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Yet another negative ivermectin study, this time in the NEJM

Yesterday the The New England Journal of Medicine published a high quality clinical trial that found no benefit in treating COVID-19 with ivermectin. Cue attacks on the study.

When last I wrote about ivermectin, the antihelminthic (anti-worm) medication that COVID-19 conspiracy theorists have been portraying (and some selling) as a miracle cure for COVID-19, I compared the drug to acupuncture. Specifically, I noted how, now that large quantities of high quality clinical evidence from various studies has failed to find even a whiff of a hint of a signal that it works, ivermectin advocates have pivoted to citing lower quality studies. I further pointed out one study in particular being touted by ivermectin believers. It is an observational study that I used to illustrate how, now that a number of randomized controlled trials (RCTs) exist that have failed to show a benefit using ivermectin to treat COVID-19, RCTs trump uncontrolled observational evidence. Again, I used that study to make an analogy with acupuncture, where, as higher quality evidence increasingly shows that it is nothing more than a theatrical placebo, advocates increasingly cite lower quality evidence.

Almost in passing, I also pointed to an RCT mentioned in a Wall Street Journal article. The reason that I mentioned this study only in passing was because it hadn’t been published yet and the only description came from a newspaper article. Even so, I couldn’t resist tweaking ivermectin cultists with it, mainly because it’s yet another study that shows no benefit from ivermectin in treating COVID-19. Of course, as I’ve described many times, the prior plausibility that ivermectin would work against COVID-19 was always very, very low, or, as I liked to put it, not homeopathy-level low, but pretty damned low. Why so low? That’s because in the in vitro (cell culture) studies in which ivermectin was demonstrated to show antiviral activity against SARS-CoV-2, the coronavirus that causes COVID-19, required concentrations over 50-fold higher than what can safely be achieved in the human bloodstream. If ivermectin were to work in humans, presumably something other than the mechanism by which it inhibited the virus in cell culture must be operative. (I’ve encountered this very same problem with another drug that I’ve tried to repurpose to treat cancer, albeit not so dramatically as having an order of magnitude difference between what is needed in vitro and what is achievable in vivo.) The bottom line, as I like to put it, is:

Very low prior plausibility

+

Equivocal clinical studies

=

Drug doesn’t work for the proposed indication

Here we are, a couple of weeks after the WSJ article, and the study has finally been published—in The New England Journal of Medicine (NEJM), yet! Known as the TOGETHER trial, this study was a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2–positive adults recruited from twelve public health clinics in Brazil. In brief, patients who had had symptoms of Covid-19 for up to 7 days and and also had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo. The primary endpoint was a composite outcome involving either hospitalization due to COVID-19 or an emergency department visit due to clinical worsening of COVID-19 symptoms (defined as the participant remaining under observation for >6 hours), either within 28 days after randomization, and what is reported here are the results for one drug, as the TOGETHER trial looked at other treatments for COVID-19, according to this schema:

Schema for TOGETHER study
Schema for the TOGETHER trial.

It also turns out that the two groups were well-matched:

TOGETHER Study
Clinical characteristics of the groups in the TOGETHER Trial.

Before I go on, I’ll be honest right here. I’ve criticized composite outcomes (outcomes that involve lumping more than one outcome together as a composite) before, particularly in trials looking at cardiovascular outcomes, where combining, for example, a composite outcome of death, MI, stroke, coronary revascularization and hospitalization for angina, a composite outcome that I viewed as a rather transparent method of taking a bunch of outcomes that weren’t significantly different between placebo and treatment groups and making them into a measure that did achieve statistical significance. So seeing a composite outcome in this trial gave me a brief pause, but the investigators justified their choice well enough to convince me that it was not unreasonable to choose this composite outcome measure:

Because many patients who would ordinarily have been hospitalized were prevented from admission because of limited hospital capacity during peak waves of the Covid-19 pandemic, the composite outcome was developed to measure both hospitalization and a proxy for hospitalization, observation in a Covid-19 emergency setting for more than 6 hours. This region of Brazil implemented mobile hospital-like services in the emergency settings (i.e., temporary field hospitals) with units of up to 80 beds; services included multiple-day stays, oxygenation, and mechanical ventilation. The 6-hour threshold referred only to periods of time that were recommended for observation by a clinician and was discounted for wait times. The event-adjudication committee, whose members were unaware of the randomized assignments, judged the reason for hospitalization or prolonged observation in the emergency department as being related or unrelated to the progression of Covid-19. Guidance for the validity of composite outcomes indicates that outcomes should have a similar level of patient importance.14

If patients who would normally have been admitted to the hospital were sent home because hospitals were overcapacity, it isn’t unreasonable to count patients who were observed in the emergency room this way. I’m not thrilled with it, as it makes the study less “pure” than I would like, but I understand it and applaud the researchers for trying to make this composite as rigorous as such composite outcomes can be.

