So with the un-blinding of the data on June 15th announced and the possible publication of top-line results at the end of June/ first week of July, one concern I've seen expressed is the possibility of the placebo group performing comparably to the treatment group.
I'll address one part of this with this post. I wanted to see what the clinical progression for patients was like from the onset of symptoms for Covid generally. I found 24 articles focused totally or partially on the characterization of the clinical course for the disease.
I quoted a relevant part of each article then extrapolated what it could mean in the context of the mild to moderate trial.
Basically what I've extrapolated is that anything from the progression to dyspnea to progression to death could occur from the onset of symptoms within a duration of time that is less that or equal to the 14 day primary outcome measure of our study.
In other words, a placebo patient could experience dyspnea, hospital admission, ARDS, sepsis and death within the duration of our trial.
I won't get into Leron's MOA for the moment, but I will say that I'm confident that the trial arm will not experience any progressions like the patients described in these studies.
Just please note the way I'm presenting this data is a bit of a simplification due to formatting issues and just sheer density of the reading involved.
This post is really just to demonstrate that it is definitely possible that placebo patients in our M2M study will progress to a more advanced stage of the disease within the duration of the study.
I have not included data regarding HOW MANY mild to moderate patients recover on their own, or how fast.
I will look into mild to moderate patient recovery data tomorrow.
With regards to my outook on the m2m trial, I think this information lends credibility to the possibility that placebo arm will not perform as well as treatment arm.
Quote "However, some patients who have mild symptoms initially will subsequently have precipitous (dangerously steep) clinical deterioration that occurs approximately 1 week after symptom onset.17,18 " https://www.nejm.org/doi/full/10.1056/NEJMcp2009249
Extrapolation to m2m Mild placebo patients in our trial may experience rapid deterioration over duration of trial.
Quote "If findings on the initial assessment are suggestive of moderate or severe illness, hospitalization is generally warranted."
https://www.nejm.org/doi/full/10.1056/NEJMcp2009249
Extrapolation to m2m Moderate placebo patients may need to be admitted.
Quote "In the report from Wuhan mentioned above, the time between the onset of symptoms and the development of ARDS was as short as 9 days, suggesting that the respiratory symptoms could progress rapidly" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169933/
Extrapolation to m2m Mild or moderate m2m patients may advance to ARDS within duration of trial.
Quote "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)." https://jamanetwork.com/journals/jama/fullarticle/2761044
Extrapolation to m2m Placebo patients may advance to dyspnea, hospital admission and ARDS within duration of trial.
Quote "The median time from onset of symptoms to dyspnea was 5 d, hospitalization 7 d and acute respiratory distress syndrome (ARDS) 8 d." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090728/
Extrapolation to m2m Placebo patients may advance to dyspnea, hospital admission and ARDS within duration of trial.
Quote "Figure 4 shows, for COVID-19 positive deceased patients, the median times, in days, from the onset of symptoms to death (8 days), from the onset of symptoms to hospitalization (4 days) and from hospitalization to death (4 days)." https://www.epicentro.iss.it/coronavirus/boll...zo_eng.pdf
Extrapolation to m2m Placebo patient may advance to death within the duration of trial
Quote "Among those who developed symptoms in the community, the median time from symptom onset to hospitalization was 1.2 days (range, 0.2 to 29.9 days) (Figure 1)." https://www.acpjournals.org/doi/10.7326/M20-0504
Extrapolation to m2m Placebo patients may require hospitalization within duration of trial.
Quote "Of the 248 patients with repeated radiology examination, the image showed progression in 163 (65.7%) patients after a median of 3 days (that is the 7th day after onset of symptoms), including three patients whose images were normal on admission." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102530/
Extrapolation to m2m Placebo patients may show disease progression / advancement via radiological exam within the duration of trial.
