The CardBoard
Bad Remdesivir news - Printable Version

+- The CardBoard (https://thecardboard.org/board)
+-- Forum: Emergency (https://thecardboard.org/board/forum-11.html)
+--- Forum: Covid-19 (https://thecardboard.org/board/forum-12.html)
+--- Thread: Bad Remdesivir news (/thread-19519.html)

Pages: 1 2

Bad Remdesivir news - dabigv13 - 04-23-2020

https://www.statnews.com/2020/04/23/data-on-gileads-remdesivir-released-by-accident-show-no-benefit-for-coronavirus-patients/

No benefit for hospitalized patients in this decently powered study (158 patients received remdesivir, 79 control patients). In fact outcomes slightly worse though not statistically significant. Study still closed earlier than anticipated because they ran out of patients to enroll to reach their original numbers with Chinese cases declining.

Perhaps it will be more effective for patients if given earlier or for patients with more mild symptoms. Gilead I'm sure hopes so because that is a larger potential customer base. But in any case, for helping the patients who need it most, not helpful. 

Fits clinical experience of no silver bullets. Disappointing though all the same.

RE: Bad Remdesivir news - Griffins78 - 04-23-2020

I read that Gilead had difficulty finding trial participants that would not be taking other medications, particularly traditional Chinese medicine. There may have been participants that dropped out because they wanted to use traditional Chinese medicine after the trial started.

They're running a number of other clinical trials in other countries.

RE: Bad Remdesivir news - OutsiderFan - 04-29-2020

So how come I see all this "Remdesivir is a Covid-19 cure" this morning?

RE: Bad Remdesivir news - stupac2 - 04-29-2020

(04-29-2020, 06:43 AM)OutsiderFan Wrote:  So how come I see all this "Remdesivir is a Covid-19 cure" this morning?

Hope is powerful, biology is complicated.

RE: Bad Remdesivir news - BostonCard - 04-29-2020

(04-29-2020, 06:43 AM)OutsiderFan Wrote:  So how come I see all this "Remdesivir is a Covid-19 cure" this morning?

Probably based on this?

https://www.wsj.com/articles/gilead-says-remdesivir-as-effective-treating-severe-covid-19-in-shorter-period-11588166509

It's a phase 3, randomized, placebo controlled trial.

I know Gilead's CMO, and he is not someone who would speak loosely, so I'm inclined to believe that the patient's did have a benefit.  However, this statement caught my eye "He said an interim analysis would be completed this week or next." so I am struggling a bit to reconcile the message coming from Gilead that it demonstrated benefit with the statement that the interim analysis hadn't been completed.

For what it is worth, the sample size of this trial (400 patients in each arm) is much higher than the one reported from the statnews article.

I am cautiously optimistic, but will await the report of the interim analysis.

BC
Quick add:

Here is Gilead's statement:

https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-sciences-statement-on-positive-data-emerging-from-national-institute-of-allergy-and-infectious-diseases-study-of-investigational-antiviral-rem

Quote:Gilead Sciences Statement on Positive Data Emerging From National Institute of Allergy and Infectious Diseases’ Study of Investigational Antiviral Remdesivir for COVID-19

FOSTER CITY, Calif.--(BUSINESS WIRE)--Apr. 29, 2020-- Gilead Sciences. Inc. (Nasdaq: GILD) is aware of positive data emerging from the National Institute of Allergy and Infectious Diseases’ (NIAID) study of the investigational antiviral remdesivir for the treatment of COVID-19. We understand that the trial has met its primary endpoint and that NIAID will provide detailed information at an upcoming briefing.


BC

RE: Bad Remdesivir news - dabigv13 - 04-29-2020

I think they are expecting 400 total patients, not in each arm. Looks like aiming to enroll 286 in each arm to end up with 200 in each reaching end point.

If there is a benefit, it probably won't be a very big one based on the prior study. Also if it was a big benefit, they likely would have stopped trial early.

RE: Bad Remdesivir news - BostonCard - 04-29-2020

It's not entirely clear.  From clinicaltrials.gov:

Quote:The initial sample size is projected to be 572 subjects to achieve 400 subjects with a "recovered" status (per the primary objective). The primary analysis will be based on those subjects enrolled in order to 400 recoveries. An additional analysis of the moderate severity subgroup (those with baseline status of "Hospitalized, requiring supplemental oxygen" or "Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care") is also of public health importance. Hence, enrollment will be permitted until the date of April 20, 2020 to ensure 400 recoveries and provide additional data about this important subgroup. With recent enrollment rates, the total sample size may be 600 to over 800.


