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Tommy D. It would be standard practice to adjust results for confounding variables. This may well be the case for steroids in this trial. It shouldn’t too long to do this. I would have thought this should already have been done before announcing top line results, though by definition top line results are unadjusted.
I do think though the wrong primary end points were chosen and the study was underpowered to detect the most clinically meaningful outcomes-severe disease and death. There is a decent chance that by combining p2/p3 and potentially adjusting for steroid use that we could still get something from this. ??

I think that makes sense. My understanding from MHRA and FDA comments is that the regulatory authorities are in discussion with the pharmaceutical companies and there is continual updating and hopefully conversations going on.

https://www.fnih.org/sites/default/files/2021-10/ACTIV-2_v7.0-wLOA%20073021.pdf#page43
Master protocol link above. Nasopharyngeal swabs at entry and day 3 in phase 3. They will have the ability to do this and I think they will. I haven’t read all the way through to see if they have said they are doing it.

….and would it lead to any orders? I guess it would depend on the data and how it’s presented! Hence the Ray Jordan requirement..,,,

Ndn. The effect size was no bigger than the trends we saw- RR 0.82. Over 2000 patients though and a much more powerful trial to detect small differences. I may be clutching at straws but I don’t think synairgen have anything to lose by bundling results together and submitting an EUA. Who knows they could do that and as part of EUA enter a large platform trial. FDA do that for diabetes drugs- approve on basis of surrogate end points and ask for CVOT trials to be done! Maybe a takeover by big pharmaceutical company would be in best interests of all- they would have clout and resources to deliver the knockout large trial.

PS the magnitude of harm if steroids given before oxygen needed is about the same as benefit if oxygen needed (Absolute harm 3.8% absolute benefit 2.9%). The biggest benefit was in those on mechanical ventilation (12% absolute benefit and RR 0.64).

Thanks Rich.
I ran ITT. That may explain it. In any case SNG is in the ball park.
This is not great science but there has been a lot of bad science get through approvals under EUA and the evidence on the ground is that these therapies are working. Here’s a brief summary.
Steroids- overall no benefit. Probably harmful if taken too early, benefit if on O2. It took several studies and a meta-analysis to show this.
Il6-antagonists- again several studies and conflicting results but approved for specific sub groups.
Mabs also failed late disease studies benefit in early. Approved now on basis of mainly lab evidence!

SNG is the only therapy that appears to work in early and late stage. It’s not great science statistically but I think SNG should bundle the results all together and make EUA. Collectively the evidence points to it working with a fairly powerful effect size. We are in a pandemic and the science isn’t perfect but judgements on the basis of available evidence have been made, and continue to need to be made. I think Synairgen are trying to get data from ACTIV2 and hopefully will bundle this and make EUA. In the meantime polygon (Big pockets) are averaging down). I think takeover…. Sadly I can’t afford to risk more on this but will stay the course. I can’t afford to crystallise loss either! Like many on this board stuck in the middle and hoping??

I ran a brief chi sq test on combining p2/3. It came out as p=0.06 for end points of severe illness or death. To be precise it would need individual patient level data. I think company will do this but what it can be used for im not sure. For EUA I think they would take a global look at all data. For peer reviewed journal I think this would be rejected- not great science. Similarly I think extending trial not an option. Some trials are now designed as event driven rather than a priori power calculations and enrolment numbers to avoid this problem. That bird has flown and I don’t think on SNG resources it would have been feasible. I suspect they really needed more than 1000patients. They also went for the wrong primary end point. Again easy with hindsight.

https://clinicaltrials.gov/ct2/show/NCT04518410
Last update to the protocol was 2nd Feb 2022 and regeneron still there.

I would have thought a protocol change needed to do anything other than regeneron. I’ve been expecting this but no news.
Agreed- not sure what they would use.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00676-0/fulltext
To emphasise the issue of power and outcome look at the tocilixumxab trial. Over 2000 patients randomised to the treatment arm and an effect size smaller than that seen with SNG001 and the outcome was statistically significant. This is what the RNS meant by large platform trial.
SNG imo would be a suitable candidate.
Hope is not lost but the question is whether or not time is on synairgens side. £25m in the bank does give a reasonable cash runway but I think buyout more likely. I’m holding and keeping fingers crossed. I’ve lost too much to walk away from a product that holds promise.

That fat lady hasn’t sung yet on synairgen. Looking at the data as a whole SNG001 appears to work. The p3 study was underpowered because of the improvement in general care. Pooling p3 and p2 data from in hospital studies gives very close by my back of envelope calculations to the magical p<0.05 significance for the most meaningful of all outcomes- death or severe disease. My calculation is p=0.06 on intention to treat basis. Given that the landscape of trial and therefore power was changing during trial there may be a logical case to pool the data. One would need accurate individual patient level data to be able to do this. There will be statistical purists who would reject this but it would certainly be worth a serious statistician looking at the pooled data to see what could be made if it. Remember molnupavir got EUAd with a study that was a game of two halfs - first half of study effective, second little better than placebo. I think this will be considered by synairgen scientists.

Activ2 p3 will be active competitor (regeneron-drug known in uk as ronapreve) or placebo, not both to the same patient at the same time. To blind the patient it will therefore be ronapreve or placebo infusion plus SNG001 or placebo of SNG001.
The standard of care now (and for a year) includes steroids for patients needing oxygen. Activ2 is an outpatient study so nobody will be on oxygen and there would be no indication for oral steroids.

No steroids are hospitalisation only therapy. They are actually harmful if given too early. Only to be used in those needing oxygen.

Tough call today. Hope investors can carry on.
I agree improving treatments decreased the power of the study. Water under the bridge now and I agree; last chance is with ACTIV-2. Fingers crossed this will salvage something.
My thoughts are with you all.

Clutching at straws but day 90 results not yet published as far as I can see. Difficult to see how that could change things, though some are intubated and ventilated for longer than 35 days reported.

Here’s another analysis.
Results in line with p2 and evidence of benefit in at home and in hospital setting would make this the most valuable therapy the world has ever known with a paradigm shift in treatment for severe viral respiratory infections.
There are already huge vested and powerful interests in current therapeutics. These will be aligned to pick any holes in data to maintain their market positions for as long as possible.
Delay at this stage could be dotting every i and crossing every t in anticipation of the scrutiny this will come under.
Current price trends not foment but fear of success. My advice is be driven by the data we know and it is very powerful. The objective parallel story of developments in appointments etc supports this analysis.

On the original thread here was a quote about us being close to the end of the pandemic and close to endemic. That may well be true- the exponential growth of infection rates are being replaced by stable BUT very high levels of infection. The end of the pandemic absolute does not mean little need for therapeutics. If SNG works as we expect there will be massive need for this for a good few years to come- both for stockpiling in event of further pandemic waves and for lots for more predictable use during endemic phase.
Fingers crossed that p3 reads out as predicted based on the 3 x p2 trials we know were successful (p2 in hospital, p2 at home and p2 in ACTIV2). It feels like we know much more about SNG than would be usual for a pre-p3 therapy and it’s all good.

I suspect 90 day data being awaited. It will make it easier to demonstrate benefit against QALY criteria if 90 data significant. Meanwhile time appears to be being well used building top class usa team and establishing partnerships.
I’m not sure if still blinded. Previous post implied that they would have access to the data from day 35.

Thanks guys. I feel very comfortable with steady output of positive tweets and developments knowing that Synairgen team know the day 35 data. Only mystery is why the share price is still languishing circa £2. Once results available we won’t be caring about this intermediate period.

I reckon mid February is last (day 90) data point, given last patient dosing was mid November.