Quote "The median time from illness onset to invasive mechanical ventilation was 14·5 days (12·0–19·0)." https://www.thelancet.com/journals/lancet/art...3/fulltext
Extrapolation to m2m Placebo patients may require mechanical ventiliation within the duration of the trial.
Quote "Median time from illness onset to dyspnoea was similar in survivors and non-survivors, with a median duration of dyspnoea of 13·0 days (9·0–16·5) for survivors (table 2; figure 1). In survivors, the median duration of fever was 12·0 days (8·0–13·0) and cough persisted for 19·0 days (IQR 12·0–23·0; figure 1). 62 (45%) survivors still had cough on discharge and 39 (72%) non-survivors still had cough at the time of death.
The dynamic profiles of fever, cough, and dyspnoea are shown in the appendix (p 6). Sepsis developed at a median of 9·0 days (7·0–13·0) after illness onset among all patients, followed by ARDS (12·0 days [8·0–15·0]), acute cardiac injury (15·0 days [10·0–17·0]), acute kidney injury (15·0 days [13·0–19·5]), and secondary infection (17·0 days [13·0–19·0])."
https://www.thelancet.com/journals/lancet/art...3/fulltext
Extrapolation to m2m Placebo patients may advance to dyspnea, sepsis ARDS, acute cardiac injury, acute kidney injury, secondary infection within the duration of the trial.
Fever and cough may persist over the duration of the trial.
Quote "Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0])" https://www.thelancet.com/journals/lancet/art...5/fulltext
Extrapolation to m2m Placebo patients may develop dyspnea within the duration of the trial.
Quote "Wang et al. [8] reported that time period between onset of COVID-19 symptoms to death ranges between 6-41 days with a 14-day median. " https://www.sciencedirect.com/science/article...7520300317
Extrapolation to m2m Placebo patients may advance to death within duration of the trial.
Quote "With COVID-19, patients typically have fever (98%), cough (76%), dyspnea (55%; median time from illness onset to dyspnea of 8.0 days), and myalgia or fatigue (44%). Other signs, such as sputum production (28%), headache (8%), hemoptysis (5%), and diarrhea (3%), may be present.
The median time from onset of symptoms to first hospital admission, shortness of breath, acute respiratory distress syndrome (ARDS), mechanical ventilation, and ICU admission was 7, 8, 9, 10.5, and 10.5 days, respectively."
https://journals.plos.org/plospathogens/artic...at.1008536
Extrapolation to m2m Placebo patients may advance to dyspnea, ARDS, ventiliation and ICU admission within duration of the trial.
Quote "The median time to onset of dyspnoea from various cohorts was found to be 6 days following exposure." https://link.springer.com/chapter/10.1007/978...5-4814-7_6
Extrapolation to m2m Placebo patients may advance to dyspnea within duration of trial.
Quote "The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days." https://www.bmj.com/content/368/bmj.m1091
Extrapolation to m2m Placebo patients may advance to death within duration of the trial.
Quote "The median time from onset of symptoms to first
hospital admission was 8.0 days in severe cases and 7.0 days in moderate cases." https://www.jci.org/articles/view/137244
Extrapolation to m2m Placebo patients may require admission within duration of trial.
Quote "4 of these 7 patients presented with fever as first symptom. The median duration from first symptom to death was 9 days (IQR, 6–11). All these patients developed respiratory failure and had three or more complications. " https://europepmc.org/article/pmc/pmc7128617
Extrapolation to m2m Placebo patients may advance to within duration of trial.
Quote "The median age of the infected patients was 47 years (interquartile range [IQR], 41.0–58.0), and the median time from onset to admission was 7 days (IQR, 4.0–8.0)." https://academic.oup.com/pcm/article/3/1/14/5722042
Extrapolation to m2m Placebo patients may require admission within duration of trial.
Quote "About half of the patients had dyspnea (the median from onset to dyspnea was 8 days)." https://www.ijidonline.com/article/S1201-9712...5/fulltext
Extrapolation to m2m Placebo patients may advance to dyspnea within duration of trial.
