So after providing ample examples yesterday of the median time (from onset) to other symptoms I wanted to dive a little bit into the question of the chances that patients in the mild to moderate study will recover in a manner that is comparable to treatment arm.
But first I wanted to make sure we understand what the data I provided yesterday really means. Because to be honest I didn’t really understand until now.
I cited 24 articles that listed the median time, from onset of symptoms, to the progression of different symptoms. It’s important to understand that these papers are not describing clinical trials that took place. They’re retrospective studies describing the clinical course that patients have been taking upon onset of symptoms.
That took a minute for me to wrap my head around. So most of these don’t break down patients by “mild” or “moderate” or “severe.” They just describe what happened to them over time.
Now with that said, upon onset of first symptom, which is usually cough / fever a patient initially presents as what we could consider mild.
We need to be a little logical about this too and realize that there will be a certain number of mild patients who may recover on their own. But there will also be a certain number of mild patients that 1) develop new symptoms that are categorically mild after onset of first symptom and 2) advance to moderate or perhaps even severe category.
So when we read the data from yesterday that describes disease progressions “from onset of symptoms” that’s basically saying “from the moment they’re still mild.”
Here’s an example of the proper way to frame this – https://jamanetwork.com/journals/jama/fullarticle/2761044
This paper describes the clinical characteristics of 138 patients who were inevitably categorically pneumonia patients.
“The median durations from first symptoms to dyspnea, hospital admission, and ARDS were 5 days (IQR, 1-10), 7 days (IQR, 4-
, and 8 days (IQR, 6-12), respectively (Table 1).”
So like I said earlier, from onset of first symptom = still mild. This quote basically says that from the moment the patient is technically still symptomatically mild, within 8 days they can develop ARDS.
This line of reasoning applies to pretty much every median duration from onset to symptom that I quote in the other 23 papers yesterday.
To wrap up this example, if a mild PLACEBO patient advanced to ARDS within 8 days, the likelihood that they would somehow magically perform AS WELL AS treatment arm is incredibly unlikely.
So I recommend everybody look back at the post from yesterday and take note of the variety of median durations from onset to symptom that can occur.
Next, we need to remember that this is a mild to MODERATE study. Those are two different groups of patients with moderate group having its own separate inclusion criteria which INCLUDES mild symptoms.
From a quote from yesterday “ If findings on the initial assessment are suggestive of moderate or severe illness, hospitalization is generally warranted.”
And
“Patients with moderate or severe Covid-19 are usually hospitalized for observation and supportive care.”
https://www.nejm.org/doi/full/10.1056/NEJMcp2009249
Also from our inclusion criteria for moderate –
• Signs of moderate pneumonia, including RR ≥ 20 but <30, HR ≥ 90 but less than 125, oxygen saturation (pulse oximetry) > 93% on room air AND
• If available, lung infiltrates based on X-ray or CT scan < 50% present
Now I would argue that if a moderate placebo patient enrolls with evidence suggestive of viral pneumonia, the likelihood of them recovering as well as the treatment are is very unlikely.
So now to focus more on duration of symptoms.
One paper looks at the recovery of 4 people with mild to moderate covid. https://jamanetwork.com/journals/jama/fullarticle/2762452
4 patients were treated with antivirals. (we assume some efficacy)
3 presented with cough or fever or both.
Symptom onset to RECOVERY ranged from 12- 32 days.
This means the first to recover took 12 days, the last took 32 days. One patient was symptomatic for 31 days.
A small study, but point being that the fastest recovery WHILE ON ANTIVIRALS in this group was 12 days.
What does that say about our placebo patients?
Here is another study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102530/
250 patients
All admitted into negative pressure ISO wards.
“The estimated median duration of fever in all the patients with fever was 10 days (95 confidential intervals [CIs: 8–11 days]) after onset of symptoms. “
Again, "after onset of symptoms - after initially presenting as mild"
“10 days after onset of symptoms, half of the patients were estimated to restore normal body temperature.”
Here they’re saying HALF of the patients fevers resolved after 10 days of first symptom. That means the other HALF did not.
Here’s the last study I want to examine because my head is hurting -
https://www.thelancet.com/journals/lancet/art...ltext#tbl2
191 patient retrospective
171 patients’ symptoms charted.
