Friday, 17 September 2021

Covid-19 & Vitamin D: Success of Calcitriol in New York study

New York: the successful RCT of Calcitriol, activated Vitamin D



To understand the basis of this important paper (details below), it is necessary to have some understanding of Vitamin D metabolism and activation. A recap:

Vitamin D (cholecalciferol) is produced only by the action of UV from the sun on the oil 7-dehydrocholesterol (7-DHC), which is synthesised in our skin and that of many other mammals. It is also synthesised in plankton in the sea, the food of fish. Vitamin D is thus produced directly in our skin (about 80%) or it is taken in our food (about 20%), mainly oily fish.

Whether produced in our skin or consumed in our food, Vitamin D is taken in the blood-stream to the liver. It is there stored while it is slowly converted into its part-activated form 25(OH)D, otherwise known as Calcifediol. If Vitamin D is taken by mouth by someone deficient, it takes up to two weeks before it achieves blood levels that are appropriate for optimal defensive immunity (greater than 30ng/ml, 75nmol/L). This is too slow for correction of vitamin D deficiency at the time of critical Covid-19 infection, and giving Vitamin D itself to the critically ill has been predictably without benefit.

It would always be sensible to correct Vitamin D deficiency in advance of possible infection so as to optimise defensive immunity. It is much more urgent to optimise defensive immunity in someone already very ill with Covid-19, whether vaccinated or not. An imaginative approach was pioneered in Spain, in C√≥rdoba and Barcelona, by treating patients admitted to hospital on account of serious Covid-19 with the activated form Calcifediol. The results have shown spectacular benefit. 

For reasons explained previously, these results have been ignored and the papers have been rubbished by individuals who should have know better. The UK National Institute for Health and Care Effectiveness (NICE) advised that doctors should not use Calcifediol. This would inevitable have contributed to the 133,000 Covid-19 deaths in the UK, and many more thousands in other countries.

A huge amount of Calcifediol is produced each year, mainly in China, but a problem has been that the great majority is destined for cattle. We accept without question the common occurence vitamin D deficiency in human beings, even at times of crisis, but it is not acceptable in cattle. Calcifediol is readily available across the counters of pharmacies in Spain and Italy, but not in other countries. Approval for human use in Covid-19 would have been a simple process but it did not happen.

Calcifediol circulates in the blood as a reservoir, ready for instant use when required. Natural vitamin D has one -OH group. The part-activation to Calcifediol requires a second -OH groups, hence -diol. When Calcifediol is required, is is taken up into target cells (including cells of immunity) and a third -OH group is added, and thereby it is converted into the fully-active form Calcitriol. When Calcitriol, 1,25(OH)D, has been used, and it can only be used once, it is inactivated by the addition of another -OH group to form 24,25(OH)D.

Most Calcitriol is created and used within cells, but there is a biological need for a tiny amount of Calcirtriol to circulate in the blood. This is created in cells of the kidneys and its purpose is calcium homeostasis, to maintain a steady blood level of ionised calcium. Clinical problems arise in advanced kidney disease, when there are insufficient specialised kidney cells to produce adequate Calcitriol, and this has been recognised for more than forty years. Calcitriol as a pharmaceutical product is now readily available for human use, and there is considerable experience of its use.

Because vitamin D is activated too slowly for use in those very ill with Covid-19, and because the proven Calcifediol is not available for human use in most countries (Spain, Italy and I think now Australia excepted), it has been suggested that the readily-available and immediately-active Calcitriol be of clinical value. 

It has now been tested as a pharmaceutical agent in severe Covid-19 infection and the result is available.

The RCT of Calcitriol

https://pubmed.ncbi.nlm.nih.gov/34508882/


Bone  2021 Sep 8;116175. doi: 10.1016/j.bone.2021.116175. Online ahead of print.

Elamir YM et al.


Mount Sinai Beth Israel, Mount Sinai Morningside, Mount Sinai West Hospitals, New York.


The clinical trial has been undertaken in New York and it was published on-line September 8th 2021 as a pre-print.

It is a study of 50 patients admitted to three hospitals on account of Covid-19 pneumonia. 25 of the 50 were randomly allocated (electronically) to receive Calcitriol in a dose of 0.5 micrograms daily for 14 days, or until discharge from hospital if earlier.

Please note that 0.5 microgram is a very tiny amount and it must not be confused with milligrams, and so it is better to avoid abbreviations. 0.5 microgram is 500 nanograms.

