Mother’s Day in Oz

poppiesI often say that living with Rett syndrome is like traveling in Oz with the Scarecrow, Tin Man and Lion. So, what would Mother’s Day look like there? I think it would happen in the Poppy Field.

Such a beautiful flower, not so unlike the bouquets many of us will get this year. But, it’s a day that makes many of us weary. As we trudge through that day, we just want to sleep. This journey is so hard. And, it’s not just the journey; it’s also the day that makes us weary. We spend part of it cherishing the children we have and we spend part of it mourning the children we’ve lost, whether it is the child we remember before Rett syndrome struck, or the child that was taken altogether, and for some the children that were not taken by Rett syndrome, but who were loved and lost all the same.

So, there we are. Amongst beautiful flowers and our daily travelers. The Scarecrow-our child who trips and falls and is so smart, but whom many people think doesn’t have a brain with an intelligent thought. The Tinman- so stiff and needing oil (therapy) all the time. And the Lion-that’s us moms. So many of us wondering how can we go on???? Convinced that we lack the courage and strength to make it to the journey’s end. And, like the Poppy Field, Mother’s Day can do us in. It can be just too much. And that is where we want to lie down and sleep. To forget. To dream. To stop-like the Lion and Dorothy.

And who is it, then, that comes to the rescue? The Scarecrow and the Tinman. The two that have needed so much help along this arduous path, they are the ones that come to the rescue. And so, our children, all of them, come to our rescue. They lift us up, they carry us through the day and we realize that their courage is great, their strength is wondrous; not just our children with Rett syndrome but the sometimes forgotten siblings who walk along, often on the sidelines, guiding us and putting us back on the path to the Emerald City when we veer off the path.

And those sweet ones who’ve left us- I cannot fathom how their mothers make it through this day, but they do- I can only say, I believe no love is wasted, however short it was with both on Earth, Love lasts for ever. The small, wee hand that wrapped around a finger must ever be wrapped around a mother’s heart. The heartbeat that was heard only within the womb is still an echo for ever and must reverberate within each mother’s soul.

I know that Mother’s Day can be bittersweet. But, in the end, while we may dwell a moment on the bitter, sweet will win the day. For the real bouquet that matters is the hearts that have loved beyond all measure, the color of poppies, but spread in a field of Life. And we will be carried through that field by the memories of all those who made us mothers.

 

Posted in Mother's Day, Rett Syndrome, Special needs Mother's Day, Uncategorized, Wizard of Oz | Tagged , , , , , , , , , , , , , | 1 Comment

Poetry Month: Strength Inspired

I thought a lot about what should be the last poem I posted for Poetry Month. Should I go with hope? accepting your lot in life? the poem about the little girl who still counts her dead siblings as alive when asked “how many are you?”, for certainly all the families that have lost their child still count them, they’re still here among us, not one forgotten by those who’ve loved them. Should it be about how happiness is a crystal ball that becomes fractured and we should be content with the pieces that we find? Because, absolutely all our families find things to be happy about…a step, getting out of the hospital, a spoken word, a conversation on the Tobii.

But, as I sit here, tired, tired of all the little things and big things that come with Rett syndrome- which medication is best, weighing the pros and cons of back surgery, going on  Facebook and seeing who’s in the hospital, who’s made it home, I feel resolute. I am not going to bow my head to Rett syndrome. There are parents out there who have to be so much stronger than I to face each day and there are days when we are all at our wits end.

Our hearts are battered, we are beaten down, but each and everyone of us stands up. We are like the soldier carrying their fallen comrade across enemy lines, to safety. And we face Rett syndrome everyday, determined that it will not beat us, that we will find a way, whether it is for our children or for those to come, to make a difference.

No matter what is sewn into the tapestry of Life or written on the scroll, we are Human. We have been gifted the ability to face our fears, fight them head on, to Hope beyond all reason that adversity can be overcome, we challenge what Fate seems to have in the cards. Like Robert the Bruce and the Spider tale, we find our inspiration in the smallest things; the coward who throws away Opportunity? We pick up that sword and carry on and will one day win. We’ll beat Rett syndrome. It’s just a matter of time.  And so, I’ve chosen “Invictus”  Our heads may be bloodied but they remain unbowed.

INVICTUS

Out of the night which covers me,
Black as the pit from pole to pole,
I thank whatever gods may be
For my unconquerable soul.

In the fell clutch of circumstance
I have not winced nor cried aloud.
Under the bludgeoning of chance
My head is bloody, but unbowed.

Beyond this place of wrath and tears
Looms but the Horror of the shade,
And yet the menace of the years
Finds, and shall find me, unafraid.

It matters not how strait the gate,
How charged with punishments the scroll,
I am the master of my fate:
I am the captain of my soul.

