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Triiodothyronine for the Treatment of Critically Ill Patients With COVID-19 Infection: A Structured Summary of a Study Protocol for an RCT

helvella profile image
helvellaAdministrator
25 Replies

There have been several posts/responses in which posters have asked about the possibility of using thyroid hormones in the treatment of COVOID-19. It certainly seems an obvious question. Hence, I am pleased to post about an upcoming trial.

I'm quite sure I'll not be the only one here shouting "Get a move on"! Of course, proper protocols need to be followed, and no-one should endure extra risk. But if use of liothyronine (Triiodothyronine) does have positive results, please let that be found out as soon as possible.

Though very much secondary to this trial's main aim, any possible impact on the perception of liothyronine as a useful, even safe, medicine in thyroid disease or for other purposes, that comes about would be ever so welcome.

Trials

. 2020 Jun 26;21(1):573.

doi: 10.1186/s13063-020-04474-0.

Triiodothyronine for the Treatment of Critically Ill Patients With COVID-19 Infection: A Structured Summary of a Study Protocol for a Randomised Controlled Trial

Constantinos Pantos 1 , Georgia Kostopanagiotou 2 3 , Apostolos Armaganidis 4 , Athanasios Trikas 2 , Ioulia Tseti 2 , Iordanis Mourouzis 2

Affiliations

• PMID: 32586399

• DOI: 10.1186/s13063-020-04474-0

Abstract

Objectives: Tissue hypoxia is the main cause of multi-organ dysfunction in sepsis. However, effective pharmacological treatments to combat sepsis-induced tissue hypoxia are not available. Emerging experimental and clinical evidence reveals an evolutionary conserved action of thyroid hormone (TH) to adapt injured tissue to hypoxic conditions via its action on p38 MAPK, Akt signaling pathways. In addition, TH has favorable effects on the immune system and viral load in infected tissue. Non-Thyroid Illness Syndrome is common in sepsis, acute myocardial infarction and trauma and is associated with increased mortality. Thus, TH may be a novel treatment in the setting of critical illness due to viral infection in which hypoxia prevails. The present study aims to address the efficacy and safety of acute administration of triiodothyronine (T3) in critically ill COVID-19 infected patients requiring mechanical respiratory support or Extra Corporeal Membrane Oxygenation (ECMO).

Trial design: This study is a phase II, parallel, 2-arm (1:1 ratio), multi-centre, prospective, randomized, double-blind, placebo controlled trial.

Participants: Male and female patients aged over 18 years old who are diagnosed with pulmonary infection due to COVID-19, admitted to Intensive Care Unit and requiring mechanical ventilation or ECMO will be enrolled in this trial. Patients will be excluded in cases of pregnancy, severe systemic disease with life expectancy less than 6 months, participation in another trial of an investigational drug or device, corticosteroid and/or sympathomimetic use before initiation of treatment. All data will be collected in electronic CRF files. Participants will start to be recruited from the ICU center of "ATTIKO" University Hospital in Greece. We aim to include two more clinical sites in the trial one from Greece and one from Germany INTERVENTION AND COMPARATOR: Intervention: T3 Solution for injection 10 μg/ml. The dose administered will be 0.8g/kg i.v. bolus and will be followed by an infusion of 0.113g. kg-1.h-1 i.v. for 48 hours (therapeutic dose). After the first 48h, a maintenance dose will be administered corresponding to 50% of the therapeutic dose (0.057g. kg-1.h-1 i.v.). Drug administration will stop after successful weaning or end of follow up (maximum 30 days). Comparator: Placebo with composition and dosage identical apart from the active substance.

Main outcomes: The primary outcome assessed in the present study will be the percentage of patients successfully weaned after 30 days of follow-up. Successful weaning is defined as no requirement for ventilatory support after extubation (mechanical support) or support from ECMO for 48 hours.

Randomisation: An allocation sequence to one of the groups will be prepared by the Sponsor of the study. A 1:1 treatment allocation will be adopted. An electronic CRF will be used incorporating IWRS in order to assure proper randomization and unblinding in emergency cases. The representative of the sponsor will get a copy of randomization codes. The information of the randomization codes will then be locked in the database until the time at which an interim analysis or final analysis is performed.

Blinding (masking): Participants, caregivers, and all investigators assessing the outcomes will be blinded to group assignment.

Numbers to be randomised (sample size): The sample size of 60 patients (that indicates 30 subjects for each group) will have 84% power to detect the estimated difference between the two study groups. The criterion for significance (alpha) has been set at 0.05 and the test is 2-tailed.

Trial status: Protocol number T3inj-02/ThySupport, version 03, May 11, 2020. The trial is not recruiting yet. The trial will start recruitment June 18th 2020. Estimated recruitment will finish June 18th, 2021.

