The CGI-I, in which the clinician rates how much the subject’s overall illness has improved or worsened, relative to baseline. 

The Clinical Global Impression – Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the participant’s illness has improved or worsened relative to a baseline state at the beginning of the intervention. and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.

3. The RTT-DSC (Rett Syndrome Domain Specific Concerns Visual Analog Scale), in which the clinician assesses on a visual analog scale the severity of concerns identified for each subject on an individual basis. Discussed in the last post

The first three of these measures each demonstrated improvement for the highest dose, compared with placebo, which was both statistically significant and clinically meaningful.  The improvement increased throughout the course of treatment right through to the time that treatment ceased.  This suggests that further benefit may be achieved with even longer treatment duration.  Some regression of benefit was observed after treatment ceased.  These results are illustrated in the following charts, in which a downward movement represents an improvement from day 14 baseline: 

So, this paragraph is GREAT NEWS! The RSBQ score, the CGI-I score and the RTT-DSC score all showed improvement. The improvement increased throughout and up to the time treatment ceased; which means that a cap on improvement was not discovered and that longer duration of treatment MAY see an even greater improvement in function. It also shows that, without Trofinetide, regression to baseline began (and presumably eventually the children returned to baseline) While this really sucks, it is still a great indicator that Trofinetide worked.

The mean (lsmean) improvements at day 54 for the 200mg/kg and placebo groups were, respectively, 16% and 6% of the day 14 baseline.

Now, for the part I was stuck on. What is an lsmean?? and how could a numeric decrease translate into a % increase. Turns out lsmean is a fairly complicated calculation of least squares mean and in my opinion and determination the exactness of how this is achieved is not relevant to our understanding of the results.

The graphs (not pictured) show a negative number and yet indicate a substantial improvement. So, this was the question I posed to Dr. Li….

So, IF a numeric scale is used to show a negative effect for example “severity of screaming” and that initially gets a “2” but then goes DOWN to “1” this is a DECREASE in measurement that ultimately shows an INCREASE from baseline toward “normal”?

scales-of-justice-clip-art-lady-tattoo-clipart-best-clipart-best-Xq22G6-clipartAnd she said that my understanding was correct. That is why I titled this post “Tipping the scales”. Picture the Scales of Justice, as one side goes down… the other side goes up, finally in our favor!

And you may ask why compared to day 14, because that was how long the placebo lead in, in all groups, lasted and is the true baseline.

22% of subjects in the 200mg/kg dose group received a CGI-I score of 2 (“much improved”) compared with 4% of subjects in the placebo group. This is self-explanatory.

The group analysis of RTT-DSC was carried out using the Exact Median Test rather than the Least squares Means that were calculated for the other four core endpoints.  This was because the Statistical Analysis Plan pre-specified that if the data for a measure did not meet statistical assumptions of a general linear model, then a non-parametric analysis method would be used.  Standard error limits are not applicable in the Exact Median Test and consequently are not presented on the bar chart.
The median improvements at day 54 for the 200mg/kg and placebo groups were, respectively, 15% and 5% of the day 14 baseline.

Basically, the RTT-DSC used a different measurement because it could not correctly be represented by the other. Regardless, it shows a similar percentage of improvement for both the placebo and the 200mg/kg dose of Trofinetide.

Whoa! Glad that part is over!!! If there is anyone out there who can explain it better, please let me know and I will happily defer and edit!

Posted in Neuren Pharmaceuticals, Trail to a Texas Trial, Trofinetide, Trofinetide Pediatric trial, ucla statistics dept., Uncategorized | Tagged , , , , , | 2 Comments

Let’s Break it Down-2

neurenSo, the last post gave a rundown on the summary, now we’ll get into the nitty gritty! Let’s break down the next section:

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

The Phase 2 trial was conducted at 12 sites in the United States, led by clinicians experienced in the diagnosis and treatment of Rett syndrome and supported by Rettsyndrome.org.  This trial in a younger population built on the results of Neuren’s Phase 2 trial, completed in 2014 and conducted in older subjects aged 16 to 45 with Rett syndrome, which showed consistent trends of clinical benefit.  The current trial design incorporated a number of refinements and additional features:  Two new measures were included as core efficacy measures – the RSBQ and the Rett Syndrome Domain Specific Concerns Visual Analog Scale (RTT-DSC).  The RSBQ has previously been used as a key efficacy measure in two clinical trials in younger girls with Rett syndrome, which were conducted at the Boston Children’s Hospital, with data on the first trial published in 2014.