Quote "After onset of illness, the symptoms are somehow mild and the median time to first hospital admission is 7.0 days (4.0–8.0). But the disease progresses to short of breath (~8 days), acute respiratory distress syndrome (ARDS) (~9 days), and to mechanical ventilation (~10.5 days) in about 39% patients.1" https://journals.lww.com/jcma/FullText/2020/0...iew.3.aspx
Extrapolation to m2m Placebo patients require admission and advance to dyspnea, ARDS and ventilation within duration of trial.
Quote "It has been stated that 81% of patients will present with mild to a moderate presentation of COVID-19 with mild symptoms up to mild pneumonia; however, in the remaining 19%, the median time to ARDS ranged from 8 to 12 days and the median time to ICU admission ranged from 10 to 12 days [22,26]." https://www.cureus.com/articles/30692-novel-c...references
Extrapolation to m2m Placebo patients may advance to ARDS and ICU admission within duration of trial.
Quote "Among all patients, there was a mean time of 5.6 ± 2.8 d (range, 2 to 14) from the onset of fever to the occurrence of dyspnea. " https://erj.ersjournals.com/content/early/202...00990-2020
Extrapolation to m2m Placebo patients may advance to dyspnea within duration of trial.
Quote "In another study of 51 patients with confirmed COVID-19, 1324 lung lesions were detected on chest CT within 1 to 14 days (median, 4 days) of symptom onset [19]." https://www.ajronline.org/doi/full/10.2214/AJR.20.23034
Extrapolation to m2m Placebo patients may develop lung lesions within duration of trial.
Quote "Zhou et al. showed that the survivors group developed ARDS and sepsis on days 9 and 10, respectively. Conversely, the non-survivors group developed ARDS and sepsis later, on days 10 and 12, respectively. Furthermore, the non-survivors group developed more complications such as acute kidney injury (AKI) and secondary infection by days 15 and 17, respectively." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138423/
Extrapolation to m2m Placebo patients may develop ARDS and sepsis within duration of trial.
I'll address one part of this with this post. I wanted to see what the clinical progression for patients was like from the onset of symptoms for Covid generally. I found 24 articles focused totally or partially on the characterization of the clinical course for the disease.
I quoted a relevant part of each article then extrapolated what it could mean in the context of the mild to moderate trial.
Basically what I've extrapolated is that anything from the progression to dyspnea to progression to death could occur from the onset of symptoms within a duration of time that is less that or equal to the 14 day primary outcome measure of our study.
In other words, a placebo patient could experience dyspnea, hospital admission, ARDS, sepsis and death within the duration of our trial.
I won't get into Leron's MOA for the moment, but I will say that I'm confident that the trial arm will not experience any progressions like the patients described in these studies.
Just please note the way I'm presenting this data is a bit of a simplification due to formatting issues and just sheer density of the reading involved.
This post is really just to demonstrate that it is definitely possible that placebo patients in our M2M study will progress to a more advanced stage of the disease within the duration of the study.
I have not included data regarding HOW MANY mild to moderate patients recover on their own, or how fast.
I will look into mild to moderate patient recovery data tomorrow.
With regards to my outook on the m2m trial, I think this information lends credibility to the possibility that placebo arm will not perform as well as treatment arm.
Quote "However, some patients who have mild symptoms initially will subsequently have precipitous (dangerously steep) clinical deterioration that occurs approximately 1 week after symptom onset.17,18 " https://www.nejm.org/doi/full/10.1056/NEJMcp2009249
Extrapolation to m2m Mild placebo patients in our trial may experience rapid deterioration over duration of trial.
Quote "If findings on the initial assessment are suggestive of moderate or severe illness, hospitalization is generally warranted."
https://www.nejm.org/doi/full/10.1056/NEJMcp2009249
Extrapolation to m2m Moderate placebo patients may need to be admitted.
