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Well...

Dr Penny Ward seems to get that showing statistical significance in small number studies where only a subset of the group are 'vulnerable' and their signal drowned out by the 'not vulnerable' group is a challenge. She also cautiously gets how good this treatment might be.

Dr Peter English (retired) says he would like to understand the mechanism of action of SNG. If he is so utterly out of touch with the enormous literature on IFN mechanisms and Covid (even BBC news would have informed him) he is embarrassing himself by posting in public on this topic!

Slowly sinking in more and more how important this finding is.

Since the start of the pandemic, the biggest question has been why many people have no symptoms/mild disease and do not require treatment. Yet, a small percentage get severe disease and many die. Because of the sheer numbers of infections the small percentage who die means a large number of deaths. A way of predicting who to treat early and a way to treat them has been a bit of a holy grail. It would never be reasonable to treat all cases when they will recover on their own. We may have found that holy grail, but statistical significant will only fall out by using the correct protocol for patient selection.

There has been an avalanche of evidence that IFN difficulties (antibodies or genetics) underlie the vulnerability to severe disease, but never reasonable to use research test on the world population to predict who to treat.

We now have an easy clinical guideline, able to be used across the world with no technology/advance needed, of 'breathlessness' early in the onset of illness to make this prediction. For this group we also have an easy to administer treatment (even at home) to specifically target this group with seemingly excellent efficacy.

I understand the P3 trial protocol can be amended. I would be shocked if ACTIV2 do not run with this and get the extra data needed to get this to EUA. The people running ACTIV2 do understand the IFN message and will understand the implications of this finding even if the concept is not easy to grasp or easy to show statistical significance unless you target the protocol correctly.

I think the ACTIV2 protocol can be amended for their P3 arm.
Assuming we get there, if inclusion criteria are amended to 'breathless', SNG may be exactly what ACTIV2 are looking for to keep people out of hospital.
That also goes for the UK home treatment venture.

1) A bit disappointing if we need to wait another 4-6 months for the P3 data, but positive results from the hospital arm are now further derisked. Application after that will be for full approval, not just EUA.

2) Armed with this information, Activ2 may still have legs in getting us EUA.
a) of the breathless patients who benefitted from treatment, 20% of them were in the home group. Not to be ignored as a potential treatment group.
b) Activ 2 are looking for a treatment to keep people out of hospital. They have mabs, camostat and SNG.
c) mabs are not very practical for home use as they need i/v infusion, are expensive, limited in supply and as shown would need to be given to very large numbers to save one hospital admission. As far as I know they do not have selection guidance to improve on this. Moving ACTIV2 to new countries they may be less effective in the face of new variants.
d) Camostat unknown, may not work, may not be available yet.
e) SNG - armned now with the selection criteria of 'breathlessness' may be the only treatment they have which will be useful to keep people out of hospital. If they can limit treatments to this group, the cost benefits may be far greater in terms of number to treat to save a hospital admission.

So, having slept on this new information, the at home treatment EUA may still arrive. Also, in India and soon to be other countries where the hospital system is overwhelmed, home treatments for sick/breathless patients may be a game changer.

In summary, we may have good news to come long before 4-6 months for the P3 data readout.

RNS a bit of a let down compared to what we might have hoped for!

However,
1) More support and derisk for SNG working very well in the sickest and most vulnerable section of the population.
2) Clarifies that 'breathlessness' is a good marker of who will benefit. This is a real advance on Scinvs suggestion that obscure research assays are needed to screen people.
3) Target areas are hospital patients, the breathless people in the car park in India who can't get a hospital bed or oxygen, but could use SNG at home, people who are breathless but not hypoxic at home to hopefully avoid need for hospital.
4) This a still a drug to change the face of covid deaths/overwhelming of inpatient services.
5) The potential demand for SNG will be far greater than supply for a long time to come.
6) It is a step forward that target patients are now easily identified. This target will also help with a pricing level when limited to the most at risk patients.
8) If only the world could start to use it. Hope India does the right thing and gives it a EUA.

Prion, the paper I remember had a test for, I think, 5 genetic markers which they said would predict a large percentage of severe cases. I may have bookmarked the link, so will see if I can find it. That would be amazing as a tool, but is very much a lab based thing at the moment and would need a long period of testing before it got in to clinical use.