The success of randomisation is given in the text of the paper, comparing baseline characteristics in the two groups. Randomisation was not absolutely perfect, and for example the average age of the control group was 64 years compared to 69 in the Calcitriol group. On the other hand 19 of the control group were over the age of 65 compared to 14 in the Calcitriol group.  There are no differences between the treatments and control groups that would be expected to have a significant influence on the outcome of the trial should there be major outcome differences, and that was the case.

The outcome measures are as follows:

Increase of oxygen concentration in the blood:

The unit of measurement is ratio of peripheral arterial oxygen saturation to the inspired fraction of oxygen (SpO2/FIO2), the greater the better.

Control group      31.2                  Calcitriol group    94.0

Discharged with no need for supplementary oxygen:

Control group      21 / 25               Calcitriol group    24 / 25

Length of stay (mean of 25 patients):

Control group      9.24 days           Calcitriol group    5.5 days

Transfer to ICU:

Control group      8 / 25                 Calcitriol group   5 / 25 

Need for invasive ventilation:

Control group      2 / 8                  Calcitriol group   0 / 5

Deaths:

Control group      3 / 25                 Calcitriol group    0 / 25

Readmission within 30 days:

Control group      4                        Calcitriol group    2

There were no ill-effects from Calcitriol and no examples of elevation of blood levels of calcium (hypercalcaemia) in the two groups. 


Conclusion

In all measures of outcome, there was a clear advantage among the patients randomised to Calcitriol. 

The most important are:

Out of 8 control patients requiring transfer to ICU, there was a reduction by 3 in the Calcitriol group. This is a 37.5% reduction and it would be great importance in reducing the pressures on ICUs.

3 control patients died, but no patients treated with Calcitriol died. 3 out of 25 deaths were eliminated, which is 12% death rate becoming zero.

Do not consider this clinical trial in isolation

This Calcitriol trial must not be considered on its own, and no clinical trial must be considered in isolation. The Criteria of Sir Austin Bradford Hill must always be in our minds, the several dimensions of proof. Is there evidence of vitamin D deficiency leading to critical or fatal Covid-19? Yes. Have there been previous studies of association and temporality? Yes. Is there consistency in the studies? Yes. Is there evidence from basic science that Vitamin D and its activated forms Calcifediol and Calcitriol would help in defensive immunity? Yes. Is it plausible that Calcitriol would be of benefit in someone critically ill with Covid-19? Yes. Are there other clinical experiments that indicate benefit from Vitamin D in its activated forms? Yes. Add this evidence to the New York clinical trial and we can see justification for using Calcitriol in the treatment of people admitted to hospital on account of serious Covid-19.

The important "significance" is clinical significance, and this involves the totality of supporting evidence as outlined. The study taken in isolation might be put aside as lacking statistical significance as indicated by high p-values, a statistical concept that is a huge oversimplification and is a short-cut taken by people who do not bother to read the results of the study in detail. A high p-value means that the result might be a chance finding, but this chance is diminished by taking into account the totality of information, as we learn from Sir Austin Bradford Hill. 

In respect of clinical significance, if we are dealing with a pandemic causing 136,000 UK deaths, if the proposed treatment is safe (the most over-riding issue), and if there is very strong supporting information, is a possibility of a chance result a reason not to give the treatment? Further surveillance will give greater information without waiting for more people to die. This is acceptance of clinical significance.

If deaths go down from 3/25 in the control group to 0/25 in the Calcitriol group, is the pragmatism of clinical medicine to use the Calcitriol overridden by the statistical purism that the difference might be a chance finding, and that the result is meaningless? The decision to use must include other evidence concerning Vitamin D and Calcifediol.

Remember that vaccines were authorised despite no evidence of an effect on hospital admissions or deaths, and without completed safety studies. Emergency Use Aurthorisation is also a pragmatic response to s serious pandemic.

What next?

There is clearly an international directive that any benefits of Vitamin D (or its active metabolites) must be denied, so as to enable Emergency Use Authorisation (EUA) for the unlicensed vaccines.

What can be done by official bodies to silence this study of Calcitriol? Some criticism will be found.

Can Calcitriol come into clinical use for patients with Covid-19 pneumonia? Yes, quite easily. It is in the power of any clinical doctor to prescribe Calcitriol in the protocol used in this trial. Will such doctors be over-ruled by hospital managers? If so what would be the logic? It would be a major interference with legitimate clinical responsibility.

Calcitriol is licensed for clinical use, but this obviously does not yet extend to serious Covid-19 infection. However off-label prescribing is acceptable. As stated by the UK General Medical Council (GMC):

"The physician must be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate safety ad efficacy. Prescribing may be necessary when no suitably licensed medicine is available to meet the patient's need (or when prescribing is part of approved research)."

