>> Thank you, Mr. Chairman.
I will present the results of the SEPSIS ACT on behalf
of the Trial Steering Committee listed here, and as for the previous speaker.
The study will be published today in the JAMA.
As you may know, by definition, norepinephrine is the recommended first line agent
to restore the blood pressure in patients with septic shock.
But it's not always effective and we have refractory situation, and maybe associated
like any other vasopressor with side effect.
Vasopressin, on this hand, is recommended as a supplementary agent,
but also has multiple effects that may not be beneficial in the setting of septic shock,
especially because of the activation of V1b or V2 receptors.
And you see on this slide the potential effect of activating Va1, Vab, or Va2.
And what we are mostly looking for is the activation of Va1 to induce vasoconstriction.
But also, together, vasoconstriction on the efferent glomerular artery
and improve the glomerular filtration rate.
Now, Selepressin has been used and tested already in pre clinical study,
but also in a small Phase 2 trial a couple of years ago.
And all these studies, pre clinical and clinical, were consistent in terms of benefit
of Selepressin in the way it was able to induce a rapid weaning of more adrenaline,
improve the duration of shock, or reduce the duration of shock,
but also supported the effects on vascular permeability by reducing the amount of fluid
to be given mostly to animals, but also to patients.
And with a reduced duration of mechanical ventilation.
So, there was a sufficient rationale to test this drug in a larger trial,
having a potential benefit, not only on shock, but on lung and water,
and also on the duration of ventilation.
And so we designed a Phase 2b/3 adaptive trial using Selepressin
in the setting of adult septic shock.
And as you will see in details, this adaptive trial consisted in two parts.
And we'll move on later on.
But the primary objective was to demonstrate a superiority of Selepressin to standard of care
versus placebo and standard of care in the number of ventilator
and vasopressor free days up to Day 30.
We also had secondary endpoints.
Ninety day all cause mortality.
The number of renal placement therapy free days up to Day 30.
And also the ICU free days up to Day 30.
So, the first part of the trial, in this adaptive design, consisted in enrolling patients
with a fixed allocation, a third of them receiving placebo, and that we had three arms
of increasing dose of Selepressin on 1, 2 and 3.
And after 200 patients, there was a first interim analysis.
And then the goal was to select one of the three arms
if it was showing a potential benefit compared to the other two arms,
and then eventually move progressively interim analysis after interim analysis
by increasing the weights of one of this arm.
And in case the third arm, so the highest dose, was associated with a better signal,
we had the opportunity to open a fourth arm with a higher dose.
Then after treated patients, we had monthly interim analysis
with a futility rule to stop eventually the study.
But this time, to update their adaptive allocation over the course of the study.
And after 800 patients, we could either stop the trial for futility, or if there was a signal
and an effect with a likelihood to be positive, we could move to the second part of the trial
where the randomization would have been one placebo versus one Selepressin dose selected
by the different interim analysis.
But the study was stopped at more than 800 patients for futility.
Now, you see that the trial design, in fact, offered 17 interim analyses.
And how this interim analysis impacted on the recruitment.
And so there was an ongoing recruitment that stayed stable over the course of the study.
So, this kind of trial design loads adequate and sustained recruitment,
but also loads for efficient testing of hypothesis.
Now, this is the course of slides.
This population for the first time also was a real life population.
There were limited inclusion criteria.
We took patients above 18.
We had suspected or proven infection.
And to have a septic shock defined by the need of noradrenaline for more than five mcgs
to maintain mean arterial pressure after adequate [inaudible].
There were a limited exclusion criteria.
All immunocompromised patients were alone in the study.
We just limited the exclusion to patient either receiving Vasopressin at the time of screening,
or, of course, if hypertension was not due to sepsis, but also oxygen dependent patient
as ventilator free days was one of the end point,
and also patient receiving active chemotherapy, or bone marrow transplant.
And you see that the follow up was adequate,
as long as we had roughly all patient followed at the 30 and up to 6 months.
You see also the different quotes of exclusion in this slide.
Now, the baseline characteristics, I will not go through all details,
just to say that by definition, hopefully they were well balanced, which was the case.
In terms of comorbidity, severity, cause of infection, and severity score.
Just to see that in more detail, the SOFA score was only 9 because we deleted the CNS score
because of the number of errors in the calculation.
You see the mean and the mean APACHE II score, you see that the mean dose, and the median dose
of norepinephrine was quite significant, and that the median lactate was also above 2.
So, they met roughly all the definition of subject three, which was not the initial intent
by the time we were designing the study.
Now, if we looked at the effect of the drug, you see on the left part of the panel in red,
the change in the mean blood pressure in the Selepressin arm and in blue in the placebo.
And you see that during the first 12, up to 24 hours, there was a significant difference
in the change in the mean blood pressure in the treated arm.
Similarly, you see the weaning of the reduction of the need in no adrenaline in the treated arm
with Selepressin compared to placebo.
And this was significant up to 24 hours.
Then the two curves evolve similarly by the improvement of patient in both arm.
And they were no longer significant.
Now, if we looked at the change in the SOFA score,
and especially the cardiovascular SOFA score, despite the fact that in this study,
as opposed to other studies, the fact that you were receiving IMP counted for three points,
we had a significant reduction in the cardiovascular SOFA score at day one.
And at day two, in the treated arm compared to placebo.
You remember that one of the rationale of the study was hypoxemia, duration of ventilation
because of the reduced permeability.
You see on the middle part of the slide that the fluid balance was significantly lower
in the Selepressin arm compared to placebo during the first 24 hours.
So, expressing that the requirement in fluid were reduced.
And this goes in line also with the need of steroids to treat shock.