 The excellent safety and tolerability profile enabled the highest dose group to be increased from 70mg/kg BID to 200mg/kg BID.  The duration of treatment was increased from 4 weeks to 6 weeks.  Notwithstanding the increase, this remained a trial of short duration for a disease-modifying agent in a syndrome with severe and complex features.

 All subjects completed a single blind period of 14 days on placebo prior to commencement of randomized treatment.  Efficacy measurements were taken on day 14, during randomized treatment on days 28, 42 and 54 as well as post-cessation of treatment on day 66.  Changes in efficacy measurements were calculated compared with the measurements taken on day 14, at the end of the placebo run-in.

The Phase 2 trial was conducted at 12 sites in the United States, led by clinicians experienced in the diagnosis and treatment of Rett syndrome and supported by Rettsyndrome.org.  This trial in a younger population built on the results of Neuren’s Phase 2 trial, completed in 2014 and conducted in older subjects aged 16 to 45 with Rett syndrome, which showed consistent trends of clinical benefit.  

This section is pretty self-explanatory. 12 sites, experienced clinicians and built on the results of the Phase II (the Pediatric trial is a IIb trial). Of note, just a small reference to the successful adult trial here…”which showed consistent trends of clinical benefit”.

The current trial design incorporated a number of refinements and additional features:  Two new measures were included as core efficacy measures – the RSBQ and the Rett Syndrome Domain Specific Concerns Visual Analog Scale (RTT-DSC).  The RSBQ has previously been used as a key efficacy measure in two clinical trials in younger girls with Rett syndrome, which were conducted at the Boston Children’s Hospital, with data on the first trial published in 2014.

Well, isn’t all that a mouthful! What the “number of refinements” are don’t appear to be enumerated. Most likely, in my opinion, whatever they are came about at least in part after talks with the FDA after there seemed some dubious concerns about how the results were represented to the FDA for breakthrough designation (whopping big ERROR on their part, in my opinion, which no, I will probably never really let go of, thanks a lot FDA). So, that leaves what ARE the RSBQ and the RTT-DSC.

The RSBQ is the Rett Syndrome Behavior Questionnaire, “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.” More on this later!

The RTT-DSC means Rett Syndrome Domain Specific Concerns Visual Analog Scale. A visual analog scale is  “a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. When responding to a VAS item, respondents specify their level of agreement to a statement by indicating a position along a continuous line between two end-points.” (taken from Wikipedia)  So, it’s like the very common pain scale you see in doctors’ offices.

pain scale.png

So, for this trial specific Rett related questions were asked and then judged by how much the observer agreed with the statement.

The RSBQ is rated by the caregiver; the RTT-DSC is rated by the clinician.

The excellent safety and tolerability profile enabled the highest dose group to be increased from 70mg/kg BID to 200mg/kg BID.  The duration of treatment was increased from 4 weeks to 6 weeks.  Notwithstanding the increase, this remained a trial of short duration for a disease-modifying agent in a syndrome with severe and complex features.

Whew, an easy paragraph! In the adult trial the highest dose given was 70mg/kg BID (twice a day), in the pediatric trial the highest dose was 200mg/kg BID. The duration of treatment in the adult trial was 4 weeks, in the pediatric trial 6 weeks. Of note, that despite a two week increase this was still a short trial.

All subjects completed a single blind period of 14 days on placebo prior to commencement of randomized treatment.  Efficacy measurements were taken on day 14, during randomized treatment on days 28, 42 and 54 as well as post-cessation of treatment on day 66.  Changes in efficacy measurements were calculated compared with the measurements taken on day 14, at the end of the placebo run-in.

The first sentence means that every participant got 14 days of placebo, single blind means that the physicians knew this but the parents did not. On day 14 baseline measurements were done and the same measurements were taken on days 28, 42 and 54 all during actual dosing and then a post-cessation of treatment on day 66.  Measurements done on days 28, 42, 54 and 66 were compared to the day 14 baseline measurements.