But what about the adaptive trial design? Adaptive trials are trials that are set up such that they can be modified while under way and still provide valid results. More specifically, adaptive studies are designed so that they can utilize results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. These changes can include (but aren’t limited to) refining the sample sizes, abandoning treatments or doses, changing the allocation ratio to trial arms, identifying patients most likely to benefit and concentrating on recruiting them, or stopping the whole trial at an early stage for lack of efficacy or for adverse reactions. For example, the TOGETHER Trial protocol had prespecified criteria for altering or stopping the study based on discontinuing interventions for futility, stopping owing to superiority of an intervention over placebo, or adding new interventions.

In addition, the authors note:

The trial began recruitment for its first investigational groups on June 2, 2020. The evaluation that is reported here involved patients who had been randomly assigned to receive either ivermectin or placebo between March 23, 2021, and August 6, 2021. The initial trial protocol specified single-day administration of ivermectin, and we recruited 77 patients to this dose group. On the basis of feedback from advocacy groups, we modified the protocol to specify 3 days of administration of ivermectin. Here, we present data only on the patients who had been assigned to receive ivermectin for 3 days or placebo during the same time period. The full trial protocol was approved by local and national research ethics boards in Brazil and by the Hamilton Integrated Research Ethics Board in Canada. The CONSORT (Consolidated Standards of Reporting Trials) extension statement for adaptive design trials guided this trial report.12 All the patients provided written informed consent.

Also:

We responded to feedback from advocacy groups regarding this administration schedule and adapted the duration of ivermectin administration to 3 days at a relatively high dose as compared with most other trials of this drug. 

So the authors actually used a higher dose of ivermectin than was used in most other studies of the drug, and they did so based on the feedback of ivermectin advocates.

So what were the results?

In the intention-to-treat population, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16) (Table 2). For those not familiar with the term, “intention to treat” means analyzing all subjects who were randomized, regardless of whether they completed their treatment or not or whether they dropped out of the study or not. Similar results were observed in the modified intention-to-treat population (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and the per-protocol population (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). In this study, the modified intention-to-treat analysis included “all the patients who received ivermectin or placebo for at least 24 hours before a primary-outcome event (i.e., if an event occurred before 24 hours after randomization, the patient was not counted in this analysis),” while the per-protocol analysis looked at “all the patients who reported 100% adherence to the assigned regimen.” Basically, this is as negative as a negative study can be, given that all the confidence intervals for the relative risks of the specified outcome (in this case the Bayesian credible intervals) overlapped 1.0—and not by a little.

The negative results continued for secondary outcomes as well:

There were no significant differences between the ivermectin group and the placebo group with regard to viral clearance at day 7 (relative risk, 1.00; 95% Bayesian credible interval, 0.68 to 1.46) (Fig. S3). The 14-day restricted mean survival time difference17 was 0.11 days (95% Bayesian credible interval, −0.23 to 0.48). There were no significant between-group differences with regard to the risk of hospitalization for any cause (relative risk, 0.83; 95% Bayesian credible interval, 0.63 to 1.10), the time to hospitalization (hazard ratio, 0.83; 95% Bayesian credible interval, 0.61 to 1.13) (Fig. S1), and the number of days in the hospital (mean difference of the log-transformed values, 1.00 days; 95% Bayesian credible interval, 0.80 to 1.25).

There were also no significant between-group differences in the time to clinical recovery (Fig. S2) (hazard ratio, 1.05; 95% Bayesian credible interval, 0.88 to 1.24), the risk of death (relative risk, 0.88; 95% Bayesian credible interval, 0.49 to 1.55), the time to death (hazard ratio, 0.88; 95% Bayesian credible interval, 0.47 to 1.67), or the number of days with mechanical ventilation (mean difference, 1.06 days; 95% Bayesian credible interval, 0.63 to 1.75). There was no evidence of between-group differences in the PROMIS Global-10 physical-component score as measured on day 28 (mean difference, −0.4 points; 95% Bayesian credible interval, −1.4 to 0.6) or mental-component score (mean difference of the squared values, 6.1 points; 95% Bayesian credible interval, −104.1 to 116.7). With regard to adverse events, there were no important between-group differences in the incidence of adverse events during the treatment period (Table S6).

