Protocol REVERSE-Long COVID-19 With Baricitinib Study (REVERSE-LC)

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EndME

Senior Member (Voting Rights)
REVERSE-Long COVID-19 With Baricitinib Study (REVERSE-LC)

The largest study on Long-Covid initiated by Wes Ely is starting in the upcoming months. In this large (n=550) Randomized, placebo-controlled, double-blind, parallel-design superiority design Phase 3 trial for Long-Covid 4 mg of Baricitinib will be given to participants daily for 24 weeks. They will be measuring a variety of clinical and biological outcome measures. The trial will be running for a total duration of 5 years.

The initial plan was to do a smaller pilot study which, if successful, would have been expanded to a large RCT, but the Wes Ely has decided to skip the intermediate step.

One of the central focuses of the trial will be neurocognitive symptoms (they will also be assessing PEM via DSQ-PEM and also plan to do a single CPET).

Full details can be found here: https://classic.clinicaltrials.gov/ct2/show/NCT05858515.

The trial is being funded by a $5.7M grant https://govtribe.com/award/federal-grant-award/project-grant-r01ag085873. (Edit: $5.7M for the first year, see the below conversation for more information on total funding)
 
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EndME said:
The trial is being funded by a $5.7M grant https://govtribe.com/award/federal-grant-award/project-grant-r01ag085873.
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I’m very surprised it’s just $5.7 million considering a) there are over 500 participants, b) the drug itself is apparently very expensive, and c) the trial will take 5 years.

If it’s indeed $5.7 million over the whole 5 years rather than $5.7 million per year, it raises big questions about why RECOVER funded so few clinical trials. They had well over a hundred million to spend on treatment trials, but, to the best of my memory, only managed to fund 4 trials - IVIG, paxlovid, one targeted at hypersomnia, then CBT.

Ah ok someone has looked into it and that $5.7 million is just for the first year.
 
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Solstice said:
A JAK-inhibitor. I think filgotinib and possibly upadicitinib were or are being tested in ME?
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Scheibenbogen is also going to conduct a Baricitinib trial (at least those were her original plans https://pbs.twimg.com/media/FbtnFb8WIAEQq4G?format=jpg&name=large).

RaviHVJ said:
$5.7 million is just fot the first year.
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Do you have details on this? The grant amount seems to be for the whole time period (at least that's what the webpage seems to say), but I also doubt that would be sufficient and it would also be possible to have funding from other sources (his even larger acute Covid study with Baricitinib was sponsored by Eli Lilly and Company but they aren’t a sponsor here).
 
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EndME said:
Do you have details on this?
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Ah yep, the NIH reporter website suggests the funding is just for 2024. Also saw someone say that it’s common practice for the NIH not to award the whole grant up front for a trial, they provide the money one year at a time. So we could be talking $25-30 million overall for the trial. Unbelievable to think that this trial alone will get almost twice the yearly ME/CFS budget, shocking degree of negligence.

https://reporter.nih.gov/project-details/10827260
 
RaviHVJ said:
Ah yep, the NIH reporter website suggests the funding is just for 2024. Also saw someone say that it’s common practice for the NIH not to award the whole grant up front for a trial, they provide the money one year at a time. So we could be talking $25-30 million overall for the trial. Unbelievable to think that this trial alone will get almost twice the yearly ME/CFS budget, shocking degree of negligence.

https://reporter.nih.gov/project-details/10827260
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At 11:25 on this Twitter interview Ely states that he has received 30 million from the NIH to run the Baricitinib trial, so that should confirm it.
 
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I wonder if there are any pilot study data?
The trial linked to looks cumbersome and without any clear primary outcome measure. (The description of the outcome measures is very peculiar, with all benefit 'outcomes' being called secondary.)

I am unclear exactly what patients are going to be treated. It sounds as if they may be recruiting people who have suffered a degree of brain damage from severe acute illness (they call it Alzheimers or other dementia).

People are still being re-infected with Covid-19 at a regular rate. My daughters school has just had another week of infections (including her). I would have thought it might be more useful to spend money on prevention and reduce the rate of LC development. If new LC cases are not occurring then a trial on established cases with an anti-inflammatory drug seems unlikely to do much. If they are, prevention is much more important.
 
The reference to Alzheimers or other dementia seems odd. The neuropsychological issues pwME (so assume similar in LC?) are related to severity. For example, pw severe ME will usually meet criteria for Mild Cognitive Impairment as defined in DSM-5. This is bad but not dementia. The 'mild' part is the differentiator between this and dementia.

I cannot see primary objective measures beyond drop out rates... it reads oddly like it was put together in a rush. Perhaps it has been.

Has anyone any experience of using or trying this medication?

On quick look it increases risk of opportunistic infections. If low grade ongoing infection is causing LC, could this not make pts more ill?

Or is it likely to treat unregulated, overactive immune responses which are possibly perpetuating symptoms?

Would pilot studies not answer that question?