And that is plenty for today!

Posted in Neuren Pharmaceuticals, Rett Research, Rett Syndrome, Trail to a Texas Trial, Trofinetide, Trofinetide Pediatric trial, Uncategorized | Tagged , , , , , | 2 Comments

Let’s Break it Down-1

 

trofinetide

Trofinetide

So, the Rett Community has had a couple of days to digest the BIG news-Trofinetide showed clinically significant improvement in the Pediatric Trial. Then we read the announcement, full of graphs and numbers and a lot of us went… what the hell is all that?!?

 

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

So, lets start with this summary:

Melbourne, Australia, 22 March 2017: Neuren Pharmaceuticals (ASX: NEU) today reported top-line results for its Phase 2 clinical trial in girls with Rett syndrome aged 5 to 15.  Rett syndrome is a serious and life threatening condition caused by a gene mutation, for which there are currently no approved treatments.
Neuren’s trial was a double-blind, randomized, placebo controlled study that tested three doses of trofinetide compared with placebo in 82 subjects.  The highest dose of trofinetide achieved statistically significant clinical benefit compared with placebo for each of three syndrome-specific efficacy measures, the Rett Syndrome Behaviour Questionnaire (p=0.042), the Clinical Global Impression of Improvement (p=0.029) and the Rett Syndrome Domain Specific Concerns (p=0.025).  These measures included assessments of both clinicians and caregivers.  Clinical improvements of 15% to 16% from baseline were observed, which was considered by leading Rett syndrome physicians to be clinically meaningful, particularly in a short duration trial.  The improvement increased through to the time that treatment ceased.  This suggests that further benefit may be achieved with longer treatment duration.
These results provide strong evidence of biological activity of the high dose across multiple symptom areas, indicating the potential for disease modification rather than simply addressing isolated symptoms.  In addition, trofinetide was well tolerated and had a good safety profile in these younger subjects, with no dose-limiting effects observed.

Neuren’s trial was a double-blind, randomized, placebo controlled study that tested three doses of trofinetide compared with placebo in 82 subjects.

Double-blind means neither the parents nor the doctors know which patients received the placebo vs one of the actual dose levels.

The highest dose of trofinetide achieved statistically significant clinical benefit compared with placebo for each of three syndrome-specific efficacy measures, the Rett Syndrome Behaviour Questionnaire (p=0.042), the Clinical Global Impression of Improvement (p=0.029) and the Rett Syndrome Domain Specific Concerns (p=0.025).  These measures included assessments of both clinicians and caregivers. 

For this I went to an expert. I’ll explain the three syndrome-specific efficacy measures in the next post. So, I asked what does (p and the numbers following mean)-here’s the explanation I got:

The p-value is an indication of the confidence that you have that the result obtained was a real result and not just one that occurred by chance or dumb luck.
It’s an indication of the reliability of the results.  For therapeutic intervention studies, any p-value below 0.05 is considered statistically significant.  Another way of looking at it is to say that at p=0.05, we are 95% confident that the result is real (or alternatively, there is only a 5% chance the result was due to chance).
 
p-values don’t indicate the size of the effect (the comparison between drug and placebo on a particular measure) but just that whether what we’re seeing is a true result or simply down to chance. 
 
There is a link between p-value , the number of subjects in your sample and the clinical effect size (difference between active and placebo for your measure). Since we had small sample sizes (For placebo, n= 24 and for 200mg/kg,  n = 27) and yet we still showed statistical significance across 3 measures, must mean that the clinical effect(or benefit) was large in each of the measures.
 
As an example, if you have a 2 drugs to treat high blood pressure, one lowers your BP by, say 5mmHG and the other lowers it by 50mmHG, you need a much larger sample size to show a statistically significant effect for the first drug than you would to show a statistically significant effect for the second. In other words, it’s easier to obtain a 5mmHg drop just by random chance than it is to show a 50mmHG drop.
 
In the paragraph you mention, this means that for the RSBQ measure (for eg), there is only a 4.2%   chance the result is down to luck,  and so  on for the other measures.