Again, all the intervals here overlap 1.0 (no increase or decrease in hazard ratio). There are no statistically significant differences in any of the secondary outcomes either this study. Subgroup analyses also failed to find a benefit from ivermectin in subgroups defined according to patient age, body-mass index, status of having cardiovascular disease or lung disease, sex, smoking status, or time since symptom onset, nor was there a benefit observed with ivermectin as compared with placebo among patients who began the trial regimen within 3 days after symptom onset.

So we have here yet another study, another RCT, that resoundingly failed to find even a hint of a signal that might indicate a benefit to treating COVID-19 with ivermectin. Quelle surprise! So how are the ivermectin advocates who claim that they are just “following the science” reacting? Not well. Not well at all.

Here are a couple of examples:

This is the sort of thing advocates say when they can’t even think up a BS reason to discount the trial.
Next up, if you can’t think of a scientific critique of the study, dig up the funding source and see if you can link it to a conspiracy theory.

Those two Tweets, however, are easy to dismiss. What about more “serious” critiques of the study? One was published on—where else?—Robert F. Kennedy Jr.’s website Children’s Health Defense just yesterday. It’s by Madhava Setty, MD, billed as senior science editor for The Defender, RFK Jr.’s news blog. (How far does one have to have fallen as a medical professional to agree to be the senior science editor for a large antivaccine blog?) In any case, based on its article, Dr. Setty accuses the New York Times‘ Carl Zimmer—Carl Zimmer, one of the best science journalists out there!—of misleading the public about the TOGETHER trial.

First, demonstrating that he didn’t bother to read the actual protocol, Dr. Setty is incensed about the composite outcome:

Also of note, the investigators chose to include emergency room visits with hospitalizations for COVID. Clearly, six hours of observation in an ER is a significantly different outcome than a hospitalization that may last a night or much longer.

When excluding the ER visits from the primary outcome and examining only hospitalizations, the ivermectin cohort had even less risk of an outcome, i.e. the relative risk was 0.84 vs 0.9 when ER visits and hospitalization were grouped together.

Seriously, as I discussed above in commenting on my misgivings about composite trial designs, the authors addressed why they chose this particular outcome. You can disagree with it, or not, but they accounted for it completely in the statistical plan for the study and explained exactly why they chose this particular composite outcome. If you’re going to disagree, fine, but address what the authors actually did and their rationale for it, rather than your pathetic straw man version. Also, how far ivermectin advocates have fallen if they’re trying to disparage this study by claiming that it shows only a 10% benefit in terms of hospitalizations due to the drug. What happened to that miracle cure? Even if there were a 10% benefit in this study due to the drug (and there most definitely is not), that is not what I’d call a miracle cure—or even a highly effective treatment!

Next up, Dr. Setty thinks that this is a slam-dunk criticism:

The NEJM study took place in Brazil between March 23 and Aug. 6, 2021.

The study examined 1,358 people who expressed symptoms of COVID-19 at an outpatient care facility (within seven days of symptom onset), had a positive rapid test for the disease and had at least one of these risk factors for severe disease:
  • Age over 50
  • Hypertension requiring medical therapy
  • Diabetes mellitus
  • Cardiovascular disease
  • Lung disease
  • Smoking
  • Obesity
  • Organ transplantation
  • Chronic kidney disease (stage IV) or receipt of dialysis
  • Immunosuppressive therapy (receipt of ≥10 mg of prednisone or equivalent daily)
  • Diagnosis of cancer within the previous 6 months
  • Receipt of chemotherapy for cancer.
Young and healthy individuals were not part of this study.

Note the moving of the goalposts. If ivermectin only works in “young and healthy” people, then it wouldn’t be much of a miracle cure, would it? Of course, the TOGETHER Trial intentionally studied people with symptomatic COVID-19 who were at the highest risk of progression to severe disease and death. If ivermectin worked, it should work in this population as well and wouldn’t be much good if it only worked in the “young and healthy,” who, as ivermectin cultists and antivaxxers so frequently remind us (to the point of perseverating about it), are at the lowest risk of hospitalization and death from COVID-19 to begin with. Also, limiting the study to those at higher risk allowed the use of fewer subjects, because in a study in which the expected rate of the primary outcome is very low a much larger number of subjects is required to see a statistically significant result in the treatment group compared to the placebo group.

This part made me laugh out loud:

The study’s authors wrote:
100 patients (14.7%) in the ivermectin group had a primary-outcome event (composite of hospitalization due to the progression of COVID-19 or an emergency department visit of >6 hours that was due to clinical worsening of COVID-19), as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16).
In other words, a greater percentage of placebo recipients required hospitalization or observation in an emergency department than those who received Ivermectin.