However, when countries don't have oxygen or hospital beds to treat the scale of their patients, suggesting that research based screening assays should be routinely used just isn't a point worth making. Even in UK hospitals anything like that would need a lot of development and testing before it got into routine clinical use. It would need as much development and validation as a drug to be accepted and we know how long that takes.

1) Scinv is making a good point that 13% of severe covid cases have interferon antibodies and if tested they would be in a group predicted to have most benefit from SNG.

2) However, a recent paper showed that a group of 63 genetic markers predicted over 90% of severe covid cases. Many of these were interferon related genetic markers. Probably most if not all of this group would also benefit greatly from SNG.

3) While having a scientific base, these tests are currently obscure research tools. They will not be widely available clinical tools even in the most high tech centres. Where they could be available, the time taken to get results would probably mean your patient was recovered or dead in actual clinical use.

4) So, perhaps the most pragmatic option to target the most high risk group and treat them quickly would be for SNG to be a hospital treatment. The hospital group may have already self selected for interferon antibodies and the other 63 genetic markers predicting severe disease. This option would not require research based screening assays and could actually be achieved in a clinical setting.

5) Scinv does make a good point that treating people earlier at home would mean treating a lot of people who would not get severe disease and would recover on their own. However, we have not yet seen whether there are benefits in terms of long Covid for early home treatment.

My impression when they mention repurposing of existing drugs is that it will be for drugs already approved after a phase 3 trial and safety data in their existing formulation. This could be existing inhalers or tablets in approved for a different condition. (eg, budesonide/asprin).
Interferon is an approved drug, but not so far in nebulised form.

I am very happy we are in the ACTIV 2 trial. I don't see any mention that ACTIV 6 will take over from ACTIV 2.

During discussion interviews after the P2 hospital trial results there was mention of retrospective longer term follow up of the hospital patients over a longer time window to look at long covid. The long covid follow up would have been introduced for the home arm of the combined P2 study at that time.

This change was a long time before unblinding and should not be seen as having any implications for the HT results.

Yes, these figures come from Verity et al.
https://www.medrxiv.org/content/10.1101/2020.03.09.20033357v1.full.pdf

Table 3: Estimates of the proportion of all infections that would be hospitalised obtained from a
subset of cases reported in mainland China22. We assume that within a UK-context, those that are defined as “severe” would be hospitalised. The rates are adjusted for under-ascertainment and corrected for demography.
Age SevereCases AllCases Percentage of infections hospitalised
(posterior mode, 95% credible interval)
0 to 9 0 13 0% (0.0, 0.0)
10 to 19 1 50 0.04% (0.02, 0.08)
20 to 29 49 437 1.1% (0.62, 2.1)
30 to 39 124 733 3.4% (2.1, 7.0)
40 to 49 154 743 4.3% (2.5, 8.7)
50 to 59 222 790 8.2% (4.9, 16.7)
60 to 69 201 560 11.8% (7.0, 24.0)
70 to 79 133 263 16.6% (9.9, 33.8)
80+ 51 76 18.4% (11.0, 37.6)

So, Bryosa's estimate of around 15% hospitalisation for the HT study demographic seems about right. We would expect 8 or 9 hospitalisations each for the SNG and placebo groups if SNG had no effect.

I heard somewhere there were a total of 10 hospitalisations during the trial, Can't remember where this came from or if it has any truth. Does this ring a bell for anyone else?

If true and this was 9 hospitalizations in the placebo group and one in the SNG group we would all be very happy.

Your posts are always great, Joey D and one of the joys of this board!
Thanks for the interesting discussion.

Just had one more random thought.
If there is an issue, it is dilution of the real benefits of SNG treatment in the face of trial participants who 'had no fire to put out'.
But thinking about this, the ?30% of people who have asymptomatic infection, perhaps in the context of a great interferon response, are the ones who really have no fire to put out.
It may be that anyone with symptomatic infection (needed for HT trial inclusion) has a fire. That could lead to very good results.

Fingers all crossed, roll on results!

To put that in context:

Oxford calculator gave risk of hospitalization over a 90 day period for uninfected people as:
White 70 year old healthy man - 1 in 548
White 82 year old man (COPD/In a nursing home) - 1 in 97

But, when these people have had a positive covid test (as in the HT trial), their risks of hospitalization will be much higher. Their figures are also based on data from the first wave, when sadly I suspect that the 82 year old man with COPD in a nursing home may not have been admitted to hospital however ill he was.

