New Paper (Therapeutic): Compassionate Use of Remdesivir for Patients with Severe Covid-19

Title: Compassionate Use of Remdesivir for Patients with Severe Covid-19

Please paste a link to the paper or a citation here:

Link: http://doi.org/10.1056/NEJMoa2007016

What is the paper's Manubot-style citation?

Citation: doi:10.1056/NEJMoa2007016

Please list some keywords (3-10) that help identify the relevance of this paper to COVID-19

remdesivir
compassionate-use

Which areas of expertise are particularly relevant to the paper?

[ ] virology
[ ] epidemiology
[x] biostatistics
[ ] immunology
[x] pharmacology

Questions to answer about each paper:

Please provide 1-2 sentences introducing the study and its main findings

Study question(s) being investigated:

How many/what drugs/combinations are being considered?

What are the main hypotheses being tested?

Study population:

What is the model system (e.g., human study, animal model, cell line study)?

What is the sample size? If multiple groups are considered, give sample size for each group (including controls).

number treated with treatment A
number treated with treatment B

For human studies:

What countries/regions are considered?

What is the age range, gender, other relevant characteristics?

What is the setting of the study (random sample of school children, inpatient, outpatient, etc)?

What other specific inclusion-exclusion criteria are considered?

For example, do the investigators exclude patients with diagnosed neoplasms or patients over/under a certain age?

Treatment assignment:

How are treatments assigned?

For example, is it an interventional or an observational study?

Is the study randomized?

A study can be interventional but not randomized (e.g., a phase I or II clinical trial is interventional but often not randomized).

Provide other relevant details about the design.

This includes possible treatment stratification (e.g., within litters for animal studies, within hospitals for human studies), possible confounding variables (e.g., having a large age range of individuals), possible risks of bias and how they are addressed (e.g., is there masking in a clinical trial? how are individuals chosen in an observational study?).

Outcome Assessment:

Describe the outcome that is assessed and whether it is appropriate.

For example: Is the outcome assessed by a clinician or is it self-reported? Is the outcome based on viral load or a functional measurement (e.g., respiratory function, discharge from hospital)? What method is used to measure the outcome? How long after a treatment is the outcome measured?

Are outcome measurements complete?

For example, are there individuals lost to follow up?

Are outcome measurements subject to various kinds of bias?

For example, a lack of masking in randomized clinical trials.

Statistical Methods Assessment:

What methods are used for inference?

For example, logistic regression, nonparametric methods.

Are the methods appropriate for the study?

For example, are clustered data treated independently or are clusters adjusted for, such as different hospitals or litters?

Are adjustments made for possible confounders?

For example, adjustment for age, sex, or comorbidities.

Results Summary:

What is the estimated association?

For example, is it an estimated odds ratio, a median difference in detected cases, etc?

What measures of confidence or statistical significance are provided?

For example, confidence intervals, p-values, and/or Bayes factors.

Interpretation of results for study population:

Can we make a causal interpretation for the individuals in the study of drug -> outcome, such as "taking drug A improves likelihood of survival twofold over taking drug B."

For example, with a well-performed animal study or randomized trial it is often possible to infer causality. If is an observational study, does it match up with some of the Bradford Hill criteria? https://www.edwardtufte.com/tufte/hill https://en.wikipedia.org/wiki/Bradford_Hill_criteria

Are there identified side effects or interactions with other drugs?

For example, is the treatment known to cause liver damage or to not be prescribed for individuals with certain comorbities?

Are there specific subgroups with different findings?

For example, do individuals with a specific baseline seem to do particularly well? Be particularly cautious with respect to multiple testing here.

Extrapolation of conclusions to other groups of individuals not specifically included in the study:

If the study is an animal study, which animal and how relevant is that model?

Is the model system appropriate? Is there evidence from past use that it's highly-relevant to therapeutic design in this context?

If it is a human study, what characteristics of the study population may support/limit extrapolation?

Can results extrapolate easily to other similar groups? (e.g., same country, similar age groups)
What would happen if conditions are extended in terms of dose or duration?
Can results be extrapolated to other populations or in very different settings? (e.g., different age group, primary care setting vs emergency department etc)

Summary of reliability

1-2 sentences on concluding remarks, including summary of strengths, weaknesses, limitations.

Progress

Check off the components as they are completed. If the component is not applicable, check the box as well.

[ ] 1-2 sentences introducing the study and its main findings
[ ] Describe How many/what drugs/combinations are being considered
[ ] Describe the model system
[ ] What is the sample size?
[ ] What countries/regions are considered
[ ] What is the age range, gender, other relevant characteristics
[ ] Describe study setting
[ ] Describe other specific inclusion-exclusion criteria
[ ] Describe how treatments are assigned
[ ] Describe randomization (or not) and other relavent details about the design
[ ] Describe the outcome that is assessed and whether it is appropriate.
[ ] Describe whether the outcome measurements are complete
[ ] Are outcome measurements subject to various kinds of bias?
[ ] Describe methods used for inference
[ ] Describe whether the methods are appropriate for the study
[ ] Are adjustments made for possible confounders?
[ ] Describe the estimated association
[ ] What measures of confidence or statistical significance are provided?
[ ] Describe whether a causal interpretation can be made
[ ] Are there identified side effects or interactions with other drugs?
[ ] Are there specific subgroups with different findings?
[ ] If the study is an animal study, which animal and how relevant is that model?
[ ] If it is a human study, what characteristics of the study population may support/limit extrapolation?
[ ] Summary of reliability

Title: Compassionate Use of Remdesivir for Patients with Severe Covid-19

Please paste a link to the paper or a citation here:

Link: http://doi.org/10.1056/NEJMoa2007016

What is the paper's Manubot-style citation?