Quote "In the report from Wuhan mentioned above, the time between the onset of symptoms and the development of ARDS was as short as 9 days, suggesting that the respiratory symptoms could progress rapidly" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169933/
Extrapolation to m2m Mild or moderate m2m patients may advance to ARDS within duration of trial.
Quote "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)." https://jamanetwork.com/journals/jama/fullarticle/2761044 Extrapolation to m2m Placebo patients may advance to dyspnea, hospital admission and ARDS within duration of trial.
Quote "The median time from onset of symptoms to dyspnea was 5 d, hospitalization 7 d and acute respiratory distress syndrome (ARDS) 8 d." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090728/
Extrapolation to m2m Placebo patients may advance to dyspnea, hospital admission and ARDS within duration of trial.
Quote "Figure 4 shows, for COVID-19 positive deceased patients, the median times, in days, from the onset of symptoms to death (8 days), from the onset of symptoms to hospitalization (4 days) and from hospitalization to death (4 days)." https://www.epicentro.iss.it/coronavirus/boll...zo_eng.pdf
Extrapolation to m2m Placebo patient may advance to death within the duration of trial
Quote "Among those who developed symptoms in the community, the median time from symptom onset to hospitalization was 1.2 days (range, 0.2 to 29.9 days) (Figure 1)." https://www.acpjournals.org/doi/10.7326/M20-0504
Extrapolation to m2m Placebo patients may require hospitalization within duration of trial.
Quote "Of the 248 patients with repeated radiology examination, the image showed progression in 163 (65.7%) patients after a median of 3 days (that is the 7th day after onset of symptoms), including three patients whose images were normal on admission." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102530/
Extrapolation to m2m Placebo patients may show disease progression / advancement via radiological exam within the duration of trial.
Quote "The median time from illness onset to invasive mechanical ventilation was 14·5 days (12·0–19·0)." https://www.thelancet.com/journals/lancet/art...3/fulltext
Extrapolation to m2m Placebo patients may require mechanical ventiliation within the duration of the trial.
Quote "Median time from illness onset to dyspnoea was similar in survivors and non-survivors, with a median duration of dyspnoea of 13·0 days (9·0–16·5) for survivors (table 2; figure 1). In survivors, the median duration of fever was 12·0 days (8·0–13·0) and cough persisted for 19·0 days (IQR 12·0–23·0; figure 1). 62 (45%) survivors still had cough on discharge and 39 (72%) non-survivors still had cough at the time of death.
The dynamic profiles of fever, cough, and dyspnoea are shown in the appendix (p 6). Sepsis developed at a median of 9·0 days (7·0–13·0) after illness onset among all patients, followed by ARDS (12·0 days [8·0–15·0]), acute cardiac injury (15·0 days [10·0–17·0]), acute kidney injury (15·0 days [13·0–19·5]), and secondary infection (17·0 days [13·0–19·0])."
https://www.thelancet.com/journals/lancet/art...3/fulltext
Extrapolation to m2m Placebo patients may advance to dyspnea, sepsis ARDS, acute cardiac injury, acute kidney injury, secondary infection within the duration of the trial.
Fever and cough may persist over the duration of the trial.
Quote "Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0])" https://www.thelancet.com/journals/lancet/art...5/fulltext
Extrapolation to m2m Placebo patients may develop dyspnea within the duration of the trial.
Quote "Wang et al. [8] reported that time period between onset of COVID-19 symptoms to death ranges between 6-41 days with a 14-day median. " https://www.sciencedirect.com/science/article...7520300317
Extrapolation to m2m Placebo patients may advance to death within duration of the trial.
Quote "With COVID-19, patients typically have fever (98%), cough (76%), dyspnea (55%; median time from illness onset to dyspnea of 8.0 days), and myalgia or fatigue (44%). Other signs, such as sputum production (28%), headache (8%), hemoptysis (5%), and diarrhea (3%), may be present.
