[BostonCard]

This is what I shared with my colleagues:

The NIAID has published its preliminary results from the Remdisivir trial in the New England Journal of Medicine:

https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

Note that this data is based on the full 1059 patients enrolled (not the ~400 analysed at the time of the press release).  I haven't had time to digest it in full, but it appears that remdisivir looks to work best in less severe patients (those not requiring mechanical ventilation at baseline).  This makes some sense, since at that point, it's no longer the virus driving the pathophysiology but rather the immune response.

Unfortunately, there was not an overall significant mortality benefit, though  not all patients had made it through to Day 28 yet, so the Day 28 mortality wasn't calculated.  Of note, there was a mortality benefit for patients with a baseline ordinal score of 5, but not at the higher baseline ordinal scores. 

The good news from a safety perspective is that remdisivir looks to have a fairly benign safety profile:

Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4). The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group); acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]); pyrexia (27 events [5.0%], as compared with 17 [3.3%]); hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]); and increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]). Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.

BC

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One quick addition.  At the time of the press release, the study was criticized for changing its primary endpoint shortly before the end of the trial.  I noted that this was not likely to be a big deal.  The study authors address this head on in the study.

The primary outcome of the current trial was changed with protocol version 3 on April 2, 2020, from a comparison of the eight-category ordinal scale scores on day 15 to a comparison of time to recovery up to day 29. Little was known about the natural clinical course of Covid-19 when the trial was designed in February 2020. Emerging data suggested that Covid-19 had a more protracted course than was previously known, which aroused concern that a difference in outcome after day 15 would have been missed by a single assessment at day 15. The amendment was proposed on March 22, 2020, by trial statisticians who were unaware of treatment assignment and had no knowledge of outcome data; when this change was proposed 72 patients had been enrolled. Although changes in the primary outcome are not common for diseases that are well understood, it is recognized that in some trials, such as those involving poorly understood diseases, circumstances may require a change in the way an outcome is assessed or may necessitate a different outcome.14 The original primary outcome became the key secondary end point. In the end, findings for both primary and key secondary end points were significantly different between the remdesivir and placebo groups.

Note that regardless, the study met the old primary endpoint:

The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50; 95% CI, 1.18 to 1.91; P=0.001; 844 patients) (Table 2 and Fig. S5).

As I suspected, I don't think this critique is a big deal.

BC

[BostonCard]

This is what I shared with my colleagues:

The NIAID has published its preliminary results from the Remdisivir trial in the New England Journal of Medicine:

https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

Note that this data is based on the full 1059 patients enrolled (not the ~400 analysed at the time of the press release).  I haven't had time to digest it in full, but it appears that remdisivir looks to work best in less severe patients (those not requiring mechanical ventilation at baseline).  This makes some sense, since at that point, it's no longer the virus driving the pathophysiology but rather the immune response.

Unfortunately, there was not an overall significant mortality benefit, though  not all patients had made it through to Day 28 yet, so the Day 28 mortality wasn't calculated.  Of note, there was a mortality benefit for patients with a baseline ordinal score of 5, but not at the higher baseline ordinal scores. 

The good news from a safety perspective is that remdisivir looks to have a fairly benign safety profile:

Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4). The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group); acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]); pyrexia (27 events [5.0%], as compared with 17 [3.3%]); hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]); and increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]). Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.

BC

---

One quick addition.  At the time of the press release, the study was criticized for changing its primary endpoint shortly before the end of the trial.  I noted that this was not likely to be a big deal.  The study authors address this head on in the study.

The primary outcome of the current trial was changed with protocol version 3 on April 2, 2020, from a comparison of the eight-category ordinal scale scores on day 15 to a comparison of time to recovery up to day 29. Little was known about the natural clinical course of Covid-19 when the trial was designed in February 2020. Emerging data suggested that Covid-19 had a more protracted course than was previously known, which aroused concern that a difference in outcome after day 15 would have been missed by a single assessment at day 15. The amendment was proposed on March 22, 2020, by trial statisticians who were unaware of treatment assignment and had no knowledge of outcome data; when this change was proposed 72 patients had been enrolled. Although changes in the primary outcome are not common for diseases that are well understood, it is recognized that in some trials, such as those involving poorly understood diseases, circumstances may require a change in the way an outcome is assessed or may necessitate a different outcome.14 The original primary outcome became the key secondary end point. In the end, findings for both primary and key secondary end points were significantly different between the remdesivir and placebo groups.

Note that regardless, the study met the old primary endpoint:

The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50; 95% CI, 1.18 to 1.91; P=0.001; 844 patients) (Table 2 and Fig. S5).

As I suspected, I don't think this critique is a big deal.

BC