Seriously, one wonders how Dr. Setty got through medical school if he couldn’t pass a basic biostatistics course. Look at those confidence intervals! Again, as I pointed out, they overlap 1.0. Of course, Dr. Setty probably didn’t flunk biostatistics. Rather, he falls back on that favorite excuse used to explain a negative study, namely, “You didn’t use enough subjects”:

As is demonstrated in nearly every subgroup, the Ivermectin recipients fared better than those who received the placebo.

However, these data were not statistically significant given the size of the study.

This is how the authors were able to conclude there was no benefit to ivermectin use in preventing hospitalization in high-risk patients in their study.

Funny how apologists like Dr. Setty always assume that more subjects would translate into a statistically significant difference rather than the more likely outcome that it would not. Really, the only time this sort of appeal to “more subjects would’ve resulted in a positive study” is valid is when the results as reported are close to statistical significance. Such is not the case with the TOGETHER trial.

Dr. Setty continues to demonstrate that he can’t science by then arguing:

Only 288 of 679 participants randomized to receiving the placebo reported 100% adherence to the study protocol. Nearly 400 didn’t.

Why not? We asked Dr. Meryl Nass, an internist and member of the Children’s Health Defense scientific advisory committee.

Nass told The Defender:
Presumably they knew the difference between ivermectin and placebo, and the placebo subjects went out and bought ivermectin or something else … but whatever they did, they didn’t bother with the pills they were given. So, it was not actually a double-blinded trial. Yet the 391 people who didn’t take the placebo but did something else were included in two of the three calculations of ivermectin efficacy anyway.
So, was this the definitive answer proclaimed by mainstream sources? Nass thinks otherwise:
I would say that instead, it was a failed trial due to the 391 placebo recipients who admitted they did not follow protocol versus the 55 in the ivermectin arm.

Dr. Nass isn’t exactly what one would call a reputable source. But what about this criticism? This is an example of Dr. Nass and Dr. Setty ignoring the intention-to-treat analysis and modified intention-to-treat analysis to focus on this one analysis. In fact, best practice in clinical trials is to include both intention-to-treat analyses and per-protocol analyses:

The use of ITT analysis ensures maintenance of comparability between groups as obtained through randomization, maintains sample size, and eliminates bias. In addition, results obtained in such analysis more closely represent clinical practice, dealing with “effectiveness” of the intervention rather than “efficacy.” In view of these advantages, ITT is today considered as a defacto standard for analysis of clinical trials, though a minority school of thought believes that this approach is too conservative.[1]

In contrast, per-protocol (PP) analysis refers to inclusion in the analysis of only those patients who strictly adhered to the protocol. The PP analysis provides an estimate of the true efficacy of an intervention, i.e., among those who completed the treatment as planned. However, as discussed above, its results do not represent the real life situation and it is likely to show an exaggerated treatment effect.

The CONSORT guidelines for reporting of “parallel group randomized controlled trials” recommend that both ITT and PP analyses should be reported for all planned outcomes to allow readers to interpret the effect of an intervention.[3]

In fact, contrary to what Drs. Setty and Nass argue, the completely negative per-protocol analysis is likely more damning to ivermectin, because per-protocol analyses tend to exaggerate positive results. But leave it to cultists to try to point to a sign of more rigor in a study as evidence that the study shows the opposite of what it shows. I also can’t help but note that one criticism of this study is that ivermectin was available over-the-counter in Brazil at the time of the study, which could mean that those in the placebo group could have been using ivermectin over-the-counter. The per-protocol analysis excludes those people, who would have violated the protocol. Indeed, I’d be willing to bet that the reason that so many people in the placebo group dropped from the protocol was because they took ivermectin in addition to placebo, given how available it was, but the authors would have to comment.

Then there is the adaptive trial design, which means that different treatment groups in the overall trial “shared” placebo control groups, one of which took placebo for three days:

The per-protocol population included all the patients who reported 100% adherence to the assigned regimen. Although all the participants who had been assigned to the 3-day and 14-day placebo regimens were included in the intention-to-treat population, only those who had been assigned to the 3-day placebo regimen were included in the per-protocol population.

It’s clear that either Drs. Setty and Nass don’t understand adaptive trial design or that they do and are ignoring this issue as part of the potential explanation for why the per-protocol analysis lost a lot of placebo group subjects because they know that their readers don’t understand adaptive trial designs. Of course, their readers in general very likely don’t understand clinical trial design or proper study analysis in general, and RFK Jr. and his sycophants, toadies, and lackeys (like Dr. Setty) know that.