William Ernest Henley

 

Posted in cure, hope, Rett Research, Rett Syndrome, Trail to a Texas Trial | Tagged , , , , , , , | Leave a comment

Poetry Month: Pain inspired

KONICA MINOLTA DIGITAL CAMERA

Many, many years ago, while taking a course in college they gave us this book of poems, rather we BOUGHT this book of poems. And it is my favorite. I still read it from time to time. One of my favorite discoveries after my beloved Aunt Gloria passed away (we share a birthday) was that she had the exact same book and now I have both. Sometimes I flip through to see if we ever wrote the same thing in the sidelines.

When Katelin was first beginning to regress and the doctors threw out numbers like …dead before 5, won’t make it to 12, and I needed a good cry, I turned those yellowing pages to… can someone have a favorite grief poem??… a poem that touched me deeply as a mother, even though I am an atheist. In this poem, the first night of being without her girl, a mother sends a plea to Heaven. One even my non-believing head might allow my wishing heart.

There are always so many girls and boys leaving us. It is the greatest heartbreak of connecting with families, that these beautiful children you’ve cheered on, cried for, clapped for, who beats the odds so many times, finally fly through that final door.

I’m sure we all think about “when”. Not that it consumes us, but there is always, always that fear…will these be the last good night kisses. Will this be the last time she’ll rest her head upon my heart. And I think, please, please on that last night, let her dreams be filled wonderful, beautiful things. And, my girl for the most part is perfectly healthy. I cannot imagine what medically fragile children’s parents go through.

In any case, this poem allows me to cry. It touches my mother’s heart; it is every mother’s hope, that as our child leaves our caring arms they are welcomed into equally caring arms. At times like that, I don’t question the confliction between my views and this hope. Poetry is meant to touch and heal and make you ponder. That is enough reason. And, I am grateful for the written word.

Prayer for a Very New Angel

God , God , be lenient her first night there.
The crib she slept in was so near my bed;
Her blue-and-white wool blanket was so soft,
Her pillow hollowed so to fit her head.

Teach me that she’ll not want small rooms or me
When she has You and Heaven’s immensity!

I always left a light out in the hall.
I hoped to make her fearless in the dark;
And yet, she was so small—one little light,
Not in the room, it scarcely mattered. Hark!

No, no; she seldom cried! God, not too far
For her to see, this first night, light a star!

And in the morning, when she first woke up,
I always kissed her on her left cheek where
The dimple was. And oh, I wet the brush.
It make it easier to curl her hair.

Just, just tomorrow morning, God, I pray,
When she wakes up, do things for her my way!

 

Posted in grief, national poetry month, Poetry, Rett Syndrome, Uncategorized | Tagged , , , , , | 1 Comment

April is Poetry Month-Katelin Inspired

tyler_23-235x300One of the first “poems” I wrote that was inspired by Katie was actually turned into a book! “Tyler and the Spider” is a story of acceptance, no matter the differences. It’s meant to show that being nervous and afraid is not one sided, and that with just a bit of understanding these differences can be overcome.

Having a disability doesn’t mean you can’t be talked to. It doesn’t mean children can’t ask questions; my goodness how are they to learn but to ask questions? Yes, there are things that are “different” about our children and adults with disabilities-sometimes they can’t talk, they may move funny, they may spit, have seizures, vocalize in odd ways that, in the eyes of a child or parent that hasn’t had much experience with something like that, may be disconcerting.  And,  it can be unnerving, make people anxious; they just aren’t sure how to respond. Do they approach? Will they offend if they do? Maybe they are made aware in that moment just how fragile life can be and that truly no child is safe, so they  move to protect their child not from ours but from the sudden fear that it “could be my child”. Or, they could just be rude, because that happens so much more often than it should (which is never).

And, disabilities aren’t the only obvious differences that cause misunderstanding… it can just as easily be glasses or braces or skin color; it could be an accent, a style of clothing. Maybe even that a child is adopted or in foster care. Maybe they have a parent in prison and are being judged for that or an immigrant. Truly it could be anything that makes another person “stand out”. And, I believe, “Tyler and the Spider” addresses these fears from both points of view-of a boy and of a spider. Everyone would guess that the boy may be afraid of the spider, but would anyone guess that the spider is afraid of the boy???

In this story, each “person” is judging the other based upon what they’ve been told, and when a chance meeting brings them they discover somethings for themselves….

….

And each closed their eyes in fright

thinking that the other might

just do some awful, horrible thing!

But Tyler didn’t squash the Spider.

And the Spider didn’t bite Tyler…

And that’s when the realized,

As they looked at each other in surprise,

That just because someone is different than you,

Doesn’t mean you can’t be friends, too…

As now as they go to bed each night,

Each thinks the other might

Just be their best friend!

And that really is the crux to life. Life is filled of different and amazing people, let’s strive to see past our difference, decide for ourselves what people are really like, and become the friends the world needs.

I have a 10 copies of “Tyler and the Spider” and will happily send them free of charge to anyone who wants one, just pm me your address at m3ml@hotmail.com

Ps.

Everyone is a poet. Just write!