The respect paid to Hill's Criteria is obviously of great importance.

The New York RCT stated at the end, rather modestly, that further larger scale trials should follow. To state this is not the reponsibility of the researchers. Benefit has clearly been demonstrated and to this we must add the powerful scientific basis, and the results of positive trials of Calcifediol. 

It is perhaps logical that a second trial might be undertaken, but there are ethical constraints as we are dealing with life and death.

If a further clinical trial of Calcitriol were to take place, it must be with informed consent of the subjects. Would such informed subjects agree to be controls and deny themselves treatment demonstarted to eliminate a 12% death rate and other disadvantages?

Would any informed person refuse treatment with Calcitriol if admitted to hospital with Covid-19 pneumonia?

It will be interesting to watch the sequence of events to silence this RCT and prevent the use of Calcitriol.

What about Calcifediol

The use of Calcifediol is more physiological, optimising circulating blood levels and provide a source of the precursor of Calcitriol to be produced within the immune cells. Normally we would not expect Calcitriol from the circulation to become active within immune cells where so much of it can be produced.

In practical terms it would seem to be the best plan for clinical doctors to prescribe Calcitriol 0.5 micrograms daily for 14 days in the treatment of patients with Covid-19 pneumonia, until our national leaders approve of Calcifediol to be used in appropriate dose (already worked out) in the treatment of human beings, in addition to cattle.

The pandemic continues. Covid-19 deaths continue. WHO states "population controls and vaccines", but we clearly need something in addition. The New York study provides the immediate answer.










Saturday, 11 September 2021

Covid-19 & Vitamin D : "How do we get out of this mess?"

 "How do we get out of this mess?"


Scene: 10 Downing Street, Prime Minister’s office.


PM – UK Prime Minister, Boris Johnson


Well, er, thanks you for coming in to se me today


PV – Sir Patrick Vallance, Chief Scientist


It is always a great pleasure to see you Prime Minister..


CW – Professor Chris Whitty, Chief Medical Officer


Yes, and also a great honour.


Prime Minister

Well, thank you. But today we have a very serious problem. It looks as though we are in a bit of a mess.


Patrick Vallance

Really, PM. I thought the vaccination programme had gone really well with most adults being vaccinated.


Prime Minister

Well, yes. But it does not seem to be working.


Chris Whitty

What, Prime Minister? The vaccines are not working?


Prime Minister

That is the view of many Members of Pariament who have been contacting me, and also some newspaper editors.


Patrick Vallance

They can’t really mean it. If this news were to be broadcast they would be no end of disruption. There would be a riot.


Prime Minister

They have spoken me very confidentially and no news of this sort has been issued. But they point out to me that despite all the work of our mathematician advisors, the numbers are not going down as they should and are in fact going up!


Chris Whitty

What do you mean Prime Minister?


Prime Minister

To put it simply, they tell me that there have been more Covid-19 cases and deaths in 2021 than in 2020. They expected that the vaccination programme would have made the pandemic better, not worse. Patrick, please tell me precisely what is happening out there.


Patrick Vallance

It is all very difficult, Prime Minister.


Prime Minister

I want you to explain it to me in clear and simple terms.


Patrick Vallance

Well yes, there have been more Covid-19 cases and deaths in 2021 than in 2020. The Worldometer data informs everyone that we have just passed 7 million cases. In 2020 there we had about 2.5 million cases, but this year we have had 4.5 million cases –


Prime Minister

This is terrible, and it is only early September! Is it going to go away or is it going to get even worse?


Patrick Vallance

We hope that the pandemic will come to an end, but the mathematicians think that there might be another peak.


Prime Minister 

They always say that there is going to be another peak but I suspect that they have no real idea. They have got it so wrong previously, predicting major epidemics that did not happen. We might as well appoint a government Chief Astrologer as ask the mathematicians what will happen in the future.


Chris Whitty

I agree, Prime Minister.  The leaders of the medical professional organisations have no confidence in the mathematical projections and are fed up with covering up for what is going wrong.


Prime Minister

We must give a  positive impression to the public, no matter how negative the news. At a time like this we could do with Dom. He would be able to spin the bad news to make it look good, with a quick catch-phrase.


Patrick Vallance

We must continue the policy of vaccinating the entire population, with comprehensive vaccination of all young people in secondary schools, and as soon  possible those in primary schools.


Prime Minister

Well said. This will be a positive step which might keep bad news out of the headlines.


