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New Paper (Therapeutic): Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial #169

Open ajlee21 opened 4 years ago

ajlee21 commented 4 years ago

Title: Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

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

Link: https://www.medrxiv.org/content/10.1101/2020.03.21.20040691v1

What is the paper's Manubot-style citation?

Citation: doi:10.1101/2020.03.21.20040691

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

Which areas of expertise are particularly relevant to the paper?

This paper was cited by the Penn COVID symposia about the development of antibody therapy

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).

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?

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.

hufengling commented 4 years ago

Title: Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

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

Link: https://www.medrxiv.org/content/10.1101/2020.03.21.20040691v1

What is the paper's Manubot-style citation?

Citation: doi:10.1101/2020.03.21.20040691

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

Which areas of expertise are particularly relevant to the paper?

Questions to answer about each paper:

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

The study compared 17 patients treated with meplazumab + standard care to 12 patients treated with standard care. Study found meplazumab-treated patients had higher discharge rates and lower case severity.

Study question(s) being investigated:

How many/what drugs/combinations are being considered?

Meplazumab + standard care vs standard care. It is important to note here that this hospital and study define "standard care" to include lopinavir + ritonavir, recombinant human interferon a-2b, glucocorticoids, and antibiotics.

What are the main hypotheses being tested?

Does add-on meplazumab improve discharge rate and case severity?

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).

For human studies:

What countries/regions are considered?

China

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

Add-on meplazumab: median age = 51 (IQR 49-67), number of men = 11 (65%), any comorbidities = 9 (53%), case severity: common = 4, severe = 6, critical = 7.

Standard care: - median age = 64 (IQR 43-67), number of men = 5 (46%), any comorbidities = 4 (36%), case severity: common = 4, severe = 4, critical = 3.

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

In-patient.

What other specific inclusion-exclusion criteria are considered?

The inclusion criteria are as follows: men and women aged 18 to 78 years; patients with common, severe, or critical COVID-19 pneumonia were laboratory and clinical diagnosed, the subjects must understand the study and be willing to participate in the study.

The exclusion criteria are as follows: allergic reactions or a history of allergy to any of the ingredients treated in this trial; patients not suitable to participate in this study by the judgment of the investigator.

Treatment assignment:

How are treatments assigned?

Interventional study.

Is the study randomized?

No

Provide other relevant details about the design.

This is an open-label, non-randomized study. Patients that consented to study participation were allocated to add-on meplazumab arm. Patients that did not consent to study participation were allocated to standard care arm. This is ethically problematic.

Sample size is small (n = 28 overall) which makes generalization difficult. Study is non-blinded, meaning provider bias may influence clinical decisions and assessor bias may influence outcome labeling. Study is non-randomized, so confounding plays a role.

Study is pre-registered on clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT04275245). Primary outcome was changed, without explanation, from virological clearance to discharge rate and case severity. A number of secondary outcomes were not assessed in the manuscript, without explanation. Statistical testing for outcomes were not specified. This makes interpretation difficult, as testing unspecified hypotheses increase false positive risk and excluding specified hypotheses could hide negative results. Not specifying statistical tests is problematic because many statistical tests could be appropriate, but only some might show significant results.

Outcome Assessment:

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

Primary outcomes are discharge rate and case severity. Both are physician-made decisions, but in the absence of blinding, both could be influenced by physician expectations for the drug.

Are outcome measurements complete?

No individuals are lost to follow-up. Outcome measurements seem to be complete.

Are outcome measurements subject to various kinds of bias?

Study is non-randomized and non-blinded. Outcomes are subject to confounding and physician bias.

Statistical Methods Assessment:

What methods are used for inference?

Mann-Whitney tests, log-rank tests, and ordinal regression are used.

Are the methods appropriate for the study?

Both tests are appropriate, if pre-specified, but must be interpreted with caution since they are not. (For example, perhaps the authors originally planned to run a t-test which gave a p-value > 0.05. They then tried a Mann-Whitney test and got a p-value < 0.05. Which result is appropriate to report? Whichever one the authors pre-specified! If they didn't pre-specify, we can't know whether p-hacking occurred.)

Mann-Whitney tests are run on sequential data without correction for multiple comparisons.

I don't think ordinal regression is the appropriate method, but I'm not familiar with ordinal regression. Many significant p-values are reported in the ordinal regression, but I think most of them are unrelated to the author's scientific question.

Are adjustments made for possible confounders?

No adjustments are made for possible confounders. Potential confounders could include age (standard care group had higher median age), initial case severity (add-on meplazumab group had more severe initial cases), comorbidities, glucocorticoid use (add-on meplazumab group had more glucocorticoid-treated patients), and sex.

If this study were a randomized controlled trials, adjustment would not be necessary, though it would increase the power. Since this study is not, adjustment is important for interpretation, but it is not included.

Results Summary:

What is the estimated association?

Add-on meplazumab group had increased discharge rates compared to standard care group (p = 0.006). Add-on meplazumab group had different case severity distribution compared to standard care group (p = 0.021). Add-on meplazumab group had shorter average time to negative virus conversion compared to standard care group (p = 0.014).

What measures of confidence or statistical significance are provided?

P-values.

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

Are there identified side effects or interactions with other drugs?

No

Are there specific subgroups with different findings?

The authors argue add-on meplazumab showed especially good outcomes in severe and critical cases (p = 0.021). This subgroup analysis is not pre-specified, so suspicion of it being a false positive increases.

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?

N/A

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

Summary of reliability

This study is limited by: lack of randomization, open-label design, small sample size, deviation from trial pre-registration, lack of correction for multiple comparisons, uniformly beneficial outcomes, and "standard care" that includes many other experimental therapies. Interpretation should be made with great caution. Larger, rigorous clinical trials are necessary.

Progress

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