Dr. Setty concludes by JAQing off (“just asking questions,” for those not familiar with the term:

Rather than pounding the final nail in the coffin around ivermectin’s utility in treating COVID, the NEJM study raises more questions.
  • What would the effect have been if a higher dose shown to be effective were administered?
  • What would be the benefit of this medicine in patients with no risk factors?
  • How statistically significant would the results have been if more participants were enrolled?
  • Why weren’t more participants enrolled as the study progressed given the emerging benefit of the drug and the absence of adverse events?
  • Why did the investigators define a primary outcome with such different real-world implications (ER visits vs hospitalizations)?
  • With less than 50% of the placebo arm adhering to the study protocol, why were their outcomes included in the analysis?
  • What effect did vaccination status have on outcome? If this is the primary means endorsed to prevent hospitalization, why wasn’t vaccination status mentioned as a confounder?
  • Did the investigators choose to limit the study as it became clear that an Ivermectin benefit would be too big to ignore?

These questions are all handwaving, although the question about vaccination status might be a valid criticism of the study. My guess as to why it wasn’t included in the final analysis, given that vaccinated people were allowed to enroll, is speculation, but, I hope, knowledgeable speculation. Given the dates of the study, my guess is that the number of vaccinated patients were so small as to be insignificant. First, if you look at the statistics, at the beginning of the trial, only a very small number of people in Brazil were even partially vaccinated, and by the end only about one-fifth were fully vaccinated and one-half partially vaccinated. Given that the Delta variant only arose late in the study and the Omicron variant hadn’t arisen at all yet, it’s likely that the number of breakthrough infections in Brazil was very small in the study population by the end of the study in August 2021. Still, it would have been helpful if the authors had explicitly discussed this issue, in order to preempt this criticism.

And, of course, Dr. Setty claims that the dose was too low, citing the Frontline COVID-19 Critical Care Alliance (FLCCC) protocol (remember the FLCCC?), which recommends 600 μg/kg for five days. Never mind that at the time this study was designed the authors increased the duration of treatment based on what advocates recommended.

Basically, critics are doing this:

Yeah, I’m stealing this meme.

Not that that stopped ivermectin believers:

Also, one notes the…selectivity…with which ivermectin fans apply their criticisms to the TOGETHER study:

Of course, and then when these studies are criticized for having glaring problems, the ivermectin fans either ignore the criticisms or accuse critics of being “pharma shills.”
I can’t help but add that many of the exclusion criteria above were chosen to exclude people with severe disease on presentation, given that the claims for ivermectin were that it was effective as an “early treatment” for COVID-19 to prevent progression to severe disease, hospitalization, and death. Also, excluding pregnant patients is entirely reasonable; that is, unless ivermectin believers like to subject the pregnant to a drug that might be teratogenic.

And, relevant to my discussion of the per-protocol analysis above:

And:

Same as it ever was.

The bottom line is that this study is yet another nail in the coffin of ivermectin as a treatment for COVID-19. At this point, I will, as is my wont, refer to a famous Monty Python sketch and note that at this point ivermectin is “pining for the fjords,” or, to paraphrase:

Ivermectin for COVID-19 is no more! It has ceased to be! It’s expired and gone to meet its maker! It’s a stiff! Bereft of life, it rests in peace!…It’s kicked the bucket, shuffled off its mortal coil, run down the curtain and joined the bleedin’ choir invisible!! THIS IS AN EX-COVID-19 TREATMENT!!

Picture the shopkeeper as Drs. Setty and Nass (and the entire FLCCC) and me as John Cleese, with the parrot being ivermectin for COVID-19:

Drs: Setty and Nass:

Monty Python Dead Parrot Sketch as a study
See, see! You didn’t use a high enough dose. You excluded all these groups. You used a composite outcome!

Orac:

Ivermectin
Hellloooo, Polly!

And:

Ivermectin as an ex-parrot
According to this study, ivermectin is an ex-treatment, although it was never a treatment in the first place; so I guess I can’t say “ex.”

My prediction is that ivermectin fans will keep responding in the same way as the shopkeeper in the sketch did and keep stubbornly denying that the parrot is, in fact, dead and insisting that it’s “pining for the fjords.”

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

40 replies on “Yet another negative ivermectin study, this time in the NEJM”

A fine selection of the classic excuses, from this great paper: “Key opinion leaders guide to spinning a disappointing clinical trial result” by Hartley et al, BMJ 2018.