Chris Whitty

There is a problem with vaccinating children in that doctors are very unhappy about it, especially paediatricians. They are very concerned about the known side-effect of myocraditis, heart damage, and even more about unknown side-effects in the future.


Prime Minister

But the paediatricians do not see the big picture, and that is our responsibility. We must stop Covid-19 now. The future is less important than the present, and the future will be somebody else’s problem, not our's. Did the clinical trials not show that the vaccines are very effective and very safe?


Patrick Vallance

Yes, but there has been a re-analysis of the data. The vaccines did show a reduction of Covid-19 cases, but when all illness were put together, the subjects vaccinated were at a slight disadvantage. It is possible that in young people disadvantages outweigh benefits to the individual.


Prime Minister

We must keep that quiet. I have not heard of it in the newspapers. We must emphasise benefits to the population at large rather than to an individual. It is the duty of people to be vaccinated. But my MPs are telling me that there are reports that most of the Covid-19 cases and deaths are in people who have been vaccinated.


Chris Whitty

That is true, but only in very recent studies. If we look at the first six months of this year, we find that most cases and deaths are in the non-vaccinated. This is obvious because so few people had been vaccinated early in the year. Using the old data in the USA has enabled there to be continuing reports of a pandemic of the unvaccinated.


Patrick Vallance

Yes, that is a clever spin, as during the early part of the year not many people had been vaccinated and so they inevitably made up the majority of cases and deaths. 


Prime Minister

This is the line that we must take. 


Patrick Vallance

Yes, and it is going well. The press have been very helpful. I noted a headline in the Guardian on September 14th that  informs its readers that only 1.2% of those dying from Covid-19 had been fully vaccinated. It was in smaller print that it was revealed that the data were from January to July when initially very few if any people had been double vaccinated, in fact virtually no-one before the end of March.


Chris Whitty

The other point is that there was a very large number of deaths from Covid-19 in January and February, about 1,000 each day, and at that time vaccination rates were very low, with large numbers of non-vaccinated people dying. In the early summer death numbers were very few, just single figures each day in May and June, with very little influence on the six month total. 


Prime Minister

I hope we will be able to suppress the very recent data. I am told that August data will show a very different and much higher proportion of double vaccinated people dying from Covid-19.


Chris Whitty

I doubt if we will be able to keep the recent data hidden from the public for long, Prime Minister. The data are on the Worldometer and Our World in Data every day, and these websites are closely followed.


Prime Minister

Yes, there are too many amateur epidemiologists.


Chris Whitty

Many people follow me on Twitter. On August 20th I tweeted: “Four weeks working on a Covid ward makes stark the reality that the majority of our hospitalised Covid patients are unvaccinated and regret delaying. Some are very sick including young adults. Please don’t delay your vaccine”.


Prime Minister

Very good Chris. That is excellent. I hope many people have re-tweeted it. But I hear that the majority of Covid cases and deaths are now in people double vaccinated. Perhaps your information is out of date.


Patrick Vallance

Recent data is that most of those with Covid-19 are fully double-vaccinated. The numbers published by Public Health England are that up to August 15th, of Covid-19 hospital admissions in those over the age of 50, 31% were unvaccinated, 10% single vaccination, 58% double vaccinated.

When it comes to deaths there is a very similar picture. Just 30% unvaccinated, 9% single vaccination, 61% double vaccination.


Prime Minister

Gosh, that is terrible news. Are the vaccines really helping? What about those below the age of 50?


Patrick Vallance

Better news. With hospital admissions 74% unvaccinated, 15% single vaccination, 9% double vaccination. With deaths, 64% unvaccinated, 10% single and 24% double vaccinated.


Prime Minister

That is much better. Well we must concentrate on these numbers for the younger age groups so as to encourage more vaccinations. However, we must be aware of what I am being told about the pandemic getting completely out of hand, mainly in the far East.


Chris Whitty

People are becoming aware about what is happening in Israel. Although it is about the first and the most vaccinated nation in the world, there is now an increasing peak of cases and deaths almost entirely among the double vaccinated. People are very alarmed. In fact during the past week the number of vaccinations per day has gone down my more than a half. 


Prime Minister

Perhaps people in Israel are starting to suspect that vaccinations are more of a problem than a help.


Patrick Vallance

But the goverment of Israel is proposing booster vaccinations as soon as possible. Also there is a major peak in Japan, even more dramatic than in Israel.


Prime Minister

I had also heard about Israel, and that the proposal is for extensive third vaccinations. I suppose the peak in Japan could be due to the Olympic Games.


