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

[SNT Gatchaman]

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

 

[SNT Gatchaman]

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

 

[SNT Gatchaman]

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

None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19.

 

[Hutan]

The design looks pretty solid - big enough, and plenty of effort made to maintain blinding.

COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple- blinded placebo-controlled clinical trial (ClinicalTrials.gov: NCT04510194).10 Those blinded included: participants, care providers, investigators, and outcomes assessors.

Re the definition of Long Covid - the criteria seems to be that a doctor has given that diagnosis during the 300 days following the onset of a Covid infection - with monthly followup to ask 'any diagnosis?'. I assume the point about medical providers and patients being wary of 'using diagnosis labels in the medical record unnecessarily' is to suggest that this is a conservative approach to assessing Long Covid incidence. Of course, potentially, it might underestimate the incidence of Long Covid if there are doctors and patients who don't want to acknowledge Long Covid. But it seems like a reasonable approach.

Because the definition of Long Covid is rapidly changing, fluctuating symptoms are challenging to assess, and ICD codes lack specificity and sensitivity, the primary method for ascertaining Long Covid was participant-reported receipt of a Long Covid diagnosis from a medical provider. Medical providers and patients are wary of using diagnosis labels in the medical record unnecessarily, because doing so can negatively impact patient psyche and have insurance ramifications.

Overall, 8.4% (94/1125) responded Yes to the question: “Has a medical provider told you that you have Long Covid?”

Long Covid incidence rates of this order seem pretty standard. Note that this question applies to all the monthly followups, and only includes people who answered at least one of the followups after 180 days. So, it includes people who, for example, still had symptoms at the 6 month survey but had recovered by the 8 month survey.

Overall, 10.6% of blinded control participants reported receiving a diagnosis of Long Covid from a medical provider, compared to 6.3% receiving metformin. .....There was no decreased incidence of Long Covid attributable to ivermectin or fluvoxamine in this trial.

Looks like metformin reduced the odds of getting Long Covid, but I haven't finished reading the report yet.

The p value (0.009) for metformin preventing Long Covid

 

[Hutan]

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

None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19.

This paper says about the primary outcome

The hazard ratio of 0.58 (95% CI 0.38 to 0.88) for metformin preventing Long Covid is consistent with results in the acute phase of the trial, in which metformin showed a consistent direction of effect for preventing ED visits, hospitalizations, or death due to Covid-19 (OR 0.58, 95% CI 0.35 to 0.94), and hospitalizations or death (OR 0.47, 95% CI 0.20 to 1.11) through Day 14.

So, they are suggesting that metformin improved acute outcomes also, although "showed a consistent direction of effect" presumably is not the same as a statistically significant effect.

 

[Hutan]

Here's the cumulative incidence of a Long Covid diagnosis (x axis is days, y axis is the rate of Long Covid diagnosis at some point prior to the x axis days). Placebo, Ivermectin alone and Fluvoxamine alone all look to give a similar result. The results suggest that when fluvoxamine is taken with metformin, the benefit from metformin disappears. But, perhaps it's just a random result.

 

[Hutan]

Setting the utility of metformin aside for a moment, the study presents some interesting data on other questions:



On the risk according to gender - it looks like being female substantially increases the chances of being diagnosed with Long Covid in this group. Of course being diagnosed is not quite the same thing as having Long Covid.




There's no good evidence that variants of Covid-19 make much difference to the incidence, but vaccination definitely seems to lower the risk. (14% in the not vaccinated people; 7% in the vaccinated people).

 

[Hutan]

Here's what the authors say about why metformin might be helping:

Mechanistic in silico modeling predicts that translation of SARS-CoV-2 viral proteins is an especially sensitive target for inhibition, and previous studies show metformin capable of suppressing protein translation via mTor.22,23 Experimentally, metformin has in-vitro activity at a physiologically relevant dose against SARS-CoV-2 in cell culture and in human lung tissue, ex vivo, and in a phase 2 clinical trial.24-27

In addition to in vitro and in vivo activity against SARS-CoV-2, metformin has been extensively studied for its anti-inflammatory actions. In human bronchial and lung epithelial cell lines infected with SARS-CoV-2, metformin restored autophagic flux, inhibited cleavage of caspase-1 by non-structural protein 6 (NSP6), and inhibited maturation and release of interleukin-1 and interleukin-18.28 Metformin also prevented a senescent phenotype induced by SARS-CoV-2 infection in dopaminergic neurons in vitro, which could be relevant to neurocognitive sequelae of infection seen in Long Covid.29

This is one of the more interesting Long Covid studies I've seen. I hope that there will be some replication. It would be good to have some detail about the symptoms the people diagnosed with Long Covid were reporting (including, severity of symptoms and whether the symptom pattern was consistent with an ME/CFS diagnosis). It would also be good to know about recovery rates.

 

[SNT Gatchaman]

Here's what the authors say about why metformin might be helping

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?

Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial glycerol-3-phosphate dehydrogenase (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on gut microbiota. Metformin also exerts an anorexiant effect in most people, decreasing caloric intake. Metformin decreases gluconeogenesis (glucose production) in the liver. Metformin inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin, which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries.

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.

 

[Jonathan Edwards]

Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total

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.

 

[Jonathan Edwards]

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.

 

[Midnattsol]

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.

The short treatment with metformin could also mean that patients have gastrointestinal side effects (that usually pass over time) which could cause them to change their diet short term and would also contribute to changes in the microbiome.

 

[Trish]

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.

I think being overweight is regarded as a risk factor for severe acute covid, and this trial's main focus/primary outcome was the severity of the initial acute infection. Maybe that's how they got funding for the trial.