And you see that there was a significant reduction in the number
of patients receiving steroid for shock in the Selepressin arm compared to placebo.
Now, regarding the primary endpoints, being ventilator and Vasopressin free days,
this slide shows you the way this was calculated, up to Day 30.
You see that a patient receiving in green vasopressor, and in blue ventilation.
You started to count free days when both were weaned in this patient.
In case you had to restart vasopressor during the study,
you only started to count free days after, once again,
you had weaned the vasopressor or the ventilation.
And there was a death penalty.
In other words, if the patient died, even they were weaned from vasopressor and ventilation,
before Day 30, you counted no ventilator, vasopressor free days.
Now, looking at the final results regarding this primary endpoint, we saw no difference
in the total of vasopressor, ventilator free days
in the treated population compared to placebo.
The mortality at Day 30 was similar in both arms.
You see that there was an initial, more rapid weaning of Vasopressin ventilation,
but this was not sustained, and this was different for a couple of days.
But for the 30 day endpoint, no difference was achieved
in the different primary and secondary endpoints.
Now, regarding safety, because there was some fear on the fact
that Selepressin may reduce especially significant ischemia in a trial design
where [inaudible] and cardiac output had not to be measured, especially,
you see that the drug was definitely safe in terms of emergent critical adverse events,
and especially you had no increase in intestinal ischemia, peripheral ischemia,
acute coronary syndrome, and myocardial ischemia.
So, the safety profile was excellent for this drug,
despite a combination of two drugs in one arm.
So, to conclude, that among patients with septic shock receiving norepinephrine,
the administration of Selepressin compared to placebo did not result in improvement
in the vasopressor, ventilator free days within the first 30 days.
Yet, Selepressin, as Vasopressin, as Angiotensin II appear
to have a norepinephrine sparing effect without increasing adverse events,
but also without evidence that their use improves patient centered outcome compared
to a classical catecholamine based strategy.
And finally, this adaptive phase 2b/3 design, with response adaptive randomization
and interim analyses allowed unambiguous testing of hypothesis with an efficient sample size
without impacting the trial execution and the recruitment.
Thank you for your attention.
[ Applause ]
>> Thank you very much.
Any question from the audience?
>> Charlie Sprung, Israel, PF.
Congratulations on your study.
Could you tell us what the instructions were given to investigators
as to when they should use steroids?
>> The instruction regarding?
>> Giving steroids to the patients in septic shock.
>> Oh, no, this was free, and this was left to the investigator practice.
And most of the time, the steroids were given according to the local practice.
In other words, sustained shock was associated with more spontaneous instruction
or prescription of steroids for the treatment of shock.
So, this is secondary observation and not this was not pre defined.
Investigators were free to use steroids if indicated.
>> Is the drug ready to be retired?
>> To be honest, no.
I'm not, I'm not linked with the company.
And it's a pity because, you know, this is definitely a potent vasopressor.
We've been probably too ambitious regarding our primary endpoints.
In between you and I, if we had selected short term response in terms
of [inaudible] parameters, and especially the duration of shock,
we would have ended up with a positive trial.
But this is the flop of the primary endpoint definition we used.
And we were probably too ambitious looking at 30 day ventilator and vasopressor free days.
>> Well, that was also my comment.
That would be my comment, actually,
because obviously this study did not fulfill your primary and secondary endpoints.
However, you had to give less fluids and less steroids to the patients.
And I neither love or hate steroids.
I use it when it's necessary.
But to give it less is always better.
And the same thing can be said for the fluids,
because too much fluid is not good for the patient.
So, I think also the question from my perspective, there is some future,
whether it would be ending good or not, but that's what I thought.
>> Yeah, I think the other point I would make, I think people know over the last there,
there's been quite a bit of controversy about P values and confidence intervals.
What goes in the abstract, what doesn't go in the abstract.
Clinical trials are remarkable attempts to clarify truth to get to validity.
And journals can't summarize the entirety of a clinical trial in an abstract.
It simply is not possible.
And so I think on occasion, one needs to actually read the entirety
of a study to truly understand its results.
And both this study, as well as the one on Vitamin C where there were many,
many secondary outcomes of which only a few were presented, one needs to read the entire trial
to really understand the results.
Thank you very, very much.
>> Yeah, and there's, there's an appendix with additional data you can look at.
[ Inaudible ]
>> Just a short question.
I mean, most of the effects, especially blood pressure
and norepinephrine sparing, vanished at 24 hours.
So, can you remind us what was the duration of the infusion of Selepressin?
And so was there it was a vanishing of the effect, or it is because you, let's say,
poorly selected the time of exposure to the agent.
>> No, no, there was, there was no fixed duration.
You started to wean the IMP.
So, the drug.
I mean, this was blind, but you were starting to wean this.
As soon as you had weaned noradrenaline, so noradrenaline was opened in both arms
because this was the drug required to be enrolled.
And then when you were able to wean noradrenaline,
you started to wean the study drug.
[ Inaudible ]
Excuse me?
>> Norepinephrine does join at 24 hours.
This means that then you would have continued to infuse Selepressin in these patients?
>> Yeah.
>> And that the effect was no more present
because the doses were exactly the same in two groups at that time.
>> Yep. But, so, you had a significant proportion of patients being weaned
from noradrenaline after one, one day and a half.
And then you don't see the infusion of the IMP in the slide here.
But the weaning process was established this way.
Noradrenaline in both arms at the start.
And then you keep noradrenaline use in both arms as long as needed.
And when you start to wean and you have weaned completely noradrenalin,
you start to wean the IMP.
>> Thank you very much.
We will go onto the next presentation.
[ Applause ]