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Noticed thanks. I pinged you the details of the stats models etc.
Yes we could reach 100p again and more, but for that to happen we need significantly positive developments. The next few weeks or month will be telling, maybe longer.
Joshholdforgold - I believe I joined the group r/synairgen which has 956 members. It says so. Although I can see posts, quite old, I can’t see or make any comments.
TommyD_19 - unfortunately it's the reality of small trials where one patient can move the dial to either achieve statistical significance or not. We can't try and blame withdrawals or protocol violations, but it won't change the outcome. It happens in every trial so contingency should've been built into the trial design and protocol to account for that. I suspect the protocol violations are much higher than expected since it's explicitly being mentioned.
Elsol - agree if you combine the trends observed across SG016 and SG018 then there is a clear trend, even if you add SG016 HOME. So the independent trends, even though each of them not statistically significant on their own, do show 'proof of significance' if you will when combined as you say. I assume the same trends were observed in ACTIV-2 phase II.
We can only hope that the combined data sets will proof to be enough to secure positive next steps, whatever that might be, for SNG001 with regard to Covid. I do struggle to see how ACTIV-2 phase III can be pulled off based on the reasons provided which is low hospitalisations. The fact that we're still in the race means the NIAID has some ideas to take this forward, the question is what are those ideas.
* just to correct. It's intubation or death and not just intubation.
Another interesting observation which caught my eye. Before anyone says something I'm not insinuating anything though!
- exactly 53 patients removed from both placebo and SNG001 groups for secondary endpoints.
- 7 deaths in SNG001 in PPP. Exactly double that number in ITT.
- 10 intubation/deaths in SNG001 in PPP. Exactly double that number in ITT.
A post for those who are experts in statistics as I’m not one. Need your assistance if you have the time and keen to participate.
I’m attempting to determine the maximum number of deaths we could afford in SG018 to show statistical significance using the data provided in the RNS. In order to do this I made use of online calculators to determine the OR (odds ratio) – refer to the link below. For starters I cannot with this or any other online calculator match the OR or p-value as per the RNS for deaths in either the ITT or PPP groups.
https://www.gigacalculator.com/calculators/odds-ratio-calculator.php
Focussing on the ITT population where 17 died in the placebo group this calculator seems to suggest we could afford eight deaths in SNG001 to show a p-value of < 0.05. Interestingly eight deaths represent 2.6% (8/309) of the ITT population. In the PPP population seven died which represents 2.7% (7/256).
I’m pretty sure it’s probably not as simple as the above and your assistance/guidance/participation would be appreciated. Just playing around with the numbers to try and determine how badly we were affected by excluded patients (ExPPP).
Some interesting numbers re ExPPP. The below indicates the likelihood of progressing to either death, severe disease or intubation if you’re in the ExPPP group vs those in the PPP group.
Death ITT vs PPP: 2.05 vs 4.83
Severe disease ITT vs PPP: 2.15 vs 3.14
Intubation ITT vs PPP: 2.63 vs PPP: 4.83
A similar trend is observed if you compare ExPPP to ITT which brings me to the conclusion the ExPPP group consisted of (potentially) more poorly patients. So the question is what proportion of these withdrew from the trial vs protocol violations.
A good case yes. Just needs statistical significance. Frustrating.
I wonder if Sprinter’s 35 day period had any impact on the numbers. All other trials used 28 days.
Yes an interesting read. Not one to get hopes up on though.
My hope is that management will be ambitious in their attempts to explore every possible avenue to get the product to market, without getting desperate of course. For example making use of surrogate endpoints (prevention of severe disease/death) while continueing trials. Provided SG018 provides supporting data. What counts for us is SNG001’s safety profile.
RM referred to something similar in his 28 Jan 2021 interview with Proactive.
That got changed. The 6th bullet point under 'Exclusion criteria' states the following:
'Receipt of other investigational treatments for SARS-CoV-2 any time before participating in the study (not including drugs approved and taken for other conditions/diseases or COVID-19 vaccines).'
https://clinicaltrials.gov/ct2/history/NCT04518410?A=96&B=96&C=merged#StudyPageTop
Synairgen are responsible for preparing and providing the SNG001 (and placebo) kits to the NIAID. It is these activities that need pausing.
Gunto - agree very much. In short we cannot rule anything out, good or bad. (Just don't like the latter.) You mentioned the relationship dates back to 2013. It could be that the NIH realised that if SNG001 was given a helping hand back in the day they could've had a drug to administer during the pandemic. Understandably the science behind the innate immune system, how it interacts with respiratory viruses, how respiratory viruses circumvent it and SNG001 being virus agnostic is now much better understood than 10 years ago. So it could be a case of them not wanting to let the grass grow under their feet (again) i.e. pandemic preparedness. It might cost them let's say $100m - $200m to assist SNG to get over the line, but in the bigger scheme of things that's nothing. Purely speculating though.