Posted in acceptance, poetry month, Rett Syndrome, Uncategorized | Tagged , , , , , , | 3 Comments

Let’s Break it Down-5 (Neuren Aims, Shoots, Scores! Slam Dunk!)

 

slamdunk-1405577.jpg

I chose this picture because of the absurdity. An elephant playing basketball… Margaret Brimble discovering how to repair the brain. Both eemingly impossible, yet…here we are!

Yes, we have finally reached the last part of the Pediatric Trial Results. Hooray. It was quite a challenge for me and hopefully I made it understandable for everyone. I want to thank those people who explained things to me until I grasped the concept/s so that I could explain it in my own words. I want to thank the girls and their parents who were so very brave, forging ahead on to unknown waters.

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

 

This last little bit doesn’t need a whole lot of explaining, but I don’t want to stop with the shore insight, so here we go!

Lower dose groups and pharmacokinetics
The two lower dose groups of 50mg/kg BID and 100mg/kg BID did not demonstrate evidence of efficacy.  However, two important observations were confirmed by pharmacokinetic analyses:  The level of efficacy measured by each of the RSBQ, CGI-I and RTT-DSC correlated with exposure to drug (which varies within dose groups).  Lighter subjects experienced lower levels of drug in their blood compared with heavier subjects receiving the same dose.  This was also observed in Neuren’s previous trial in older subjects as well as in the completed Phase 2 trial in Fragile X syndrome.  In this younger population, the effect was that the nearly threefold increase in the highest dose compared with the previous trial resulted in significantly lower actual exposure to drug than expected.   In a pivotal trial, Neuren intends to use dosing that will aim to achieve similar exposure in subjects regardless of their weight.     

And what can we take away from all that? The lower doses (under 200mg/kg) did not demonstrate evidence of efficacy.  In my opinion and from the fact that PRE-trial efficacy measurements had to be met, I find it unlikely that there was NO improvement, just none that reached that PRE-CLINICAL bar. So, even if a change was noticed it couldn’t be counted if 1. it just didn’t reach the bar set and 2. if it was something that wasn’t already pre-determined to be measured. They can’t just go… oh, wow, we see this change! Let’s add it into the protocol. Nope, none of that. And the same thing actually goes for the higher dose group if they saw something that was not already pre-decided as a goal.

Lighter subjects had lower levels of the drug in their blood. This was a trend seen in all three Trofinetide trials; the adult, the Fragile X (on boys), and the pediatric Rett trial. So, Neuren’s going to work on that. No worries there, they’ll get it figured out. Of course, people might be wondering why that’s so, and I don’t know. Perhaps a higher metabolism? Maybe it binds somehow to fat molecules, this is a question for someone with way more education than me! I’ll see if later I can get a suppositional answer, or maybe someone out there knows.

So, we’re pretty sure Trofinetide is working. But what good is something that works if it’s not safe? Well, good news there as well!! Super safe!!

Safety
The primary endpoint of the trial was safety in this younger population.  The safety profile appears benign, with the following key observations:  There were no time-dependent patterns of adverse events (AEs) and no pattern of AEs evident with initiation or cessation of treatment.  The majority of AEs during double-blind treatment period were either mild or moderate in intensity.  The most commonly reported AE across trofinetide treatment groups was diarrhea, which was not dose-limiting.  Four serious adverse events unrelated to treatment were reported in 3 subjects. There was one discontinuation – the caregiver withdrew the subject from the study due to AEs of vomiting and diarrhea.  There was no systematic pattern of objective laboratory, vital sign, fundoscopy/tonsil or ECG abnormalities.

So, basically the worst thing was some diarrhea. It is my opinion that Trofinetide may have corrected the neurogenic bowel seen in Rett syndrome and the body was unprepared for that. (This is absolutely only my opinion-it could as easily been the strawberry flavoring or some other issue. I know Katie didn’t need her laxative at all during the trial she was in, but I do not know if she got the placebo or Trofinetide)  I’m sorry someone had to withdraw because of that. However, as a parent, and while you can’t count it here as an adverse effect, the fact that the girls regressed AGAIN afterwards is a terrible consequence of such a trial and one of the reasons these parents were so incredibly brave.

So, to sum up all of the last five installments:

Trofinetide improved many symptoms significantly at the 200 mg/kg dose vs placebo.

Trofinetide is safe.

There was no “cap” seen; meaning, improvement continued throughout the trial on the 200mg/kg dose.

There was a correlation between how much drug was measured in the blood and improvement; lighter girls did not have as much drug in their blood despite the high dosing level. This was observed in all three Trofinetide trials and Neuren is working on a solution.

The Natural History Study is an important data collection study and has resulted in standards that can be used in clinical trials.

It’s not mentioned here, but subsequent announcements put Phase III starting in 2018.

But, the greatest thing you can take from all of this is that….THERE IS HOPE!

Thank you to Neuren, the researchers and all those who believed before us parents ever got an inkling, you are changing our world.

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

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