Patrick Vallance

Third vaccines for all would certainly be good news for the vaccine manufacturers. Even more so if vaccines had to be given every few months in the forseeable future.


Chris Whitty

But there is concern expressed that the vaccines might doing more harm than good,  and that natural immunity is better than immunity provided by vaccines.  Vaccines seem to be losing their benefit much earlier than expected, and the risk of the Delta variant is much higher among those vaccinated. The evidence is that people vaccinated are several times more likely to be infected than those who have natural immunity from previous infection.


Prime Minister

That makes me feel good having had Covid-19. What exactly is the Delta Variant?


Patrick Vallance

It emerged in India, immediately after the vaccination programme took off. It is sometimes called the Vaccine Variant, but only behind closed doors.


Prime Minister

I am told that in the Observer on August 29th there was a report that Covid-19 cases in the UK are 26 times higher than a year ago. Is this true?


Patrick Vallance

I am afraid it is. We expected that with the vaccination programme cases and deaths would be even lower in 2021 than in 2020, but it is not working out that way.


Chris Whitty

I also read the Observer article. In addition it stated that hospital admissions and deaths are a fraction of what they were in August 2020.


Prime Minister

Is this true?


Chris Whitty

I suspect not. According to Worldometer Covid-19 deaths suddenly started to increase in mid-August and now exceed 2020 figures. For example on September 7th 2020 there were just 3 Covid-19 deaths, but on the same day this year there were 209. This is the general pattern at present.


Prime Minister

Cripes! This is terrible. What can we do?


Patrick Vallance

We can hope that it improves, but otherwise we must divert attention. We must continue to make vaccination for the young our main priority, and blame the unvaccinated young for the deteriorating situation.


Prime Minister

But what if there is a backlash against vaccinations?


Patrick Vallance

Well Prime Minister, the main impact will be on the share prices of the pharmaceutical companies. Many of us have a lot to lose.


Chris Whitty

We must continue to emphasise the importance of vaccinations.


Prime Minister

What about the other things, vitamin D, ivermectin, hydoxychloroquine and so on?


Chris Whitty

We have followed your instructions and kept these out of the news and out of clinical use. I must say that the doctors have been very unhappy about this. They are aware that we have had 133,000 Covid-19 deaths and they think that most of these could have been avoided had we used vitamin D in particular from the very beginning.


Prime Minister

Well, that is just speculation.


Chris Whitty

The doctors have been concerned that they have been unable to offer any treatment to Covid-19 patients until they arrive on the intensive care units. If Pfizermectin materialises, that will be a help.


Prime Minister

As I have said I appreciate your success in keeping vitamin D in particular hidden from view, but I am very pleased to have received it myself when I was so very ill with Covid-19. We have had to follow WHO and FDA instructions that there must be no alternative to vaccines, otherwise the Emergency Use Authorisations would not have been granted.


Patrick Vallance

Whatever the benefits Prime Minister, if we bring Vitamin D and its activated form Calcifediol into use now, there will be public outcry from the relatives of the dead as to why we did not do so at the beginning.


Prime Minister

It is all very difficult. We really are in a mess but at present beneath the surface. We simply must continue with vaccinations, otherwise the public will lose confidence in us.


Patrick Vallance

And if cases and deaths increase we must blame it on new variants.


Prime Minister

And people who have not been vaccinated.


Chris Whitty

Prime Minister, I am still concerned that the public might become aware of what is happening around the world. The public have been expecting that the vaccinations would make things better. What will happen if the pandemic continues to get worse?


Patrick Vallance

It is inevitable that the pandemic will settle in time, and the official line is that when it does, it will be the result of the highly successful vaccination programmes.


Prime Minister

While we are here, what is the situation with deaths and ill-effects from the vaccines?


Chris Whitty

The Yellow Card system is functioning but there seems to be little notice taken and certainly no actions. We rely on the fact that in individual cases, proof is not possible and we emphasise that co-incidences do happen.


Patrick Vallance

I read that the coroner concluded that the death of Lisa Shaw, the BBC presenter, was the direct result of the very recent vaccination. 


Prime Minister

I am told that the BBC will keep quiet about this unfortunate case. Let’s hope so. The last thing we want is a succession of claims of vaccine damage,


Patrick Vallance

Especially as the government has accepted financial liability.  


Prime Minister

I certainly never expected the Covid-19 pandemic to turn out to be anything like as bad and complicated as it has turned out to be. And it seems to be far from over. The end of September is likely to see the mess even worse, unless the pandemic goes away. I am sure we will be meeting again very soon. 


Exit Patrick Vallance and CW.