I've had a look at the ACTIV-2 protocol last night to see if I can find anything in the protocol that could explain their support for SNG001 i.e. why it wasn't kicked off like SAB-185 was. This is what I find. I shall stress that I'm not saying these are the reasons, rather differences which could potentially explain their actions.
1) (Page 24): Although recent data from monoclonal antibody treatments have documented associations between higher baseline levels of viral shedding in NP swabs and and higher rates of hospitalization and all-cause death [17], it is unknown if an investigational agent that is effective in reducing symptom duration and/or viral shedding will have meaningful impact on the clinical outcome of hospitalization or death. Therefore, an investigational agent that has shown preliminary evidence of effects on viral shedding, clinical symptoms, and/or hospitalization/death compared to placebo, and has an acceptable safety profile in phase II evaluation will be considered by the TOC for graduation to phase III evaluation.
2) (Page 240) It does seem, although not 100% clear, that in phase III only high risk patients who report moderate to severe shortness of breath or difficulty breathing at day 0 were considered for SNG001 (p. 240 of the protocol) whereas all high risk patients were considered for SAB-185. This potential difference, if confirmed, could mean that the probability of SNG001 achieving statistical significance is potentially higher.
To clarify I’m not attempting to put a positive spin on it. Merely trying to understand.
It does seem, although not 100% clear, that in phase III only high risk patients who report moderate to severe shortness of breath or difficulty breathing at day 0 were considered for SNG001 (p. 240 of the protocol) whereas all high risk patients were considered for SAB-185. This potential difference, if confirmed, could mean that the probability of SNG001 achieving statistical significance is potentially higher.
We already have the supplies, it’s just we need to pause activities in getting them ready for the trial.
I agree we are not out of the woods yet. Need to be cautiously optimistic and hope for the best. The fact that we’re still in seems to suggest something and this is why I made the earlier statement on another thread. How come we’ve not been kicked out while SAB-185 got kicked out for a reason which very well applies to us. What’s their (NIH) thinking as to how they think they can make this work - if they thought it won’t work it would’ve been culled. I’m not sure it’s to do with a contract, because there’s also a contract with SAB and that was ended.
It would be great to understand all this. I just hope we’ll have some kind of ACTIV platform at the end.
Those details will be in the SAP which is not publicly available.
8.7 Other Analyses
Tabulations will be provided for completion/withdrawal status, protocol deviations, study populations, demographic and other baseline characteristics, use of concomitant medications, and exposure of and compliance with study drug.
8.8 Subgroup Analyses
The following subgroups will be considered for analysis:
- Age category
- Presence of comorbidities
- Current smoking status
- Sex
- Race
- Prior duration of symptoms
- BMI
The details of analyses to be performed for the subgroups will be defined in the SAP (Statistical Analysis Plan).
The SPRINTER protocol states that blood samples (for immunogenicity test) are to be collected on day 0 i.e. pre treatment and on day 45 (+- 5 days). The footnote does state 'where feasible'.
Here's the full text.
6.13.2 Blood sample for immunogenicity testing
A blood sample will be taken as per the study schedule for immunogenicity testing. This will be completed in all sites and for all patients, where collection of samples is feasible. If a site is not able to participate in immunogenicity sample collection, this will not preclude them from participation in the study. The sample will require processing to obtain serum which is required for the analysis. A laboratory manual describing the requirements for the blood sample and the processing of the sample will be provided separately by the Sponsor (or delegate).
Thx Gunto - reassuring read and sounds all good. We now just need to deliver the goods.
What I’m curious to know is how the NIH is planning on modifying ACTIV-2 to ‘make it work’ for SNG001 in an Omicron world. The reason why SAB-185 was kicked off could very well apply to SNG001 which is what got me really worried yesterday.
So the question is what are they thinking? And please they better come up with a plan!
TommyD_19 - totally get that you're not trying to sugar coat today's news. It's true what you say about SAB-185 not meeting other end points, however the phase II trial was small and the change to lower risk patients didn't do them any favours. So I'd be careful to read too much into that.
Agree SNG is good at preventing severe disease and death, just need it proven in a bigger trial. Fingers crossed ACTIV keeps us on.
Thx gunto2020. If for argument sake ACTIV-2 is being halted then news should've been released by both companies at the 'same' time, ideally, and not in this manner where a huge amount of uncertainty is being created. If this is the case then it would have been an irresponsible action by the NIH.
Synairgen now needs to update the market pretty quickly re ACTIV-2. I hope they're in a position to do so; that's if the NIH have discussed next steps with them already.
Yeah, as in zero. They (ACTIV-3) need candidates and we need a platform. It's a favour both ways :-)