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!

Advertisements
This entry was posted in Neuren Pharmaceuticals, Rett Research, Rett Syndrome, Trail to a Texas Trial, Trofinetide, Trofinetide Pediatric trial, Uncategorized and tagged , , , , , . Bookmark the permalink.

2 Responses to Let’s Break it Down-2

  1. Rose and Renée says:

    This is such a big help. Thank you lots .

  2. melelllan says:

    Feels like I’m back in school trying to plug through all this! But I am determined!!

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s