So you are correct that they were aiming for 286 per arm in order to record 200 recoveries in each arm. On the other hand, for better or worse, enrollment in COVID-19 trials has been brisk (great for generating data, but unfortunately it also means that lots of patients are being hospitalized for the disease) so I wouldn't be surprised if the final trial is oversubscribed.  If the primary outcome is time to recovery by Day 29, the final data won't be available until May 18 when the last patients reach the primary endpoint date, so this will be an interim analysis.

The one other thing about the trial is that it is an adaptive trial, so it will continue even if it meets its endpoint:


Quote:If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. 

So (assuming that the efficacy bar was hit), the trial will likely become X + remdisivir versus remdisivir alone going forward (possible it will be remdisivir against x, but you probably can't withhold remdisivir).

BC

One last add: accrual rates fro COVID-19 trials are so fast that they probably couldn't have stopped the trial after an interim.  Hypothetically, if they had planned to analyze the data when a quarter of the patients reached Day 28 (that's a pretty standard), it seems likely that 28 days after the first 25% of patients were enrolled, they will have been able to enroll the other 75%.

RE: Bad Remdesivir news - 2006alum - 04-29-2020

I will admit to being confused by why we're suddenly so excited about remdesivir the same day this comes out:

[tweet]https://twitter.com/BogochIsaac/status/1255534661721305095?s=20[/tweet]

BC and others, can you clarify why this datapoint should be disregarded vis-a-vis the much more vague statements from Gilead?

RE: Bad Remdesivir news - dabigv13 - 04-29-2020

I think this may be the final version of the study posted at the top of this thread, need to read it more closely. It's a smaller study than the trial being discussed in the WSJ article today. But it's otherwise a decent study, and can't be discounted. If remdesivir was a miracle cure, that would be clear. It's possible remdesivir is helpful. More data will help to distinguish this, and I'd very much welcome being wrong.

Edit:
Yup, this is the same study as posted in the stat news article above.

The most positive thing in the study is that if you got remdesivir within 10 days of symptom onset, the time to improvement was shorter than placebo, but not to a statistically significant degree. Maybe a larger study can get a statistically significant result. Even if true, not a silver bullet.

Quote:Although not statistically significant, in patients receiving remdesivir or placebo within 10 days of symptom onset in the ITT population, those receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo (median 18·0 days [IQR 12·0–28·0] vs 23·0 days [15·0–28·0]; HR 1·52 [0·95–2·43]; appendix p 6


RE: Bad Remdesivir news - BostonCard - 04-29-2020

Thanks for finding it.  This was the study referred to in the STAT article linked by the OP.  As noted, the study had to close earlier than planned due to the lack of cases.  I agree with dabigv, that remdesivir is not a miracle cure, but that a negative, underpowered study doesn't exclude a benefit.  Also, there are some hints it might work in patients given the drug early:

Quote:Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]).

(from the abstract)


Quote:Although not statistically significant, in patients receiving remdesivir or placebo within 10 days of symptom onset in the ITT population, those receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo (median 18·0 days [IQR 12·0–28·0] vs 23·0 days [15·0–28·0]; HR 1·52 [0·95–2·43]; appendix p 6).
(from the discussion)

This has some biological plausibility, since an antiviral would expect to have its maximum benefit if instituted early.  And although not statistically significant, if it is replicated in another study, a decrease of time to clinical improvement from 23 days to 18 days would be fairly clinically meaningful.

We should all wait until the NIAID study to be reported.

BC

RE: Bad Remdesivir news - Goose - 04-29-2020

New piece of data, I think.

https://www.medpagetoday.com/infectiousdisease/covid19/86218?xid=NL_breakingnewsalert_2020-04-29&eun=g1475875d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=GileadAlert_042920&utm_term=NL_Daily_Breaking_News_Active

RE: Bad Remdesivir news - dabigv13 - 04-29-2020

Quote:An interim analysis of the Adaptive COVID-19 Treatment Trial (ACTT) found the drug had a 31% faster time to recovery versus placebo (median 11 days vs 15 days, respectively, P<0.001). It also trended toward a survival benefit (8.0% mortality rate in remdesivir group vs 11.6% in placebo, P=0.059), the NIAID said in a statement.