Trial registration: Triiodothyronine for the Treatment of Critically Ill Patients With COVID-19 Infection (Thy-Support), ClinicalTrials.gov Identifier: NCT04348513, date of trial registration: April 16, 2020, EudraCT Identifier: 2020-001623-13, date of trial registration: April 22, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Keywords: COVID-19; Randomised controlled trial; hypoxia; multi-organ dysfunction; protocol; thyroid hormone; triiodothyronine; viral infection.

pubmed.ncbi.nlm.nih.gov/325...

Trial registration:

clinicaltrials.gov/ct2/show...

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helvella
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25 Replies
greygoose profile image
greygoose

Wow! That is interesting. Do you think that might mean that those of us on largish doses of T3 might be less at risk of catching the disease? Or at least of having an easier ride with it?

helvella profile image
helvellaAdministrator in reply togreygoose

I don't think it affects our chances of catching the disease.

Possibly, and I'd put it no stronger than that, if you continued to receive your usual high dose throughout treatment, you would do better than someone else in whom their T3 level drops while being treated.

greygoose profile image
greygoose in reply tohelvella

Disappointing. Although, read in conjunction with your previous two posts, it does still make me wonder…

jimh111 profile image
jimh111 in reply togreygoose

Doesn't affect chance of catching. Assuming we are clinically euthyroid on our L-T3 it should not make a difference on recovery. EXCEPT serious illness lowers T3 levels but we will be taking the same dose (if we are able to or have ensured we are given L-T3).

jimh111 profile image
jimh111

'The dose administered will be 0.8g/kg'. Seems a decent dose! Maybe it's the made up solution? I weigh 70 kg, I wouldn't fancy receiving 56,000,000 mcg L-T3.

helvella profile image
helvellaAdministrator in reply tojimh111

Odd the way the units change from micrograms per millilitre to grams per kilogram.

I started to try to work it out then realised that I was far too likely to make a mistake and post something misleading - so stopped. :-)

jimh111 profile image
jimh111 in reply tohelvella

microgrames per muillitre is the concentration of the drug. grams per kilogram is the dose but I don't know what they are measuring, surely not the T3 Solution for injection, they would have to inject 80L per kg! I hope they sort their units out before they start the experiment.

helvella profile image
helvellaAdministrator in reply tojimh111

It was the swap from millilitres to grams I couldn't get - why from volume to weight (mass)?

0.113g. kg-1.h-1

The above looks like a dose in grams per kilogram per hour. And then it says to be done for 48 hours. I can't make that any rational dose!

jimh111 profile image
jimh111 in reply tohelvella

The T3 solution has 10 mcg in 1 ml of solution. So a 5 ml vial would contain 50 mcg liothyronine. This is too easy so they supply injectable liothyronine in powder form bnf.nice.org.uk/medicinal-f... !

They then say to give 0.113g per hour for each kilogram the patient weighs. For me that would be 7.91g or 7,910,000 mcg liothyronine per hour or 791 litres of solution per hour. I’m not volunteering for this trial.

Seriously, it’s very common for doctors to prescribe medicines to be administered by drip, a certain dose to be given per hour. Nurses can never do these calculations, the only thing that stops them killing patients with order of magnitude errors is they can’t split up a vial or locate 10 or 1000 vials. If you are prescribed drugs by drip make sure you always check the calculations.

Marz profile image
Marz

As it seems to be the elderly who are badly affected then I would put money on the fact they have LOW T3 to begin with along with Low VitD due to being stuck inside in Care Homes.

If both are optimal then it could contribute to a stronger immune system and prevention.

Thanks for the post !

SlowDragon profile image
SlowDragonAdministrator

Notice they start with injections of T3

Guess other countries aren’t paying eye watering price of injectable T3 that’s paid by NHS ...currently £1567.50 for 5 injections

drugtariff.nhsbsa.nhs.uk/#/...

tattybogle profile image
tattybogle

Funny you should post this....... that's the second time i've read about hypoxia today.

I started thinking about Covid and blood oximeters when i saw it here this morning;

thyroidpatients.ca/2020/06/...

"D3 is dedicated to T4-RT3 and T3-T2 inactivation pathways.

What makes DIO3 epigenetically upregulate its presence in tissues? 1) ..........2) hypoxia caused by obstructed blood flow or pulmonary function, and 3) inflammatory cytokines."

But i've run out if working brain cells for today, so i don't know if it point's to anything clever , or if i've just put hypoxia and hypoxia together and come up with bollox.

helvella profile image
helvellaAdministrator in reply totattybogle

T3 has also been investigated for procedures which could cause reperfusion injury. When blood supply is cut off for a while then restored it seems to be the return of blood that actually causes the damage.