**important to note that almost all of them received some type of treatment, antiviral, antibiotic, etc.
2 charts, survivors vs non survivors durations of symptoms
Durations
Fever – 12/13 (surv/non-surv) days from onset (again from starting out as “mild”)
Cough – 19/16 days from onset
Dyspnea– started day 7 from onset, ended day 19 (surv) , started day 7 from onset, ended day 18.5 (non-surv)
ARDS - on day 10/12 from onset
Sepsis - on day 9/10 from onset
So as you can see, the duration of symptoms for these patients lasted quite a bit in spite of many of them being given some form of treatment. Some symptoms occurred several days after onset.
So although this was not comprehensive, it at least gives me some idea of how this could progress. Here’s how I organize this data in my mind and how it informs my thought process regarding our mild to moderate:
1) All patients, regardless of final outcome will present as mild / moderate.
2) Mild is categorically different from moderate, with an increasing likelihood that moderate patients who present with pneumonia will not perform as well as treatment arm.
3) The symptoms a patient presents with initially, may not be the ONLY symptoms they experience during the trial.
4) There is ample evidence supporting that patients who initially present as mild (from onset) will experience symptoms such as dysnpea, ARDS, sepsis, death.
5) There is evidence suggesting that since patients receiving treatment (efficacy debatable/ but antibiotics certainly help prevent secondary infections) still experience symptom durations that last 10+ days and still develop new symptoms/ conditions.
6) With all this in mind, it is not unreasonable to speculate that SOME placebo mild patients will also develop new symptoms during the duration of the trial.
7) It is also not unreasonable to speculate that SOME placebo patients will advance to moderate condition or perhaps further.
It is not unreasonable to speculate that SOME placebo patients’ symptoms will persist through the duration of the trial.
9) And lastly, it is not unreasonable to speculate that for those placebo patients that do advance to moderate or worse, that do develop new symptoms that persist or whose existing symptoms persist – will not perform as well as trial arm.
I have to add it is an assumption that the treatment arm will find great efficacy with leronlimab. I base this on dr. P’s preprint that clearly shows reduction in IL-6, return of lymph. Homeostasis and reduction in viral load all within the first week. (and all the crazy good eIND data working on the worst possible patients)
I grant that additional second week for the clearance of all symptoms in trial arm in case clinical outcomes lag behind immunological markers.
So this is just the best I can do guys. From what I’m reading and seeing, I think the trial arm will compare very favorably against the placebo arm.
Please feel free to ask any questions or poke holes or whatever.
By no means is this totally reliable, this is just the best I can do and I hope it helps.
But first I wanted to make sure we understand what the data I provided yesterday really means. Because to be honest I didn’t really understand until now.
I cited 24 articles that listed the median time, from onset of symptoms, to the progression of different symptoms. It’s important to understand that these papers are not describing clinical trials that took place. They’re retrospective studies describing the clinical course that patients have been taking upon onset of symptoms.
That took a minute for me to wrap my head around. So most of these don’t break down patients by “mild” or “moderate” or “severe.” They just describe what happened to them over time.
Now with that said, upon onset of first symptom, which is usually cough / fever a patient initially presents as what we could consider mild.
We need to be a little logical about this too and realize that there will be a certain number of mild patients who may recover on their own. But there will also be a certain number of mild patients that 1) develop new symptoms that are categorically mild after onset of first symptom and 2) advance to moderate or perhaps even severe category.
So when we read the data from yesterday that describes disease progressions “from onset of symptoms” that’s basically saying “from the moment they’re still mild.”
Here’s an example of the proper way to frame this – https://jamanetwork.com/journals/jama/fullarticle/2761044
This paper describes the clinical characteristics of 138 patients who were inevitably categorically pneumonia patients.
“The median durations from first symptoms to dyspnea, hospital admission, and ARDS were 5 days (IQR, 1-10), 7 days (IQR, 4-
, and 8 days (IQR, 6-12), respectively (Table 1).” So like I said earlier, from onset of first symptom = still mild. This quote basically says that from the moment the patient is technically still symptomatically mild, within 8 days they can develop ARDS.
This line of reasoning applies to pretty much every median duration from onset to symptom that I quote in the other 23 papers yesterday.
To wrap up this example, if a mild PLACEBO patient advanced to ARDS within 8 days, the likelihood that they would somehow magically perform AS WELL AS treatment arm is incredibly unlikely.
So I recommend everybody look back at the post from yesterday and take note of the variety of median durations from onset to symptom that can occur.
Next, we need to remember that this is a mild to MODERATE study. Those are two different groups of patients with moderate group having its own separate inclusion criteria which INCLUDES mild symptoms.