 

Clinical improvements of 15% to 16% from baseline were observed, which was considered by leading Rett syndrome physicians to be clinically meaningful, particularly in a short duration trial.  The improvement increased through to the time that treatment ceased.  This suggests that further benefit may be achieved with longer treatment duration.

So, a couple of important things here. 1. With the highest dose of 200mg/kg there was a 15%-16% improvement in only 6 weeks. HUGE. That’s between 1/6 th and 1/7th improvement. In my opinion…WOW. 2. The longer they were on it, the more improved they became. That means it’s possible that an even greater improvement will be seen when participants are on it longer! This tells me that a “cap” on improvements hasn’t been seen yet, which is super exciting. Where will the “cap” be??? Don’t know yet. Exciting stuff! The third phase may give us the answers or maybe only the actual use for years will tell us if a cap is reached before “normal” or not. Exciting times we are living in, here.

These results provide strong evidence of biological activity of the high dose across multiple symptom areas, indicating the potential for disease modification rather than simply addressing isolated symptoms.  In addition, trofinetide was well tolerated and had a good safety profile in these younger subjects, with no dose-limiting effects observed.

This reads, to me, that multiple symptoms were improved per person. This leads researchers to believe that Rett syndrome’s course can be modified rather than just addressing one symptom here and there. Again, HUGE news. Trofinetide was found to be safe and no side effects and again, no dose-limiting effect (meaning a place where improvement plateaued; improvement continued throughout the entire trial).

Watch for further installments!

 

Posted in cure, Neuren Pharmaceuticals, Rett Research, Rett Syndrome, Trail to a Texas Trial, Trofinetide, Trofinetide Pediatric trial, Uncategorized | Tagged , , , | 2 Comments

…And Slam Dunk Pulls Ahead of the Pack to Win by a Mile!!!

secretariat1It wasn’t even a photo finish!

Neuren’s trial was a double-blind, randomized, placebo controlled study that tested three doses of trofinetide compared with placebo in 82 subjects.  The highest dose of trofinetide achieved statistically significant clinical benefit compared with placebo for each of three syndrome-specific efficacy measures, the Rett Syndrome Behaviour Questionnaire (p=0.042), the Clinical Global Impression of Improvement (p=0.029) and the Rett Syndrome Domain Specific Concerns (p=0.025).  These measures included assessments of both clinicians and caregivers.  Clinical improvements of 15% to 16% from baseline were observed, which was considered by leading Rett syndrome physicians to be clinically meaningful, particularly in a short duration trial.  The improvement increased through to the time that treatment ceased.  This suggests that further benefit may be achieved with longer treatment duration.
These results provide strong evidence of biological activity of the high dose across multiple symptom areas, indicating the potential for disease modification rather than simply addressing isolated symptoms.  In addition, trofinetide was well tolerated and had a good safety profile in these younger subjects, with no dose-limiting effects observed.

And some commentators’ remarks on the brilliant finish…

 Dr Kaufmann commented:
“The outcome of this trial is very encouraging.  Safety, the primary goal, was achieved.  As important and with broad implications, there was a clear clinical improvement covering several common symptoms in Rett syndrome, which are known to impair the quality of life of girls affected by the disorder.  The variety of improved symptoms suggests that trofinetide is a drug that targets mechanisms underlying the disorder rather than a symptomatic medication.  Similar to the previous adult trial, the results are particularly significant because of the relatively short duration of the trial.  The impact of the study goes beyond the suggested efficacy of trofinetide, since it shows the potential of neurobiologically-based drugs for the treatment of Rett syndrome and other neurodevelopmental disorders.”
Alan Percy, MD, Professor of Neurology and Director of Clinical Neuroscience at the Civitan International Research Center & Sparks Clinics, The University of Alabama at Birmingham, was an investigator for this trial and for Neuren’s previous trial in adults and adolescents with Rett syndrome. :
“The clear results from this trial of trofinetide in children support and strengthen the promising results that were obtained in the Neuren trial in older individuals with Rett syndrome.  I now look forward to the pivotal trial.” 
Steve Kaminsky, PhD, Chief Science Officer of Rettsyndrome.org commented:
“These pediatric study results are very exciting.  The data suggest that trofinetide is having a positive change on a number of challenges of Rett syndrome.  We at Rettsyndrome.org are very proud to have supported this game-changing study, believing that the best is yet to come.”  
What a race! What a finish!!! Bring on Phase III.
Hooray!!!!
And to Margaret Brimble and her team: we all owe you a debt so profound to our hearts as the earth owes the sun.
Posted in Neuren Pharmaceuticals, Rett Research, Rett Syndrome, rettland.org, rettsyndrome.org, Trofinetide, Trofinetide Pediatric trial, Uncategorized | Tagged , , | 2 Comments