These would be really positive results if borne out in final analysis. Not a game changer, but at least something to throw at this terrible thing.

What is tricky though is that this med is given by IV, and seems most useful if given early in patients without severe disease. The logstical issues this raises will limit the ultimate effectiveness of this medication in limiting the pandemic.

RE: Bad Remdesivir news - Griffins78 - 04-29-2020

(04-29-2020, 11:27 AM)dabigv13 Wrote:  What is tricky though is that this med is given by IV, and seems most useful if given early in patients without severe disease. The logistical issues this raises will limit the ultimate effectiveness of this medication in limiting the pandemic.
Do they need to be hospitalized and for how long? If so, then it seems like if we're going to treat people "early," before they have severe symptoms, we're going to have to hospitalize and treat a lot of people.

RE: Bad Remdesivir news - BostonCard - 04-29-2020

(04-29-2020, 11:54 AM)Griffins78 Wrote:  
(04-29-2020, 11:27 AM)dabigv13 Wrote:  What is tricky though is that this med is given by IV, and seems most useful if given early in patients without severe disease. The logistical issues this raises will limit the ultimate effectiveness of this medication in limiting the pandemic.
Do they need to be hospitalized and for how long? If so, then it seems like if we're going to treat people "early," before they have severe symptoms, we're going to have to hospitalize and treat a lot of people.

You could have patients treated in an outpatient infusion center, but obviously that would need to be tested.

The other result that was reported today (by Gilead) was that a five-day treatment course had similar outcomes to a ten-day treatment course which would make the drug more viable for use in an outpatient setting.

I’m sure Gilead will be testing remdisivir in an outpatient study, with an outcome of the need for hospitalization.

Lastly, there will probably be a move to make the drug available as a subcutaneous auto-injector.  It shouldn’t be too difficult to show that the pharmacokinetics of the SC administration can be made similar to IV.

BC

RE: Bad Remdesivir news - Griffins78 - 04-29-2020

Thank you, BC. Your explanation makes me more hopeful.

RE: Bad Remdesivir news - OutsiderFan - 04-30-2020

So in laymen’s terms, there is no way to know who might develop serious complications from Covid-19, this drug (like all anti-virals) must be given early, so in order to work, everyone would have to be given this drug. Because there isn’t going to be enough of it to go around, and there is no way of knowing who would benefit from it, the odds of it being given to those it would help are really low.

Given Remdesivir will likely cost a fortune if in high demand, and it’s only marginally better than nothing, the reaction of speculators to drive up the Gilead stock price seems like a massive overreaction. Based on the study results, I wouldn’t want the drug given to me because the side effects likely have a higher chance of hitting me than the drug does having much of a benefit.

RE: Bad Remdesivir news - M T - 04-30-2020

(04-30-2020, 01:48 AM)OutsiderFan Wrote:  Based on the study results, I wouldn’t want the drug given to me because the side effects likely have a higher chance of hitting me than the drug does having much of a benefit.

I haven't looked at the study, but some of us are at a higher risk of a fatal outcome from COVID-19.  The risk of side effects may be too high for some, but the same risks are acceptable for others.

Now, a more subtle point... If CFR is 20% for an 80+ person in S. Korea that has symptoms & a positive test, what is the IFR for an  80+ person in the US who has a positive test but no symptoms (yet).   That number matters for judging the benefit/risk ratio of a treatment.

I haven't seen any studies that give the age-based incidence of asymptomatic cases.   The whole infection rate is so poorly understood right now.  (As I've said before, the Stanford antibody study may actually show in fact that there is very little community infection, suggesting relatively few asymptomatic cases.  But the maternity studies suggest high infection rates in those locales)

We may actually get numbers for some of the risk groups if areas are doing full (& repeated) testing in retirement homes.  Such numbers don't help with judging herd immunity, but they do help for treatment decisions for those at-risk individuals.

RE: Bad Remdesivir news - 2006alum - 04-30-2020

Someone noted that the remdesivir study's main outcome of interest was changed mid-study:
[tweet]https://twitter.com/jeremyfaust/status/1255627351876079616?s=20[/tweet]

Here's a side-by-side comparison of the original study parameters and the amended ones:
https://clinicaltrials.gov/ct2/history/NCT04280705?A=10&B=16&C=Side-by-Side#StudyPageTop

Can anyone with knowledge about this explain whether those changes are unusual or indicate reasons to be bullish or bearish about the ultimate findings?