Hey Orac, there is an another reason for the low number of placebo patients in the per protocol analysis. It has to do with the adaptive design. Different treatment groups “shared” the control group, so not all the placebo patients had an identical pill regimen. Quoting from the NEJM paper

“The per-protocol population included all the patients who reported 100% adherence to the assigned regimen. Although all the participants who had been assigned to the 3-day and 14-day placebo regimens were included in the intention-to-treat population, only those who had been assigned to the 3-day placebo regimen were included in the per-protocol population.”

“My prediction is that ivermectin fans will keep responding in the same way as the shopkeeper in the sketch did and keep stubbornly denying that the parrot is, in fact, dead and insisting that it’s ‘pining for the fjords.'”

A safe prediction indeed, I suspect. I’d sure like to think though, that the press given to big negative studies would help shrink that fan base somewhat. I think there may be more of those coming: a couple months ago the Minneapolis paper had a story about a big ivermectin trial at the U of MN that was nearing completion. When I saw that story, I wondered why ‘the U’ would be putting so much effort into something already proving to be pretty sketchy — perhaps not thinking how much lead time is involved. Anyway, Today I did a Google and found this description of the study: https://www.eurekalert.org/news-releases/742246

The first thing I noticed is that the funding source is the same as the TOGETHER trial: Rainwater and Fast Grants. But — and maybe Orac or other folks in the know about medical research can help out here — as i read the press release that funding appears to have been premised on the possibility that ivermectin might actually work.

An ongoing COVID-19 clinical trial studying the outpatient use of metformin… has expanded and will now be the nation’s first to include fluvoxamine, an antidepressant, and ivermectin, an antiparasitic, as possible treatment options to prevent hospitalization and “long COVID. Led by the University of Minnesota Medical School, the multi-site clinical trial received new support – $1 million from the Rainwater Charitable Foundation and $500,000 from Fast Grants – to expand the study… The clinical trial launched after U of M Medical School researchers identified, through computer modeling and observational studies, that outpatient metformin use may decrease the likelihood of dying from or being hospitalized for COVID-19… These findings, along with other prospective studies supporting the use of fluvoxamine and ivermectin, helped provide enough evidence to expand the randomized clinical trial to include all three medications as well as combination arms.

This suggests, to me anyway, that the Rainwater funding may indeed be relevant, for exactly the opposite reason implied in that bonkers Tweet. I also have to note how that conspiracy theorist tries to tie the TOGETHER study to the latest Fox News / far-right boogie-man — Gays! / Pedophilties! / DISNEY!

Well, of course. In general, private foundations like Rainwater don’t fund a study because they think the treatment being studied won’t work. They fund a study because they think the treatment being studied will work—or, at least, is more likely to work than not. Foundations like positive studies and generally won’t fund studies that they consider likely to produce a negative result. A negative result is a disappointment to private foundations funding the study, because to such foundations negative results don’t mean an answer. They mean that the foundation chose poorly.

“Maybe the people in placebo went out and bought Ivermectin pills”

OK, now it’s ridiculous. Well, more ridiculous.
Although the guy dragging in Disney into the mix made me laugh.

Eh, maybe the people receiving the real Ivermectin also thought they were on placebo and went out to buy some horse paste or sheep broth, and got 10 times the dose.

Oh, something else which we have seen since HCQ’s days and now for IVM:

“Young and healthy individuals were not part of this study.”

According to HCQ/IVM/Zinc fans, Covid19 is a very mild disease and “Young and healthy individuals” don’t need to worry about it at all, but at the same time if you don’t take their miracle drug you are all going to die. Or be seriously inconvenienced anyway.
So, which is it?

I’ve marveled at that too.

Outrage over “suppression” of miracle remedies doesn’t square with the bland assurance that Covid-19 is a minor annoyance.

Strange reversal – I remember some saying that the reason that the vaccine trials were bad, was that they were only ‘Young and healthy individuals’…

Am I misreading something here? Dr. Setty is quoted as writing:
The study examined 1,358 people who expressed symptoms of COVID-19 at an outpatient care facility (within seven days of symptom onset), had a positive rapid test for the disease and had at least one of these risk factors for severe disease:
Age over 50
…etc

but Table 1 of the study states a median age of 49 for both groups. The risk factors do not seem to add up either. In the treatment group 239 out of 679 are reported as having a risk.

I understand anonymizing patients information, but why are the ‘ivermectin advocacy groups’ the communicated with also anonymous?