Citation: doi:10.1056/NEJMoa2007016

Please list some keywords (3-10) that help identify the relevance of this paper to COVID-19

remdesivir
case study
compassionate use

Which areas of expertise are particularly relevant to the paper?

[ ] virology
[ ] epidemiology
[x] biostatistics
[ ] immunology
[x] pharmacology

Questions to answer about each paper:

Please provide 1-2 sentences introducing the study and its main findings

Of 53 patients provided with compassionate-use remdesivir, 36 showed clinical improvement by day 28 after treatment start. No control group was provided, so this study should be treated as a preliminary case study suggesting further study with large, rigorous clinical trials.

Study question(s) being investigated:

How many/what drugs/combinations are being considered?

Remdesivir + standard of care is studied.

What are the main hypotheses being tested?

No hypothesis was testing. Study sought to describe outcomes of patients treated with remdesivir.

Study population:

What is the model system (e.g., human study, animal model, cell line study)?

Human

What is the sample size? If multiple groups are considered, give sample size for each group (including controls).

53 patients treated with remdesivir
No comparison group

For human studies:

What countries/regions are considered?

Patients were enrolled in the United States (22 patients), Japan (9), Italy (12), Austria (1), France (4), Germany (2), Netherlands (1), Spain (1), and Canada (1).

What is the age range, gender, other relevant characteristics?

Age: Median = 64, Q1 = 48, Q3 = 71 Gender: 40 males (75%) Started on invasive ventilation: n = 34 (64%) Comorbidities: n = 36 (68%)

What is the setting of the study (random sample of school children, inpatient, outpatient, etc)?

Inpatient.

What other specific inclusion-exclusion criteria are considered?

Inclusion: approved request for compassionate-use remdesivir. Necessary, but not sufficient conditions for approval are: confirmed SARS-CoV-2 infection by rtPCR, SpO2 < 94% on room air OR oxygen support, creatinine clearance above 30mL/min, serum ALT and AST < 5x upper limit of normal range, no use of other investigational agents for COVID-19.

Exclusion: No approved request for compassionate-use remdesivir. Not specified.

Treatment assignment:

How are treatments assigned?

All included patients received remdesivir

Is the study randomized?

Non-randomized. No comparison group.

Provide other relevant details about the design.

This is a case study describing outcomes of patients treated with remdesivir. No comparison group was included.

Outcome Assessment:

Describe the outcome that is assessed and whether it is appropriate.

Outcomes include: changes in oxygen-support requirements, hospital discharge, adverse events, and decrease of at least 2 points from baseline on WHO COVID-19 scale. Outcomes are appropriate, but authors note outcomes were not pre-specified. This means decisions on what outcomes to report are data driven, which increases risk of biased reporting of outcomes beneficial to study sponsor.

No data on viral load or virological conversion was collected.

Are outcome measurements complete?

Outcome measurements are not complete. Study reports 61 patients received at least one dose of remdesivir. Eight of these patients are excluded because 7 had no post-treatment data and 1 was dosed incorrectly. Censoring of data prior to death, discharge, or 28-day limit is common.

Are outcome measurements subject to various kinds of bias?

Reported outcomes were decided using data-driven approach. Patient treatment and outcome assessment were non-blinded. Of all patients provided compassionate-use remdesivir by Gilead, only these 61 were mentioned - it's uncertain how/why these patients were chosen for inclusion. Study is sponsored, designed, conducted, and written up by Gilead, which has financial stake in the success of remdesivir.

Statistical Methods Assessment:

What methods are used for inference?

No methods are used for inference. This is a case study.

Are the methods appropriate for the study?

Methods are appropriate. Study is very transparent with design choices, conflicts of interest, and limitations.

Are adjustments made for possible confounders?

Survival curves are reported overall as well as with respect to baseline oxygen support and age range. Adverse events are also reported with respect to baseline oxygen support. It is important to note availability of ventilators at a given location may impact whether patients were on invasive baseline oxygen support.

Results Summary:

What is the estimated association?

On average, clinical improvement is seen in the cohort. On average, more clinical improvement was seen in patients with non-invasive baseline oxygen support than those with invasive baseline oxygen support, though both show improvement. On average, more clinical improvement was seen in young patients, though all age ranges (<50, 50-70, >70) showed improvement.

Thirty-two patients (60%) reported at least one adverse event. Twelve patients (23%) reported at least one adverse serious event (multi-organ-dysfunction syndrome, septic shock, acute kidney injury, hypotension). More adverse events occurred in patients with invasive baseline oxygen support. Four patients discontinued remdesivir treatment prematurely due to adverse events.

What measures of confidence or statistical significance are provided?

None are provided or necessary.

Interpretation of results for study population:

Can we make a causal interpretation for the individuals in the study of drug -> outcome, such as "taking drug A improves likelihood of survival twofold over taking drug B."

No causal interpretation is possible.

Are there identified side effects or interactions with other drugs?

Adverse events occurred to many patients, but it is uncertain whether these events were caused by remdesivir.