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 Córdoba 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
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
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.
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.
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.