In the U.K., sheep are being used to encourage young people to get vaccinated against Covid-19.

“Shetland sheep – called Lashes, Cumin, Coriander Clove and Cardamom – were at hand in a petting zoo for the youngsters who went for their Covid-19 vaccination at Epsom’s North East Surrey College of Technology (Nescot) on Saturday.”

tandard.co.uk/video/news/sheep-support-children-being-vaccinated-v4e021788

Cute, even though antivaxers are no doubt fulminating about “sheeple”.

So I was prescribed ivermectin. The practice mentioned in this study was not the protocol recommended by my doctor:
o 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days.

1) the dosage was to begin as soon as symptom onset, not 7 days later.
2) the dosage was supposed to be taken for 5 days not 3.
3) The dosage also doesn’t match what I took.
This is a kin to someone making a study to discredit the vaccine that says they gave one of the shots as opposed to the recommended 2 jab regimen. It’s meaningless and indeed looks specifically designed to fail.

“This is a kin to someone making a study to discredit the vaccine that says they gave one of the shots as opposed to the recommended 2 jab regimen. It’s meaningless and indeed looks specifically designed to fail.”

Says the moron with so little understanding of science he stated that results from designed experiments were equivalent to hearsay. By all means, continue to demonstrate why nobody should take you seriously or even think that you’re interested in honest discussions.

Results aren’t hearsay. An expert repeating results with conclusions offered for their truth is hearsay. This is pretty basic first principles of evidence. But whether an expert’s representations are hearsay depend on the specifics around those representations. Mere ministerial recording by the same person and recounting such could be mere testimony; relying asserting the truth of third party representations is more like hearsay. See e.g https://link.springer.com/article/10.1007/BF01499136 for a longer explanation. Or this https://digitalcommons.law.uga.edu/cgi/viewcontent.cgi?referer=&httpsredir=1&article=1785&context=fac_artchop, which highlights the concerns.

Yeesss. That’s the usual response. It didn’t work, give more. Funny how you object to that approach when it comes to boosters eh?

It’s surreal you’re commenting this on a post that has already addressed these false points. It’s like you want us to think you’re a bot.

1) Half the IVM group received the dose within 0-3 days. They did worse than those who had it 4-7 days. Nobody took it after 7 days.
2) So this wonder drug that has been miraculously curing everyone the second they took it for 2 years now, suddenly has zero effect until the 4th or 5th dose?
3) The dosage was not only max upper limit of the FLCCC protocol at the time, but higher than most of the positive IVM studies.

Despite the FLCCC continuously ramping up their dosage prescription in an attempt to post hoc discredit negative evidence for IVM, it is in fact still within the bounds of what they recommend as of Jan 2022 (0.4-0.6 mg/kg). Not that I understand why they are an authority on anything, or where on earth they get their safety/efficacy data from.

I suppose the 0.2-0.4 mg/kg they’ve recommended for treatment the past 2 years has in fact been completely ineffective, rendering all their clinical anecdotes and every study they’ve held up as evidence completely null.

If you are going to copy-paste Twitter talking points, it’s best to be transparent about it and not pretend it’s personal experience. If you find yourself lying to prop up your argument, it’s a good measure of your own bias. Best take some time to reflect on that.

Why a different dosage did not have any effect at all ? If ivermectin is a wonder drug, why it works only when started immediately after onset of symptoms,not later. Notie that there is a negatie study about ivermectin prophylaxis. Window nis narrowing.

Not sure it is a wonder drug. I think maybe there is a mechanism of action for it as an antiviral if dosed right and given before viral replication is not controllable with an antivirall. This study doesn’t seem to give much insight either way. I don’t know re later stages or prophylaxis, but this study makes no comment on that either.

Antiviral working before replication ? This would be quite useless

I took ivermectin as soon as I had a positive test…before I had symptoms. 6 mg per day for 4 days along with a z-pack. 2 of my friends did the same thing. None of us ended up in the hospital. We are all over 70. We reside in a senior housing complex and 2 individuals who did not take ivermectin passed away. I believe the difference between us and the NEJM study is that we took it immediately and in conjunction with the antibiotic. We took the human tablet form, not horse paste. Obtained in Mexico. Ivermectin must be given immediately, before the spike protein has time to replicate itself. Not after 7 days as in this study.

Your anecdotes do not mean that ivermectin works. You would almost certainly gotten better anyway, and if those two who died had taken ivermectin they would almost certainly have died anyway. Ivermectin doesn’t work.

