Friday, June 19, 2020

Even worse than 'Recovery,' potentially lethal hydroxychloroquine study in patients near death

What could be worse than giving potentially lethal doses of hydroxychloroquine to Hospitalized Covid-19 patients?

The REMAP-Covid study is using the same HCQ dose as the Recovery trial for 6 days.  But it is even worse for the following reasons:

  1. You have to be close to death, either on a ventilator or in shock, on pressor medications, to be included in the trial, according to the trial documents.  However, in a talk by Professor Anthony Gordon, less invasive means of oxygenation: HFNO (high flow nasal oxygen), CPAP (continuous positive airway pressure) and NIV (noninvasive ventilation) are listed as inclusion criteria.
  2. You may receive HCQ alone, or HCQ in combination with 2 more drugs, lopinavir/ritonavir.  Yet lopinavir/ritonavir predisposes to QT prolongation, as does HCQ, and the L/R drug label states, "Avoid use in combination with QTc- or PR-interval prolonging drugs."
  3. Patients who are in shock or on a ventilator may be unable to give their consent to enroll in a clinical trial. But the trial investigators have deemed that consent may not be required"For patients who are not competent to consent, either prospective agreement or entry via waiver of consent or some form of deferred consent can be applied, as required by an appropriate ethical review body."
  4. For patients too sick to swallow a pill, the drug will be administered via a feeding tube. This might entail an extra procedure for patients.
From the REMAP-Covid protocol page 23:
Dosing will be hydroxychloroquine administered by the enteral route. A loading dose is important because of the large volume of distribution. The loading dose will be 800 mg, administered 6-hourly, until 2 doses have been administered. Subsequently, starting 12 hours after the first loading dose, the dose will be 400 mg administered 12-hourly for 12 doses. The preferred method of administration is tablets swallowed whole but, if a patient is unable to swallow, crushed tablets dispersed in water can be administered via an enteral tube (a large bore gastric tube is preferred). No dose adjustment is required when hydroxychloroquine is administered via a gastric tube. No dose adjustment is necessary for renal dysfunction or concomitant use of renal replacement therapy. Clinicians should consider a dose adjustment in the presence of liver failure, however no dose adjustment is necessary for abnormal liver function tests in the absence of liver failure.
This is 2400 mg hydroxychloroquine in the first 24 hrs, over 1.86 g of the "base," then 800 mg/day for 5 more days or until discharge from the ICU, up to 6.4 g total. Dosing fails to take into account weight, renal or hepatic function (unless the patient is in liver failure) although there are good reasons why each should be considered, especially when using such high doses. 

The ignorant doctors who justified toxic doses by invoking 'volume of distribution' (which is 40,000 liters) failed to notice that the high 'volume of distribution' is an artifact related to the drug accumulating in tissue as opposed to plasma.  Drug levels in lung tissue are 200-700 times higher than in plasma, explaining why standard doses are effective. Furthermore, "renal and hepatic insufficiency lead to higher plasma concentrations for a given daily dose and raise the risk of toxicity."

WHO's consultant Weniger reported in 1979 that a single dose of 1.5-2 g of chloroquine "base" "may be fatal." A detailed discussion of therapeutic and toxic doses of chloroquine and hydroxychloroquine can be found in my article of June 14. I acknowledge that hydroxychloroquine is a bit less toxic than chloroquine.  But this trial studies the most fragile human beings, who have a 49% mortality at baseline. If the trial investigators were unsure of the right dose, they could have started low and gone slow as they watched the effect on the patient, as clinicians do. They could have tested the dose in a variety of ways. They could have read a toxicology text.

The REMAP-Covid study protocol acknowledges that the combination of lopinavir/ritonavir and hydroxychloroquine increases the risk of ventricular arrhythmia, but states that the risk is mitigated because patients this sick will be on cardiac monitors, with QTc monitoring.  However, it fails to say that the most likely arrhythmia in this setting is torsade de pointes, which is very difficult to treat.  Patients who are already critically ill are unlikely to survive if it occurs.  So why use an excessive hydroxychloroquine dose on these patients and risk it?  That is not explained.

The REMAP clinical trial is said to be ongoing in 200 sites in 14 countries. They include: 
Australia,   Belgium,   Canada,   Croatia,   Germany,   Hungary,   Ireland,   Netherlands,   New Zealand,   Portugal,   Romania,   Spain,   United Kingdom, USA.

All the online protocols have been stamped "Not for IRB (Institutional Review Board) submission," which makes one wonder what was changed when the trial arms were put before IRBs for approval. 

Four UK chief medical officers and the NHS Medical Director wrote a "Dear Colleague" letter, begging physicians to enroll their Covid patients in clinical trials, including 'Recovery' and REMAP, and discouraging "off-label" treatments for Covid outside of trials.  Did they know they were asking treating physicians to increase the risk of death for their patients?  Are they aware that as of today, June 19, the UK has had more deaths from Covid-19 than any country in the world outside the US and Brazil, with 5 and 3 times the UK population, respectively.  In other words, although many thousands of hospitalized Covid patients in the UK have been enrolled in clinical trials to identify optimal treatments (over 11,000 in the Recovery study alone), the UK has instead achieved the 2nd highest mortality rate (Covid deaths per UK person) on the planet. Belgium is 1st. Have the 4 Chief Medical Officers and the Medical Director of the National Health Service failed to notice this?

Why is public health being turned on its head?  REMAP-Covid is the third major multicenter clinical trial of hydroxychloroquine to give toxic doses to Covid patients.  The Recovery and Solidarity trials (with almost identical HCQ doses as REMAP) abruptly ended their hydroxychloroquine studies in the past two weeks, coincidentally soon after people began noticing the excessive doses, especially on Twitter.  Who or what is behind this concerted effort to maim or kill patients in order to to kill any appearance of benefit from hydroxychloroquine in the treatment of Covid-19?

Disclosure:  I am a longtime board member of the Alliance for Human Research Protection (AHRP), and our organization is taking the design and conduct of these clinical trials very seriously. The AHRP principles, ignored by those who planned and have conducted these trials, are the basis for good medical practice:

1.  Freedom of choice, to choose or refuse therapy
2.  Honest disclosure of risk and conflicts of interest
3.  Informed consent for every medical intervention
4.  Truth and scientific integrity.  Uncensored, open debate about scientific and empirical evidence


Justin said...

Thank you, Dr. Nass! Numerous very troubling issues with this trial!

Anonymous said...

Does anyone know what happened to the patients in the HCQ of the REMAP trial? I have been unable to find trial results.