Trial Report Outpatient treatment of Covid-19 and the development of Long Covid..., 2023, Bramante et al

Edit: Paper now published
Post with abstract here.

Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial
Link (Open access to full paper)


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Preprint abstract

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Spoiler: Authors: University of Minnesota and other US centres

Carolyn T Bramante, John B Buse, David Liebovitz, Jacinda Nicklas, Michael A Puskarich, Ken Cohen, Hrishikesh Belani, Blake Anderson, Jared D Huling, Christopher Tignanelli, Jennifer Thompson, Matthew Pullen, Lianne Siegel, Jennifer Proper, David J Odde, Nichole Klatt, Nancy Sherwood, Sarah Lindberg, Esteban Lemus Wirtz, Amy Krager, Kenny Beckman, Spencer Erickson, Sarah Fenno, Katrina Hartman, Michael Rose, Barkha Patel, Gwendolyn Griffiths, Neeta Bhat, Thomas A Murray, David R Boulware

Background: Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid.

Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14.

Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385).

Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial. Trial registration: NCT04510194; IND 152439

Link

 

Short treatment courses following documented infection in overweight or obese adults. Reporting on the secondary outcome of "diagnosis of Long Covid" by day 300.

 

The primary outcome was reported in Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19 (NEJM, 2022) and concluded —

 

If it were acting directly against virus as per their first explanation, I might expect stronger effects in the acute setting to more closely match the late effects.

Metformin acts to lower blood glucose levels somehow. The study participants are overweight/obese and would likely have a degree of insulin resistance. Does the same protective effect occur in those who are normal weight or underweight, with normal insulin sensitivity/glucose levels? And, of course, is there any benefit with established Long Covid?

Is the observed effect here occurring as a result of lowering glucose (± inflammation), or more fundamentally at mitochondrial level (where lowering glucose is a side-effect), or by modulating the gut microbiome? The short treatment course might imply the first two, as alteration of the gut microbiome might be expected to occur over a longer timeframe. But if the latter, perhaps the synchronous use of fluvoxamine may oppose beneficial gut microbiome changes in this instance. There's also the anti-platelet and serotonin aspect of SSRIs to consider.

See Serotonin Reuptake Inhibitors and the Gut Microbiome: Significance of the Gut Microbiome in Relation to Mechanism of Action, Treatment Response, Side Effects, and Tachyphylaxis (2021) for a recent hypothesis paper on how SSRIs might be working in psychiatric disease via the gut-brain axis.

 

I am bothered by this sentence. Titration of a drug means varying the dose according to response. To be able to titrate you have to be able to measure a response reasonably reliably. Which means it is not blinded.

It may be that they are misusing the term titrated but nothing very much in this study seems to hang together. My understanding was that rates of Long Covid were not very closely related to the severity or length of acute illness. So a drug ameliorating the acute illness ought not to make much difference if it was working through the general anti-viral or anti-inflammatory mechanisms quoted.

 

I am also puzzled as to why ivermectin was included, since this seems to be largely a fringe treatment. And why the treatment groups were asymmetrical to metformin. Metformin seems to have been the main focus of the trial. Alos I am not clear why people needed to be overweight. Overweight people are at high risk of acute Covid but I am not sure that one would expect that to apply to LongCovid.

 

The abstract says the trial was designed to look at effects on LongCovid. I guess that is not strictly true.

I sense a good degree of angle shifting in the way these results are presented.

Which would also destroy blinding.

 

Uh huh. Well, one of those is true, just not the way most people would think. Documenting is critical to getting insurance coverage, refusing to document has always been with the intent to deny support and save healthcare costs, the lie about "impacting psyche" is just that, a lie. In fact it's quite the opposite, the mental torture of being told there's nothing wrong is so often cited at this point it's malpractice to keep this lie going, but then it always was.

In fact the same old stories are happening, with patients demanding their status get documented, and physicians refusing for obviously arbitrary and fake reasons such as pretending the patients don't want them. I still regularly see patients being screamed at for even mentioning POTS, being laughed in their face, now that is something that actually and severely impacts patients' psyche, in fact they say so all the time and no one listens and lies about it instead.

The reflexive adding of mental health labels that do explicitly harm patients' future healthcare options makes that an especially ugly lie. Unnecessary diagnostic labels are added to healthcare records on no basis all the time, and they only go one way.

Of course it was. You hadn't heard of it, not the same thing.

So this is a modified study that didn't intend to study LC as they weren't aware of it, or something like that.

It's frankly hard to imagine a more useless way to assess LC than "Has a medical provider told you that you have Long Covid?".

It's suggestive of something but I doubt it holds up to a rigorous study. Way too many confounding factors and a weak assessment of primary outcome.

 

If its easy to do could you share what that difference was please Trish? Dont worry if too much hassle just wondering & my brain is too fried to read the study through to fond it

 

Is it clear that this supposed blinding continued for the duration of the LongCovid data acquisition period? Is it possible that this blinding only applies to the initial acute phase?
Both fluvoxamine arms seem to go in the wrong direction if anything?