Also, did you bother to read the study, rather than lies about it? None of the patients started ivermectin after seven days of symptoms. That’s the point. Early treatment was defined as starting within seven days of symptoms. Patients were screened for that and excluded if they’d had symptoms for more than seven days. Most patients started ivermectin within three days of symptoms. Seriously. Read the study, rather than the propaganda about it.

Seriously, there are weaknesses in the study that can be addressed. (Indeed, I addressed at least one of them in my post.) None of your criticisms are directed at actual weaknesses in the study, and your criticism that patients took ivermectin more than seven days after symptoms started is just plain incorrect. Again, read the study.

Re: “If ivermectin only works in “young and healthy” people, then it wouldn’t be much of a miracle cure, would it?”

Then if Ivermectin worked on young & healthy people, then young & healthy people wouldn’t have any incentive to be vaccinated, which is the only reason you are so obsessed with discrediting Ivermectin.

That’s literally the only reason, isn’t it.

Because in the past, you have repeatedly stated that your primary reason for not supporting compassionate use of relatively harmless treatments for cancer, involving what in your opinion, only provides placebo effects: Is that predatory providers are exploiting those patients for financial gain.

With a cheap, widely available product such as Ivermectin, it’s not necessary to surrender oneself to exploitation to obtain it. Sure, you can choose to go the convenient route & pay for concierge consultations & prescriptions but if you don’t have those resources, like me; you don’t have to.

Your ONLY motivation to campaign against Ivermectin, is the potential devaluation of vaccination.

My anecdotal experience with Ivermectin, as an unvaccinated, over 50 year old person with no other comorbidities; involved a 50 ml vial ($39) of “Ivermax”, which is an injection for livestock, containing 10 mg per ml. I dosed by weight, opting for a 15 mg p.o. q. d. dose.

That was 1.5 ml drawn up daily & placed in a few oz of grape juice. The first dose I opted to only consume 0.75 ml, to assess tolerability. Despite the half-dose, all adverse Covid symptoms began to lessen in severity within about 12 hours. Within 12 hours of the second & full dose; I was completely asymptomatic.

I mean, carry on with your campaign against Ivermectin but at least acknowledge that you are not doing so out of a concern for lack of positive outcomes but rather; because you believe it will discourage vaccination.

A. Having an available treatment is not a reason not to vaccinate, so no, we want to have working treatments for covid-19. That’s why it’s good to have a few approved treatments that can help. The reason to oppose ivermectin is that evidence doesn’t show it works. We actually want both a preventive and a cure here, if possible. Your conspiracy theory is baseless.

B. I’m glad your symptoms self-resolved. I do find it a little sad that you were misled into misusing animal medicine this way, but at least now we can be relatively sure you’re free of worms.

1) Medications formulated for IV administration are often not formulated for oral administration and may not survive the stomach acid. They are buffered differently, among other things. So you don’t actually know what dose reached your bloodstream.

2) $39 for one vial of not-for-use-in-humans material is still $39 more than what I have paid for all three of my COVID vaccine shots. So, how is medication that one would presumably have to take every time one was exposed to COVID cheaper than free shots?

Actually, the reason I oppose the use of ivermectin to treat COVID-19 is because science shows that it is not effective treating COVID-19 in anyone.

Have you read the RCTs ? How they are part of campaign against ivermectin ? Conspiracy, I presume.
Ivermectin is not very useful as a drug, if it works only if young and healthy people take it. Trials have patients who really need the drunbgn

“Then if Ivermectin worked on young & healthy people, then young & healthy people wouldn’t have any incentive to be vaccinated, which is the only reason you are so obsessed with discrediting Ivermectin.

That’s literally the only reason, isn’t it”

Don’t be silly. Stop being self obsessed. As an individual I don’t personally give two hoots if you vaccinate to protect yourself. I don’t care if you kill yourself off through arrogance at all. What I do care about is that your pseudo-knowledge and arrogance prevents other people from getting a chance to make that decision voluntarily.

“Then if Ivermectin worked on young & healthy people, then young & healthy people wouldn’t have any incentive to be vaccinated.”

But…but young and healthy people supposedly have nothing to worry about from Covid-19; we’re told that it’s no worse than the common cold. Why would they need to dose themselves with bovine injection fluid?*

*this bit of weirdness reminds me of the antivaxer who “challenged” MDs to drink vaccine ingredients. Apparently all routes of drug administration are interchangeable, if you’re a moron.

Isn’t it ironic that people who appear to be terrified of vaccines are not afraid to utilise untested, ineffective, worthless or even dangerous treatments to treat a condition that could have been virtually eliminated as a threat to their health?

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