I believe SNG must be a fantastic treatment for Covid with so much evidence piling up for the interferon story. Just hoping that the ramifications of clinical trials and statistics don't let us down in showing that!

Great post Joey D, excellent to put some figures to this and understand that while SNG is very likely to be a miracle treatment for the interferon vulnerable population there may be many people who mount their own interferon response and get no benefit from it.

Once they arrive in hospital they are selected to be the interferon deficient population with great chance of benefit. For the at home population any result will be diluted by those who are able to put out their own fire.

Regarding your figures though, I think the Oxford calculator gives figures for the general well population. The home trial has already selected those with a positive diagnosis, which will (doh!) increase their risk of hospitalisation greatly over the figures here for the general uninfected population. So, the chances are less alarming than the ones you state. However, your point is very well made that the study size may need to be bigger to tease out the real benefits.

Lets hope we have luck on our side, or that everyone is a bit interferon deficient in the context of pesky covid action.

Interesting discussions tonight.

I think if there is an issue it will be the population and the size of the study.
For the people who would be destined to end up in hospital SNG should work for them and hopefully better when given earlier before they get to hospital.
If there is a problem it would be that the group who were destined to recover on their own may be mounting enough of their own interferon response and gain no benefit from SNG as they have no fire to put out.
So, the effect might need a larger population to show a benefit which is possibly only there in 20% of the subject group.
I am hoping for fantastic positive results from the home trial, but this has to be a consideration.

Message from the Menendes et al does seem surprising as it seems at odds with the wide range of literature on this.

The paper has not yet been peer reviewed and may not end up published in this form.

Looking at what they did, they seem to have measured levels of the RNA template for production of the different IFNs and found this was high for IFN-beta in the severe Covid group. This is not the same as showing that IFN-beta was high in this group (as their title suggests). If Covid blocks IFN production it seems possible there could be high levels of RNA template yet still low levels of IFN itself. Inability to produce IFN could feedback to drive higher levels of RNA production.

I suspect peer review will ask for this to be clarified. They can't assume that high RNA levels mean high IFN levels without measuring them.

Could be interesting if nasal swab RNA levels could be a biomarker for patients benefitting most from SNG001. Am not sure how easy this analysis would be though. It may be a technique only available in limited labs and have limited practical real world use.

Haha, motley fool again.
Saying city analysts predicts 2021 revenue of 150m if approved.
For 100,000 treatments a month that would be a price per treatment of £125, or £250 if they are basing 2021 revenues on six months of sales.
I think city analysts may need to look at their price predictions again!

Second topic. Patents are not a problem for anyone testing inhaled interferon in a study. They would only be a problem if someone tried to sell a drug which infringed a patent. So, these trials could just be good advertising for using an approved and patented drug as a treatment (that would be SNG). Or, if their own drug fell fowl of SNG patent protection am sure there would be an option to agree a licence on the SNG patent (at a price). However, using another interferon in inhaled form without the SNG preparation and safety/side effect data SNG have built up would probably mean going through a bigger P3 trial to check this. So, either way I don't see scientists using other inhaled interferons as a proof of concept as a big issue for us.

I doubt anyone will come forward and admit they put Jacob Rees-Mogg on their form!
So unlikely to get any track and trace for their movements.
Amazing how this government can make plans which fail every time.

In one of the videos, I think Tom Wilkinson, said they were also following up the P2 hospital patients over longer timelines to check for long covid. So I suspect longer term follow up may be for this reason and will not affect unblinding and analysis of the first set of data.
Hoping for a result from mid March, so excited.

Sorry if already posted.
https://www.cam.ac.uk/research/news/likelihood-of-severe-and-long-covid-may-be-established-very-early-on-following-infection?utm_campaign=alumni&utm_medium=email&utm_source=282656_M11329%20Vice-Chancellors%20video%20message%20to%20alumni%20and%20donors%20Lent%20Term%2021&dm_i=6DCH,623K,1XU7KR,PAEF,1

Sorry, I hadn't seen that oilornothing had answered!
Trying to watch Peston at the same time as typing!