Not sure if it is actively used - but seems quite likely.

tattybogle profile image
tattybogle in reply tohelvella

Getting covid or putting a tourniquet on an artery on seems a pretty extreme way to get a T3 trial though, i think i'll wait for an endo.

pennyannie profile image
pennyannie in reply totattybogle

Hey there Tatt,

I guess it depends how long one has to wait, and there's no guarantee and if your health is declining surely sooner it better than sometime, so maybe consider DIY and I'm not meaning the answer is at B & Q !!

shaws profile image
shawsAdministrator

Thanks for posting helvella and it would not be surprising if T3 worked. Greece had no lockdown and very little of the Coronavirus deaths.

Confirmed Recovered Deaths.

3,343 1,374 191

theguardian.com/world/2020/...

shaws profile image
shawsAdministrator

Greece acted as other countries should have done but didn't.

"The health ministry’s daily coronavirus briefing then begins with Sotiris Tsiodras, a soft-spoken Harvard-trained professor of infectious diseases, delivering the latest facts and figures with the occasional emotional plea. Nikos Hardalias, the civil defence minister, invariably follows, invoking the gravity of the situation with warnings that Greeks “must stay at home”.

The bookish professor and no-nonsense former mayor are the faces who have come to be associated with the government’s drive to contain the spread of Covid-19. Their efforts at keeping the country virus-safe appear to be paying off: in a population of just over 11 million, there were, as of Monday, 2,145 confirmed cases of coronavirus and 99 fatalities, far lower than elsewhere in Europe.

In a population of just over 11 million, there were, as of Monday, 2,145 confirmed cases of coronavirus and 99 fatalities, far lower than elsewhere in Europe. Italy to date has registered 20,465 deaths.

theguardian.com/world/2020/...

(The above was printed two months ago).

Marz profile image
Marz in reply toshaws

I think the big difference in Greece is the lack of heavy industry so the air is cleaner. This is described by Zach Bush in his video about the virus. A quick google should find it !

If you think of the major outbreaks they were linked to large industrial cities where there is a higher level of other health issues too. He talks about the use of polluting herbicides and Wuhan area has the highest use globally - Greece has been very strict about such things ( due to change sadly ) The virus needs a catalyst it seems and pollution is one of many affecting the health of people. There is a world map somewhere showing the use of the likes of RoundUp etc. Zach of course can describe it far better...

The other issue is Care Homes and there are very few of those in Greece - I think over a third of UK deaths were due to sick patients being sent back to Care Homes without testing and spreading the virus.

Lockdown in Greece did happen. You could only leave the house with a Pass that you obtained by texting a number and receiving a Reply - one each for the Doc - bank - supermarket - vet and so on. This worked well from the info we hear from friends. We have regular updates from our Accountant in Greece with detailed protocols - pages long ! No confusion - all clearly listed.

Tourism in Greece has been decimated and our tenants cannot pay their rent which in turn affects us here - and so the world keeps turning - just ! Oh yes stress is another contributing factor - so I must now breathe !!

Judithdalston profile image
Judithdalston

If they relying on getting 60 poorly covid 19 patients to trial in Greece and Germany they will have to wait a very long time...perhaps need to consider including some Brazilian patients if they want to finish the trial!

helvella profile image
helvellaAdministrator in reply toJudithdalston

Germany seems to be getting a lot of new cases related to their food factories. So maybe not that long, unfortunately.

Given the timescales, I don't think this research will be much benefit to covid-19 itself. Hopefully, for future illnesses.

Lora7again profile image
Lora7again in reply tohelvella

I have just heard that Leicester might be put in lockdown because of a spike of new cases.

DandyThyro profile image
DandyThyro

Oh-oh. T3 is already so hard to get hold of, watch what few supplies we have vanish once this gets out. On the up side, maybe a certain most powerful man in the world will start taking it and find his brain!

shaws profile image
shawsAdministrator in reply toDandyThyro

I think he lost it years ago but still was able to make pots of money. Oh! how does the song go! money, money, money make more money?

I do wish people would get their facts straight:

Liothyronine is the synthetic and pure form of "T3" available (sometimes) as tablets.

Triiodothyronine is the natural form of "T3" available as one of the ingredients of the output from the thyroid gland.

They may or may not act in exactly the same way and they are certainly presented to the body in a different manner, but each form has a different chemical composition and it is in the realms of science fiction to say that they actually are identical.

Having said that, it is perhaps possible that those who organised these trials may actually have been using natural T3 extracted from human or porcine NDT, but I do not believe that suggestion to be remotely credible.

JGBH profile image
JGBH

Thanks for this information. Good to know scientists keep looking for various ways/treatment to help with this nasty virus.

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