T-?Minutes: Musing 3-Down to the Wire

horse raceWell, we’re down to the wire now. This race of results is coming to an end. What a wild ride the last few days have been for the Rett community. Time to stand up and peer down the final stretch. The horses have all rounded the curve and they’re coming in hot. So, who will win? The one with 81 jockeys called “Slam dunk”? or the one called “Not so Great” or “Not too bad”?

I don’t know if it’ll be Slam Dunk or Not too bad, but I’m fairly certain Not so Great will be left in the dust. What a race it’s been. Straight outta the gate we could tell it was going to be a show stopper. So many hopes are riding on it. We’ve got our betting cards out. Did we guess right? Whatever the results, I want to thank EVERYONE-parents, researchers, rettsyndrome.org, rettland.org, Neuren and it’s stockholders-for laying their money down and betting on the outcome we’re hoping for. You all made this 2nd race of the Triple Crown possible.

The tension is almost like thunder in my ears; like hooves pounding in the dirt-that’s my heart. Come on, Slam Dunk. Come on, bring it home.

Posted in Neuren Pharmaceuticals, Rett Research, Rett Syndrome, rettland.org, rettsyndrome.org, Trail to a Texas Trial, Trofinetide Pediatric trial, Uncategorized | Tagged , , , , , | 2 Comments

T-?Hours: Musing 2-The Stuff of Dreams

imageSo, the results didn’t come out today. Bummer, that. Well, then, it’s just another sleep and a wakeup give or take. So we all get to sleep on it.

I’m not worried about tomorrow; I’m certain that, no matter what it shows, there will be a Phase III, which will be longer and since it will contain both younger girls and women will be a good gauge of how it might be affecting them differently. Say for instance that the Pediatric trial doesn’t show a huge recovery of skills, well maybe that’s because they aren’t as far gone in the younger group as in the older group and they have less to recover. Or, maybe it’s because their brains are still developing around the age of 5/6, so there are other factors in play than in the older group which has reached a more “chronic” than “acute” level. That would be important to find out. Maybe they’ll learn that IGF1 is better for the girls up to a certain age and then Trofinetide should be brought in. Maybe it’s a slam dunk! Who knows. But, I’m not worried.

The brain is such a mystery; what we learn most about discoveries dealing with the brain is that there are more mysteries than we thought. And one of those mysteries, to me is a dream. I’ve heard the dream you think is hours and hours long is a mere few seconds, a blink of the eye. That seems crazy to me. But, if you had told me twenty years ago that one day someone named Margret Brimble would figure out how to repair/partially repair the Rett brain, I would’ve said that’s crazy, too.

That is just the sort of crazy dreams of all sorts are made of, though. Did I really believe I would be a published author? Hell, no. Just a crazy dream. Did I believe all those years ago, that I could be a single parent and do it well enough that my other two are on their own, supporting themselves AND they still talk to me? Hell, no. I hoped, but I was far from sure. And did I have the audacity to dream, those twenty years ago, that my girl would regain her hand use to a good extent, that I would hear the word “mommy” every day after the age of 7, that I could give my Katie a full life with friends, surrounded by family and adventures to remember?…I did. I had that audacity. The biggest dream of all and I believed it. That’s crazy, huh. And yet, here we are.

Now, I have the audacity to actually BELIEVE that Rett syndrome is going to be, in the life of all our girls and boys,  soon like how they say dreams are…seemingly an eternity yet just a mere bit of time and then it will be gone.

That will be the Stuff of Dreams tonight.

Posted in boys with Rett syndrome, cure, hope, Neuren Pharmaceuticals, Rett Research, Rett Syndrome, Trail to a Texas Trial, Trofinetide Pediatric trial, Uncategorized | Tagged , , , , , | 1 Comment