The incidence of LC in the 3 control groups ranged from 7.5% to 10.6%, and the treatment incidence of LC for the 3 drugs ranged from 6.3% to 10.1%. That amount of variation between control group LC incidence doesn't give me much confidence that the drug results are any more than random variation.

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.

Possibly the most interesting result in this paper is the significant difference in incidence of LC between vaccinated and unvaccinated.

 

[Jonathan Edwards]

I think being overweight is regarded as a risk factor for severe acute covid, and this trial's main focus/primary outcome was the severity of the initial acute infection.

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.

The short treatment with metformin could also mean that patients have gastrointestinal side effects

Which would also destroy blinding.

 

[rvallee]

Medical providers and patients are wary of using diagnosis labels in the medical record unnecessarily, because doing so can negatively impact patient psyche and have insurance ramifications

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.

Ten-month follow-up for Long Covid was not in the original protocol as Long Covid was not a known entity in fall 2020

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

The pre-specified secondary endpoint on Long Covid was added to the protocol in April 2021, and survey tools were IRB-approved in July 2021. Participants enrolled before the Long Covid surveys were approved were contacted for reconsent to receive the Day 300 Long Covid survey. An overview of protocol changes is in the Supplement

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.

 

[Hutan]

Possibly the most interesting result in this paper is the significant difference in incidence of LC between vaccinated and unvaccinated.

I agree, that and the gender incidence.

The incidence of LC in the 3 control groups ranged from 7.5% to 10.6%, and the treatment incidence of LC for the 3 drugs ranged from 6.3% to 10.1%. That amount of variation between control group LC incidence doesn't give me much confidence that the drug results are any more than random variation.

But I think you are being a touch hard with this.

Among those randomized to metformin the cumulative incidence for developing Long Covid was 6.2% (95% CI 4.2% to 8.2%), and 10.6% (8.0% to 13.1) in the blinded controls (Figure 1, Table 2). For those randomized to ivermectin, the cumulative incidence was 8.0% (95% CI 5.2% to 10.8%) and 7.5% (95% CI 4.7% to 10.2%) in blinded controls (Supplemental Table 2). Among those randomized to fluvoxamine, the cumulative incidence was 10.1% (95% CI 6.6% to 13.5%), and 7.5% (95% CI 4.4% to 10.5% in the blinded controls (Supplemental Table 2).

The outcomes for the three "placebo" groups were 10.6% (metformin placebo), 7.5%(ivermectin placebo) and 7.5%(fluvoxamine placebo). The people in those groups that the results were reported for weren't necessarily just receiving nothing. Part of the 'placebo' group for ivermectin is actually a 'treatment' group for metformin, for example. So that tends to reduce the variation between 'placebo' groups and 'treatment' groups if metformin really is lowering risk. Only one group out of the possible six combinations was actually placebo + placebo and therefore truly a placebo group.

The best place to look at the differences is that chart with cumulative incidences up thread, where there is a line for each of the six possible combinations of drugs. There, we can see that ivermectin does seem to be doing nothing at all, with the placebo and ivermectin only lines looking about the same, with an incidence of around 10%, and the metformin only and metformin +ivermectin looking about the same, with an incidence of around 5%. The results for the groups with fluvoxamine look a bit weird, not sure what is going on there, hard to explain with a treatment that was just administered for a short time.

Another thing is that all pregnant women were allocated to either the 'metformin +placebo' treatment or the 'placebo +placebo' treatment, and 7% of the women in this study were pregnant. I assume that's the reason why there were 58% women in the metformin placebo group and only 51-52% in the placebo groups for the other two groups. With an incidence of LC diagnosis of 14.1% in all females in the placebo group and only 5.5.% in all males in the placebo group, we could expect the incidence of LC diagnosis to vary between the "placebo" groups, and to be highest in the metformin one simply because of the gender percentages.

As for blinding, I guess it's possible that side effects gave the game away to some people, but there was a lot going on with the two different sets of pills. I think that a decent effort was made. There's a note that the Fluvoxamine arm was closed by the data safety monitoring board in Jan 7 2022 - I'm not sure what implications that had.

I still think the metformin result is interesting enough to warrant further investigation. Searching the forum, I see that some members have reported reduced fatigue when on metformin. And others have reported not having a good time on it. So, for sure I'm not convinced that metformin is helpful for treating or even preventing Long Covid. But I'd like to see another decent sized trial.

(edits for clarity)

 

[JemPD]

Possibly the most interesting result in this paper is the significant difference in incidence of LC between vaccinated and unvaccinated.

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

 

[Hutan]

Re vaccinated/unvaccinated - copying from upthread (the first column is the placebo group)

"

"

"There's no good evidence that variants of Covid-19 make much difference to the incidence, but vaccination definitely seems to lower the risk. (14% in the not vaccinated people; 7% in the vaccinated people)."

 

[Jonathan Edwards]

As for blinding, I guess it's possible that side effects gave the game away to some people, but there was a lot going on with the two different sets of pills. I think that a decent effort was made. There's a note that the Fluvoxamine arm was closed by the data safety monitoring board in Jan 7 2022 - I'm not sure what implications that had.

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?

 

[Hutan]

Those blinded included: participants, care providers, investigators, and outcomes assessors. The trial was decentralized, with no in-person contact with participants

Enrollment ended January 28, 2022 and all investigators except the unblinded statistician remained blinded to group-level results through February 14, 2022. The Day 300 follow-up ended Nov 27, 2022. All investigators, outcome assessors, treating clinicians, and participants remain blinded to individual treatment allocations.