The latest Investing Matters Podcast episode featuring Jeremy Skillington, CEO of Poolbeg Pharma has just been released. Listen here.
I wonder whether the NIH would now consider SNG001 for the ACTIV-3 hospital trial.
We discussed this earlier today. A potential explanation could be that in the second half of the trial there were significantly more protocol violations due to hospitals being overwhelmed and so wasn’t showing up as an issue in the futility analysis. All speculation of course, but a possible explanation in the absence of further info.
Refer to the thread ‘Drop out rate & major protocol violations’. Brand’s post explains it well.
TommyD_19 - worth noting not all drop outs were due to protocol violations. There would've been patients withdrawing from the trial for whatever reason. How many withdrew or how many violations are unkown to us.
Not sure if this was discussed last week. The drop out rate for SG018 was 17% (106 patients) which based on a quick search does not seem unusual or high. I assume a drop out rate would've been factored into the trial design with regards to the number of patients required. I hope so.
Now this is the interesting bit. Additional notes to Table 1 list the following major protocol violations which would've impacted the results of the trial. The extend to which it would've impacted the results we simply don't know since the RNS does not quantify the number of patients involved. Nevertheless it does not make for good reading and is incredibly unfortunate. Were these violations a result of overwhelmed hospitals or substandard hospital care?
These violations included:
- receiving fewer than 2 full doses in the first 3 days
- ongoing SARS-CoV-2 infection for more than 3 weeks prior to randomisation
- not having a positive SARS-CoV-2 test result at screening
- patients kept in hospital for reason other than the severity of their COVID-19
- patients who were not escalated to advanced respiratory support despite clinical need.
Is it possible that major protocol violations were not an issue at the futility analysis stage and therefore would explain a positive indicator?
If the number of major protocol violations are significant is it possible to replace these by recruiting additional patients? I guess so.
TommyD_19 - according to an earlier version of the protocol SNG001 would’ve been allocated patients in the lower and higher risk cohorts. A change to the protocol was made in May 2021, but what we don’t know is whether this change was applicable to SNG001 or whether it was only applicable to new trials like SAB-185. I think the change was signed off in April 2021.
Protocol wording - ‘original’
‘The study includes both infused and non-infused agents. For infused agents, enrollment will be restricted to participants at higher risk of progression to severe COVID-19. Non-infused agents will be open to participants at both "higher" and "lower" risk of progression to severe COVID-19.’
Protocol amendment on 18 May 2021.
‘The study includes both infused and non-infused agents. Version 6.0 of the protocol restricts enrollment to agents in phase II to participants at lower risk of progression to severe COVID-19, regardless of the mode of administration of the agent.’
I would advise against focussing on the word ‘compromised’ and to try and gain some kind of hope from it. SNG001 and placebo were always going to be administered on top of standard of care which includes steroids.
My current view is that the wrong primary endpoints were chosen. It would be interesting to understand why severe disease and death were not chosen when that was the biggest benefit observed from SG016 hospital and again came out as the ‘winners’ of SG018.
Also, do not place any hope on getting news from the company this week with regards to what happened, next steps or what the data says. Especially in times like this it’s better to not get expectations unnecessarily up. They’re understandably under a HUGE amount of pressure for various reasons and so they need to get all their ducks and more in a row.
How did the interim analysis get it so wrong and if a z-score analysis is so unreliable why was it even used?
I most definitely got things wrong and so it is a tough one to swallow - it'll take some time to process I guess. There's nothing more that I can add that hasn't already been said. So I'll just extend my commiserations to all.
mact4 - go read the protocol otherwise refer to my earlier post. Study was fully unblinded from the time of the primary analysis.
Expand the section on Synairgen, download the zip, open it, open the protocol pdf & go to paragraph 8.10 on page 59.
https://www.aifa.gov.it/en/web/guest/sperimentazioni-cliniche-covid-19
My comment and question’s emphasis is on FULLY UNblinded study. If there was any risk of bias the protocol would not have allowed the study to be unblinded.