From a quote from yesterday “ If findings on the initial assessment are suggestive of moderate or severe illness, hospitalization is generally warranted.”
And
“Patients with moderate or severe Covid-19 are usually hospitalized for observation and supportive care.”
https://www.nejm.org/doi/full/10.1056/NEJMcp2009249
Also from our inclusion criteria for moderate –
• Signs of moderate pneumonia, including RR ≥ 20 but <30, HR ≥ 90 but less than 125, oxygen saturation (pulse oximetry) > 93% on room air AND
• If available, lung infiltrates based on X-ray or CT scan < 50% present
Now I would argue that if a moderate placebo patient enrolls with evidence suggestive of viral pneumonia, the likelihood of them recovering as well as the treatment are is very unlikely.
So now to focus more on duration of symptoms.
One paper looks at the recovery of 4 people with mild to moderate covid. https://jamanetwork.com/journals/jama/fullarticle/2762452
4 patients were treated with antivirals. (we assume some efficacy)
3 presented with cough or fever or both.
Symptom onset to RECOVERY ranged from 12- 32 days.
This means the first to recover took 12 days, the last took 32 days. One patient was symptomatic for 31 days.
A small study, but point being that the fastest recovery WHILE ON ANTIVIRALS in this group was 12 days.
What does that say about our placebo patients?
Here is another study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102530/
250 patients
All admitted into negative pressure ISO wards.
“The estimated median duration of fever in all the patients with fever was 10 days (95 confidential intervals [CIs: 8–11 days]) after onset of symptoms. “
Again, "after onset of symptoms - after initially presenting as mild"
“10 days after onset of symptoms, half of the patients were estimated to restore normal body temperature.”
Here they’re saying HALF of the patients fevers resolved after 10 days of first symptom. That means the other HALF did not.
Here’s the last study I want to examine because my head is hurting -
https://www.thelancet.com/journals/lancet/art...ltext#tbl2
191 patient retrospective
171 patients’ symptoms charted.
**important to note that almost all of them received some type of treatment, antiviral, antibiotic, etc.
2 charts, survivors vs non survivors durations of symptoms
Durations
Fever – 12/13 (surv/non-surv) days from onset (again from starting out as “mild”)
Cough – 19/16 days from onset
Dyspnea– started day 7 from onset, ended day 19 (surv) , started day 7 from onset, ended day 18.5 (non-surv)
ARDS - on day 10/12 from onset
Sepsis - on day 9/10 from onset
So as you can see, the duration of symptoms for these patients lasted quite a bit in spite of many of them being given some form of treatment. Some symptoms occurred several days after onset.
So although this was not comprehensive, it at least gives me some idea of how this could progress. Here’s how I organize this data in my mind and how it informs my thought process regarding our mild to moderate:
1) All patients, regardless of final outcome will present as mild / moderate.
2) Mild is categorically different from moderate, with an increasing likelihood that moderate patients who present with pneumonia will not perform as well as treatment arm.
3) The symptoms a patient presents with initially, may not be the ONLY symptoms they experience during the trial.
4) There is ample evidence supporting that patients who initially present as mild (from onset) will experience symptoms such as dysnpea, ARDS, sepsis, death.
5) There is evidence suggesting that since patients receiving treatment (efficacy debatable/ but antibiotics certainly help prevent secondary infections) still experience symptom durations that last 10+ days and still develop new symptoms/ conditions.
6) With all this in mind, it is not unreasonable to speculate that SOME placebo mild patients will also develop new symptoms during the duration of the trial.
7) It is also not unreasonable to speculate that SOME placebo patients will advance to moderate condition or perhaps further.
It is not unreasonable to speculate that SOME placebo patients’ symptoms will persist through the duration of the trial. 9) And lastly, it is not unreasonable to speculate that for those placebo patients that do advance to moderate or worse, that do develop new symptoms that persist or whose existing symptoms persist – will not perform as well as trial arm.
I have to add it is an assumption that the treatment arm will find great efficacy with leronlimab. I base this on dr. P’s preprint that clearly shows reduction in IL-6, return of lymph. Homeostasis and reduction in viral load all within the first week. (and all the crazy good eIND data working on the worst possible patients)
I grant that additional second week for the clearance of all symptoms in trial arm in case clinical outcomes lag behind immunological markers.
So this is just the best I can do guys. From what I’m reading and seeing, I think the trial arm will compare very favorably against the placebo arm.
Please feel free to ask any questions or poke holes or whatever.
By no means is this totally reliable, this is just the best I can do and I hope it helps.
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