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

T- ?hours:Musing 1- Hands are Clasped

imageHand clasping is the signature sign of Rett Syndrome. It prevents most girls from using their hands. Katie is very, very fortunate to have pretty good hand use, incredible hand use if you take Rett syndrome into consideration.

This morning I told her…today may be the day we find out if the medicine you helped learn about is helping the little ones. She looked at me and smiled.

Now, I’m sitting here watching her on the patio. All I can see are her legs and hands. Her hands are clasped. And, I imagine this one time not they are not clasped because of Rett syndrome, but in a physical plea for those young girls. A plea from one Rett sufferer to the others that Trofinetide worked. I can imagine this because when Katie regressed after the last trial and cried and cried for days, the only thing that made her stop was to tell her how amazing she was and that what she was going through was going to help the little ones with Rett syndrome. You see, my girl understands all about Trofinetide. She knows what’s at stake.

And, today, I’m clasping my hands, too.

Posted in hand clasping in Rett syndrome, Neuren Pharmaceuticals, Rett Syndrome, Trofinetide, Trofinetide Pediatric trial, Uncategorized | Tagged , , , | Leave a comment

Happy St. Patrick’s Day…a Lucky Day for… EVERYONE!

irish katieThe luck of the Irish is spreading for the Rett community. Oh, no, it’s coming from Australia this year.

Neuren Pharmaceuticals Ltd-

* Requests trading halt pending announcement regarding Neuren’s phase 2 clinical trial of Trofinetide in Rett Syndrome.

Yes folks, a trading halt. Watch for results Monday. Tuesday at the latest.

To paraphrase an old Irish blessing…

The road is rising up to meet us, the wind is now at our backs, the sun is shining upon our faces, the rain is falling soft upon our fields and when we meet again, the results will be in!

Now, let’s all go dance a jig. 😉

 

grandkids

Katie’s nieces and nephew wishing all a very Happy St. Patrick’s Day!

 

 

 

 

 

 

 

Posted in Neuren Pharmaceuticals, Trofinetide, Trofinetide Pediatric trial, Uncategorized | Tagged , , , , , | 2 Comments