RE: Bad Remdesivir news - BostonCard - 04-30-2020

OK, this is going to be very wonky.

The first point is that it is not unusual for the study to be modified while it is running.  Sometimes, you can't do things you thought you could do.  One example relevant to this study is that originally, patients who had been discharged from the hospital were supposed to come in to be evaluated as outpatients.  The problem with this is that it is probably not a good idea to have people who were recently diagnosed with COVID-19 and who are probably still shedding virus to be traveling to a clinic.  It puts others at risk of infection, it requires the use of PPE for the clinic staff (which may not be available) and it requires some patients to travel, without knowing whether the patients are able to get to the clinic easily.  Once the study staff recognized the problems related to this, they can amend the protocol to say that the final assessment can be done by phone rather than in person.

Changes in the analysis plan are also not unusual.  For example, let's say that you were planning to use death as an outcome.  Your statistical analysis assumed that 20% of patients in the placebo arm would have died, and the power was based on that assumption.  But at the end of your study, only 7% of patients have died, maybe because you recruited healthier patients than you expected.  Even in the best of cases (all patients on your study drug survived), you only have 14% of patients on placebo will have died.  Now all of a sudden your assumptions about the study are wrong.  So maybe you change endpoints, maybe you change the sample size, etc.  The FDA allows the final statistical plan be filed after the study starts, as long as it is done before the study is blinded.

So, the original study looks to have used an 8-point ordinal rating as the outcome.  The ordinal rating scale captures the patient's care needs on an 8-point scale between 1 (dead) to 8 (home, and back to normal health).  The actual scale (from the clinicaltrials.gov site) is as follows:

1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

What's great about the scale is that it captures the entire spectrum of disease.  A drug could be helpful if more patients are home in the treatment group than in placebo at the primary timepoint (I believe 28 days).  It might also be helpful if fewer patients are dead at that timepoint.  It might also be that you provide small subtle shifts across the spectrum (a couple fewer patients die, a couple more patients go home, etc) which would give the study more power than using a single endpoint, and it means that you wouldn't be in a situation where your primary endpoint of going home is met, but strangely you also see more patients dying.

There are downsides to this approach, however.  The first one is that not all "steps" are created equally.  Dead versus critically ill is a much bigger difference than the difference between being in the hospital and needing oxygen versus not needing oxygen.  Plus, a bunch of other issues might crop up that are not COVID-related.  A patient may be ready to go home but have no place to quarantine and therefore they are kept in the hospital (or conversely, hospitals are so overwhelmed that they send patients home before they would have gone home under ordinary circumstances).  Hopefully that gets evened out by randomization, but if it happens a lot it makes your endpoint much less meaningful.

In addition, the statistical analysis of an ordinal endpoint is challenging.  The most likely analysis (it wasn't specified) is a proportional odds model.  The idea is that you are looking for the proportional odds of being in a higher category on treatment than placebo.  The challenge is that the resultant odds ratio is not easily interpretable (odds ratios are challenging in a conventional outcome (yes/no) study, let alone an ordinal endpoint).  How do you describe in lay terms what the drug does?  Also, if relatively few patients die, there is the issue that if you give patients enough time, most of them (except those who die) will recover.  So, if your primary timepoint is pretty far out, you are going to lose a lot of power.  At the 15-day mark, which was the old primary endpoint, half the patients on placebo would have been discharged (from reports, median hospitalization is 15 days).

By changing the primary endpoint, the study is easier to digest.  Basically, did patients on remdisivir recover (basically defined as being discharged home or being hospitalized but not requiring medical care) faster than patients on placebo?  The downside is that it doesn't tell you about the state of people in the hospital.  Again, based on reports it sounds like there is "a trend towards" mortality benefit, but the p-value was not statistically significant, and we have no idea of whether it makes a difference in patients in the ICU.

Hope this helps.

BC

RE: Bad Remdesivir news - 2006alum - 04-30-2020

Excellent and helpful analysis, BC, thank you. One quick follow-up: the pros and cons of an 8-point ordinal rating scale vs. days to recovery would presumably have been known to the researchers prior to launching the study, so do you have any insights as to why they would change midway through? I suppose my skepticism is that if it doesn't change outcomes but reduces recovery time for those who fully recover, then changing the primary endpoint would yield a more straightforward benefit from remdesivir. That's not nothing, but it does strike me as somewhat strange to change horses mid-race when the pros and cons of those horses were known out of the starting gate.