Perhaps the clinicians have seen some good results. I hope they are not biased towards seeing only the recoveries and not seeing those that stop or get worse.....
 
Jonathan Edwards said:
I wonder if there are any pilot study data?
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I can't find much on baricitinib and LC, but here's something:

Demystifying Long COVID International Conference 2023, Abstract book, Page 22:

Baricitinib, a Possible Therapeutic Option for Long COVID, Bertan et al
Materials and Methods: We present two patients, women, aged 41 and 44, with no history of heart disease, who were infected by SARS-CoV-2 (RT-PCR) in March and August 2020 respectively. None of the patients required hospitalization. Both cases
were diagnosed as Long COVID according to WHO criteria. Persistent symptoms such as fatigue, fever, arthralgia and chest pain were present in both cases; bradycardia, hypotension, syncope and diarrhea in case 1 and anosmia, ageusia, myalgia, headache and dry cough in case 2 respectively. Laboratory test, transthoracic echocardiography and coronary computerized tomography did not show alterations. Pulmonary thromboembolism was ruled out also. Decisively cardiac MRI with adenosine (140 ug/kg/min) was performed, which showed an inducible defect of circumferential subendocardial perfusion highly suggestive of microvascular dysfunction. Treatment for microvascular angina was started with mild improvement.

Only in case 1, prednisone at 1mg/kg was started to treat arthralgia, with initial improvement but with a recurrence of joint and chest pain with dose reduction. In both cases, for huge worsening and with the objective of saving corticoids, baricitinib 4mg per day was started as immunomodulatory treatment. Surprisingly, within 48 hours of starting, there was a significant improvement of functional status, with a noticeable reduction in join and chest pain, that allowed reduce corticosteroids in case 1 and cardiac treatment in both, as well as practice sports and return to work. The treatment was stopped after three and two months respectively with worsening symptoms at 48 hours after withdrawal, requiring the reintroduction of cardiac treatment. In one moth, baricitinib was started again in the two patients.

On this occasion the symptomatology improved 30 days after restarting and the cardiovascular drugs were decreased, but not fully withdrawn. The evolution of the cases was as follows: case 1 presented a worsening of chest pain and arthralgia, for what prednisone was prescribed. Finally, the chest pain occurred with minimal efforts and arthralgia and diarrhea persisted despite baricitinib treatment, so it stopped. In case
2, a reduction of baricitinb to 2 mg was performed but a reinfection by Sars-CoV-2 (treated with nirmatrelvir-ritonavir) required an increase in the dose, allowing a reduction of the dose up to the present time.

Discussion: Since one plausible causes of persistent symptoms in long COVID is immune dysregulation, immunomodulatory treatment with baricitinib may be a therapeutic option. Despite the clinical results of these two cases with significant improvement in functional status, randomized clinical trials are necessary to demonstrate the benefit of this treatment in long COVID patients.
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Here is the after party to the Wes Ely interview—some good comments might be worth a listen.

https://twitter.com/user/status/1769886085197300089


Also from the main interview it appears that Wes has a couple of case histories (2) re bari and LC and he trying to publish this shortly.

Also one legit claim that Ely makes is that even if bari fails, they will collect enough data to perhaps indicate where to go next.
 
Here is Wes Ely’s email reply to my query about whether he had any pilot scale data on Bari for LC patients—he didn’t really answer the question, but at least he responded.

“Thank you so much for your kind informative email. One of my fundamental rules before embarking on any research project is that either answer must matter. In this case, if the extent of immunomodulation that is effectively accomplished through inhibition of the JAK/STAT pathway does not do anything to improve the symptom and disease profile of long Covid patients, that will in itself be extremely informative. Either answer matters. I’m always here to learn and appreciate whatever you wish to share. Our team is large and all of us want to do our part. “
 
Jaybee00 said:
Here is Wes Ely’s email reply to my query about whether he had any pilot scale data on Bari for LC patients—he didn’t really answer the question, but at least he responded.

“Thank you so much for your kind informative email. One of my fundamental rules before embarking on any research project is that either answer must matter. In this case, if the extent of immunomodulation that is effectively accomplished through inhibition of the JAK/STAT pathway does not do anything to improve the symptom and disease profile of long Covid patients, that will in itself be extremely informative. Either answer matters. I’m always here to learn and appreciate whatever you wish to share. Our team is large and all of us want to do our part. “
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Frustrating non answer. I've been so curious as to why they are trying this. And wishing it was a shorter trial - 2029!! End date!

But interested because of Ron Davis'/Phairs interest in JAK STAT inhibitors
 
From email from Jaime Seltzer:


“I'm helping with that trial! Outside of my involvement, though, there is nothing to say that if you took the money from that trial it would automatically go towards something similar or better. This is one of many grants that received funding, and if Ely's group hadn't applied, there is a decent chance the funding would've gone outside of the field, or outside of drug development.

In addition, $30M is about right for a drug trial from scratch. Unfortunately, that is simply what it costs. Repurposing a well-researched drug is a bit cheaper.”
 
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