The median time from onset of symptoms to first hospital admission, shortness of breath, acute respiratory distress syndrome (ARDS), mechanical ventilation, and ICU admission was 7, 8, 9, 10.5, and 10.5 days, respectively."
https://journals.plos.org/plospathogens/artic...at.1008536
Extrapolation to m2m Placebo patients may advance to dyspnea, ARDS, ventiliation and ICU admission within duration of the trial.
Quote "The median time to onset of dyspnoea from various cohorts was found to be 6 days following exposure." https://link.springer.com/chapter/10.1007/978...5-4814-7_6
Extrapolation to m2m Placebo patients may advance to dyspnea within duration of trial.
Quote "The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days." https://www.bmj.com/content/368/bmj.m1091
Extrapolation to m2m Placebo patients may advance to death within duration of the trial.
Quote "The median time from onset of symptoms to first
hospital admission was 8.0 days in severe cases and 7.0 days in moderate cases." https://www.jci.org/articles/view/137244
Extrapolation to m2m Placebo patients may require admission within duration of trial.
Quote "4 of these 7 patients presented with fever as first symptom. The median duration from first symptom to death was 9 days (IQR, 6–11). All these patients developed respiratory failure and had three or more complications. " https://europepmc.org/article/pmc/pmc7128617
Extrapolation to m2m Placebo patients may advance to within duration of trial.
Quote "The median age of the infected patients was 47 years (interquartile range [IQR], 41.0–58.0), and the median time from onset to admission was 7 days (IQR, 4.0–8.0)." https://academic.oup.com/pcm/article/3/1/14/5722042
Extrapolation to m2m Placebo patients may require admission within duration of trial.
Quote "About half of the patients had dyspnea (the median from onset to dyspnea was 8 days)." https://www.ijidonline.com/article/S1201-9712...5/fulltext
Extrapolation to m2m Placebo patients may advance to dyspnea within duration of trial.
Quote "After onset of illness, the symptoms are somehow mild and the median time to first hospital admission is 7.0 days (4.0–8.0). But the disease progresses to short of breath (~8 days), acute respiratory distress syndrome (ARDS) (~9 days), and to mechanical ventilation (~10.5 days) in about 39% patients.1" https://journals.lww.com/jcma/FullText/2020/0...iew.3.aspx
Extrapolation to m2m Placebo patients require admission and advance to dyspnea, ARDS and ventilation within duration of trial.
Quote "It has been stated that 81% of patients will present with mild to a moderate presentation of COVID-19 with mild symptoms up to mild pneumonia; however, in the remaining 19%, the median time to ARDS ranged from 8 to 12 days and the median time to ICU admission ranged from 10 to 12 days [22,26]." https://www.cureus.com/articles/30692-novel-c...references
Extrapolation to m2m Placebo patients may advance to ARDS and ICU admission within duration of trial.
Quote "Among all patients, there was a mean time of 5.6 ± 2.8 d (range, 2 to 14) from the onset of fever to the occurrence of dyspnea. " https://erj.ersjournals.com/content/early/202...00990-2020
Extrapolation to m2m Placebo patients may advance to dyspnea within duration of trial.
Quote "In another study of 51 patients with confirmed COVID-19, 1324 lung lesions were detected on chest CT within 1 to 14 days (median, 4 days) of symptom onset [19]." https://www.ajronline.org/doi/full/10.2214/AJR.20.23034
Extrapolation to m2m Placebo patients may develop lung lesions within duration of trial.
Quote "Zhou et al. showed that the survivors group developed ARDS and sepsis on days 9 and 10, respectively. Conversely, the non-survivors group developed ARDS and sepsis later, on days 10 and 12, respectively. Furthermore, the non-survivors group developed more complications such as acute kidney injury (AKI) and secondary infection by days 15 and 17, respectively." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138423/
Extrapolation to m2m Placebo patients may develop ARDS and sepsis within duration of trial.
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