This is what the protocol says. Paragraph 8.10
‘A primary analysis will take place once all randomised patients have completed their Day 35 visit or have withdrawn from the study. The primary analysis will be used to assess the study data against the study objectives. All data summaries documented in the SAP will be produced for the primary analysis and will be reported in a CSR, with the exception of any Day 90 summaries. The study will be fully unblinded from the point of the primary analysis. A follow- up analysis will be conducted once all patients have completed the Day 90 visit or have withdrawn from the study.’
Beforegolf - the protocol states that data is fully unblinded and remains unblinded from the point of the primary analysis (PA) with the it (i.e. PA) being conducted as soon as day 35 data have been collected. Surely Synairgen would at least be made aware of the results of the PA? Since the protocol states that the study is fully unblinded from this point onwards they’d have access to the data too. If data remained blinded until day 90 I’d fully understand that they’d not be privy to any data/results.
Sid1222 - it’s speculated that they were waiting to complete the trial first before releasing results i.e. completing the 90 day visit of the last enrolled patient(s). The reason being that releasing results prior to the 90 day visit may result in the patients being biased towards the trial result.
Other than that I don’t know why else it would take this long. It shouldn’t since we’re only talking about top line results which is only a few metrics.
It’s worth remembering that data quality was monitored and corrected where necessary during the trial and not left until after.
This does make me laugh. Do you really think Catalent don't have any other customers except for some small company called Synairgen? So when they advertise for a couple of warehouse roles or potentially buy another site it must be linked to Synairgen.
Catalent already have five sites in the UK in Swindon, Nottingham, Dartford, Bathgate and Haverhill so this is just another site with absolutely no evidence whatsoever to link this to Synairgen. Nada.
It's the same as the other day when someone got all excited about Akron advertising for a few roles. Again this must only be for Synairgen.
Seriously people - get some perspective. We live in a big world. Until there is some kind of concrete evidence to link this to Synairgen it's not worth getting excited about.
No I don't agree alkin.
Firstly, PCAs don't require authorisation to deal. PDMRs are not allowed to deal during closed periods or any other period the company deems 'too sensitive' for dealing, unless an exemption applies for example where the PDMR require funds for an emergency situation. A company may have a blanket rule requiring PDMRs to obtain authorisation to deal outside closed periods. In my view Synairgen would deem this period too sensitive to allow any trading by a PDMR. And, remember this dealing does not involve a PDMR.
Secondly, it's wrong to suggest PDMRs generally share such sensitive information with their spouses. You may have a few bad apples that are unprofessional, but it's not a given.
Lastly the company knew the results of the trial at the end of Jan, but that is irrelevant since the dealing involves a PCA. It would be wrong to suggest Brooke would share such information with her husband who in turn bought the stock.
https://www.burges-salmon.com/news-and-insight/legal-updates/aim-companies-transactions-by-pdmrs-and-pcas
Great find Brand. Thx.
It would be interesting to know how it came about that Synairgen ended up being a 'founding client'.
Quite a few posts regarding this topic today and not surprisingly all have it (basically) wrong.
Brooke Clark is a PDMR (person discharging managerial responsibilities). Her husband is a PCA (person closely associated).
The specific dealing (i.e. shares bought at the end of Jan 2022) in question was executed by a PCA, Brooke's husband. It wasn't a dealing by a PDMR. As such the only requirement is that the PCA notify the PDMR who in turn needs to notify the company. The company has an obligation to report dealings by PCAs and PDMRs to the FCA and the market.
I've not been able to find any literature setting out any prohibitions on dealings by PCAs.
Thank you :-)
Is AMEGA Biotech the mysterious manufacturer which is one of the key global players in the manufaturing of IFN beta? It would make total geographical sense.
Anyone familiar with NHS England's hospital bed definitions i.e. type of care? They provide the bed occupation numbers for total covid hospital bed occupation which is then broken down into mechanical ventilation, adult general & acute care and lastly adult critical care. I suspect there's a fourth category as the individual numbers don't tie back to the total number.
SNG001's focus is on patients requiring oxygen so these would, I assume, be in the critical care category. Could a patient requiring oxygen be in the general and acute care category by any chance?
ThinShins - thx for sharing. Frustrating update!