Pramesh CS Profile picture
17 Oct, 16 tweets, 10 min read
The preprints of the #SOLIDARITY trial are out on MedRxiv. While many may lament that all four drugs tested did not show benefit, this is a remarkable trial for many reasons. Thread
First, this was another #MultiArmMultiStage #MAMS study design; @MRCCTU made this highly efficient trial design globally acclaimed with #STAMPEDE. The more recent #RECOVERY trial was another example of this.
@MaxParmarMRCUCL @Prof_Nick_James @PeterHorby @MartinLandray
What the #MAMS design does is enable testing multiple drugs simultaneously, flexibility to drop unpromising ones & add new promising ones even midway during the trial. This was crucial in the #COVID__19 pandemic where the situation has been constantly evolving
Second, this was the ultimate pragmatic trial (similar to #RECOVERY). Broad eligibility criteria made the findings of this study applicable to the vast majority of patients with #COVID_19 globally. With 405 hospitals in 30 countries recruiting, it reflects the real world closely
Third, trial processes were simplified, adapting remarkably well with the stressed healthcare system. Randomization processes were simple and took just a few minutes. Data collection points were minimized to what was essential. Stunning that they had a 97%+ data completion rate
Fourth, they didn't fuss much about the sample size! The protocol stated "the larger the number entered, the more accurate the results will be, but numbers entered will depend on how the epidemic develops"! This was practical, considering the uncertainty when the trial started.
Fifth, #SOLIDARITY was a real demonstration of global cooperation in a crisis. Participating countries covered local costs, @WHO covered other study costs, with no extra funding. Collaborators, committee members, data analysts and DMSs charged no costs, and drugs were donated
Finally, 11330 patients were recruited in 197 days between Mar 22nd @ Oct 4th, or a staggering 57.5 patients average recruitment every day! Along with the #RECOVERY trial, these are new benchmarks in therapeutic interventional trial recruitments during pandemics.
The #SOLIDARITY trial tested the following drugs:
#Remdesivir, #HydroxyChloroquine, #Lopinavir & #Interferon
The primary endpoint was mortality; secondary endpoints were need for ventilation & duration of hospitalization
Preplanned subgroup analyses for moderate & severe #COVID19
None of the #SOLIDARITY study drugs had an impact on mortality, need for ventilation, or duration of hospitalization. These results held, when analyzed for the whole population, and the prespecified subgroups.
WIth #Remdesivir, the relative risk of death was 0.95 (95% CI, 0.81, 1.11; p=0.5) The Kaplan Meier curves are practically on top of each other. No differences in need for ventilation (295 vs 284); no differences in hospitalization - day 7, 69% vs 59%.
With #HydroxyChloroquine, the relative risk of death was 1.19 (95% CI, 0.89, 1.59; p=0.23). No differences in need for ventilation (75 vs 66); no differences in hospitalization - day 7, 64% vs 54%.
With #Lopinavir, the relative risk of death was 1.00 (95% CI, 0.79, 1.25; p=0.97). No differences in need for ventilation (124 vs 119); no differences in hospitalization - day 7, 68% vs 59%.
With #Interferon, the relative risk of death was 1.16 (95% CI, 0.96, 1.39; p=0.11). No differences in need for ventilation (209 vs 210); no differences in hospitalization - day 7, 55% vs 51%.
Disappointingly, all four drugs tested failed to improve outcomes; yet, this is a definitive trial, which has answered these four important questions reliably. These negative trials are incredibly important. Encouragingly, results are compatible with meta analyses on these drugs.
What #SOLIDARITY (& #RECOVERY) demonstrate conclusively are:
1. It is possible to do large definitive trials, even during the crisis of a pandemic
2. Global collaboration and cooperation is key, and logistic hurdles can be overcome
3. There is no substitute for good science

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More from @cspramesh

12 Sep
I’ve been watching with increasing concern at the trend of new daily diagnoses of COVID-19 in India over the past two weeks. To me, this reflects general public mood which seems to have begun to ignore the threat this virus poses. Thread
While the good news is that our death rates haven’t been as bad as some of the other countries (we might debate the accuracy of death reporting), but with a population of 1.35 billion people, the absolute numbers are still sobering. And rural India is just beginning to get hit
What I’d like to see is reliable “Excess mortality” and a P score which will quantify the true impact of the pandemic on deaths in India. We know that Mumbai had an excess mortality of 13000 deaths between Apr and Jul 2020. We don’t yet have data for India as a whole.
Read 23 tweets
24 Aug
I can't believe the @US_FDA Commissioner @SteveFDA announced that 35 out of 100 patients treated with #ConvalescentPlasma will benefit from it. This demonstrates either a lack of understanding of basic statistics (relative risk vs absolute risk) or external pressures. (1/n)
There are several problems with this - first, this is not based on randomized evidence. This is based on "data obtained from the ongoing National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic". The preprint is available on… (2/n)
In an observational study of 35,322 patients transfused with CP, 7-day mortality was 8.7% in those where CP was transfused early (3 days or less) and 11.9% in those transfused later (>3 days). 30 day mortality was 21.6% vs 26.7%. (3/n)
Read 13 tweets
16 Jul
The power of large, pragmatic randomized trials. Conducted by academic researchers using an adaptive trial design (#MAMS), and you’ve got a winner. Strong reasons why publicly funded research is so very important. Thread
The #RECOVERY trial has answered 3 important, clinically relevant questions about #COVID_19. It has shown that #Dexamethasone is beneficial in patients requiring oxygen/ ventilation & that HCQ and Lopinavir-Ritonavir are not useful.
#HCQ results are now out in preprint!
#RECOVERY randomized 1561 pts to #HCQ and 3155 to standard of care. Primary endpoint of 28-day mortality was 26.8% in the HCQ arm and 25% in the SOC arm. Lack of benefit consistent across all sub-groups. And remember, 28-day mortality in the same trial in the Dexa arm was 21.6%
Read 6 tweets
6 Jun
The retractions of papers in @TheLancet and the @NEJM have been met with outrage, anger and calls for resignation of the editors. Let's take a moment to think about this. What is a journal's and an editor's responsibility? To ensure that they publish the best science. Thread
They also need to publish the best science reliably and in a timely manner. How do they do this? They send to peer reviewers, get comments, and make a decision. They also rely heavily on authors for the veracity and integrity of the paper and their potential or real COI
Authors sign a declaration that they vouch for the data they present. Given the present circumstances in science, is it realistic to expect that editors and reviewers get the raw data of every single study that's submitted to their journal to guide their decision?
Read 6 tweets
27 Feb
I am extremely skeptical about tests like these. Screening for cancer (or any other disease) should have strong evidence to back it, failing which the test will only exploit innocent public. What do I mean by evidence to support it?
The only reliable evidence to support screening is from large randomized trials offering screening to one arm & routine care to the other, & conclusively demonstrate decreased mortality in the screened arm. Sorry, but no alternative expedient methods of "evidence" matter. Why?
Screening has the real potential for harm, by way of unnecessary tests, interventions that can cause harm, or even death, diverting scarce health resources to useless treatment & costs involved. Which is why, if there is no mortality reduction, the screening tool is merely a tool
Read 13 tweets

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