Clinical Drug Trials: Part Three, Toxic Therapies

Hydroxychloroquine (HCQ) and Mefloquine.

On March 19th, 2020, Donald Trump announced at a news conference that the anti-malarial drug hydroxychloroquine was going to be a “game changer” in the fight against COVID-19. It is not as benign as taking aspirin as some are suggesting. This drug can cause serious side effects including a very dangerous heart arrhythmia which can be fatal, as well as damage to the retina which can lead to loss of vision. In some rare instances, severe psychiatric adverse events have also occurred. The president’s statement was, in my opinion, both dangerous and irresponsible.

In fact, numerous studies of hydroxychloroquine around the world have been halted recently because of reports of cardiac arrhythmia among test subjects. Cardiac arrhythmia is serious in that it can quickly lead to cardiac arrest and death, and was one of my main objections to using hydroxychloroquine (HCQ) as a treatment for COVID-19.

So I decided to utilize covid-trials.org and ClinicalTrials.gov to see what studies I was able to pull up on the anti-malarial drugs hydroxychloroquine and mefloquine in relation to their use as a treatment for COVID-19.

Hydroxychloroquine (HCQ)

I go to covid-trials.org and click on “(Hydroxy)chloroquine” in the area labelled “Treatment” in the upper right-hand corner, and 272 trials that come up out of a total of 1,476 today. As I scrolled through the list searching by country I noticed a lone study being conducted in Russia and clicked on it (link below).

When I read the title of the study I was absolutely stunned. The study would be testing both HCQ and mefloquine as potential treatments for COVID-19, both of which come with the possibility of causing severe adverse events. As I began reading through the protocol that would be used for the trial I was even more stunned by the dosages that are to be given to the subjects in this trial. From the knowledge that I have acquired over the last several months, I surmised that the dosages were extremely high for both drugs and posed a very significant threat to the health and safety of the subjects in this trial.

Arm	Intervention/treatment
Experimental: group 1 cohort 180 patients who receive Mefloquine prescribed according to the following scheme:1st day: 750 mg of mefloquine per day, inside, in tablets of 250 mg 3 times a day – 1 tablet every 8 hours.Day 2: 500 mg of mefloquine, inside, in tablets of 250 mg 2 times a day – 1 tablet every 12 hours.3rd – 7th day: 250 mg of mefloquine, inside, in tablets of 250 mg 1 time a day at the same time.	Drug: Mefloquine1st day: 750 mg of mefloquine per day, inside, in tablets of 250 mg 3 times a day – 1 tablet every 8 hours.Day 2: 500 mg of mefloquine, inside, in tablets of 250 mg 2 times a day – 1 tablet every 12 hours.3rd – 7th day: 250 mg of mefloquine, inside, in tablets of 250 mg 1 time a day at the same time.
Experimental: group 1 cohort 280 patients who receive Hydroxychloroquine prescribed according to the following scheme:• 1st day: 800 mg of hydroxychloroquine per day, inside, in 200 mg tablets, 2 tablets 2 times a day; 2nd – 7th day: 400 mg of hydroxychloroquine per day, inside, in tablets of 200 mg, 1 tablet 2 times a day.	Drug: Hydroxychloroquinest day: 800 mg of hydroxychloroquine per day, inside, in 200 mg tablets, 2 tablets 2 times a day;nd – 7th day: 400 mg of hydroxychloroquine per day, inside, in tablets of 200 mg, 1 tablet 2 times a day.
Experimental: group 2 cohort 1A concomitant therapy consisting of Mefloquine in conjunction with azithromycin and tocilizumab will be given for 80 patients. Dosage of Mefloquine is same as for group 1 cohort 1.	Combination Product: Mefloquine + azithromycin + / – tocilizumab1st day: 750 mg of mefloquine per day, inside, in tablets of 250 mg 3 times a day – 1 tablet every 8 hours.Day 2: 500 mg of mefloquine, inside, in tablets of 250 mg 2 times a day – 1 tablet every 12 hours.3rd – 7th day: 250 mg of mefloquine, inside, in tablets of 250 mg 1 time a day at the same time.
Experimental: group 2 cohort 2A concomitant therapy consisting of Hydroxychloroquine in conjunction with azithromycin and tocilizumab will be given for 80 patients. Dosage of Hydroxychloroquine is same as for group 1 cohort 2.	Combination Product: Hydroxychloroquine + azithromycin + / – tocilizumabst day: 800 mg of hydroxychloroquine per day, inside, in 200 mg tablets, 2 tablets 2 times a day;nd – 7th day: 400 mg of hydroxychloroquine per day, inside, in tablets of 200 mg, 1 tablet 2 times a day.

In order to confirm what I was thinking I sent the information to Dr. Remington Nevin, Vermont-based epidemiologist and specialist in the quinoline class of anti-malarial drugs. This is what he had to say:

According to the summary, 160 subjects will be given mefloquine 750 mg on Day 1, then 500 mg on Day 2, then 250 mg on Days 3-7. This is, simply put, a recipe for psychosis. 
There are no apparent provisions for stopping the administration at the onset of prodromal symptoms such as insomnia or abnormal dreams. Nor does the summary appear to acknowledge the risks of this dosing schedule.

Dr. Remington Nevin
Director, The Quinism Foundation

A Study of the Effectiveness of an Off Label Mefloquine Use for the Treatment of Patients With COVID19

https://clinicaltrials.gov/ct2/show/NCT04347031

Mefloquine

ClinicalTrials.gov contains more than just information about COVID-19 testing, so I took the opportunity to do a search of all registered trials for the antimalarial drug mefloquine, finding a total of 74 worldwide. Some were completed while others were just in the process of recruiting volunteers. I scanned the list looking at the conditions that were to be treated and, as expected, most were for the treatment and prophylaxis of malaria and included routine studies for bioequivalence and safety profiles.

Row number 6 on the list caught my eye immediately however because it was to be used to treat Progressive Multifocal Leukoencephalopathy (PML) which is a very rare, very serious brain infection caused by the John Cunningham (JC) virus. It is typically seen in patients who are HIV positive and is often fatal.

It was first registered in 2008 and the final results were posted in 2014. The tests were to be conducted at a dozen research hospitals across the US. Investigators were only able to find a limited number of subjects and the trial was halted following the deaths of two of them. Of this study Dr. Nevin would say:

It’s hard to draw any conclusions from these results. PML is a serious and potentially fatal illness, and the number of subjects in each arm is very small. About the only thing that can be concluded is that mefloquine is not a miracle treatment for the condition. 

Dr. Remington Nevin
Director, The Quinism Foundation

A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758507/

The use of mefloquine as an adjunct to chemotherapy for glioblastoma has also been explored.

This Phase I trial sponsored by the M.D. Anderson Cancer Centre in Houston, Texas, is studying whether mefloquine would be effective as part of the chemotherapy regimen for the serious type of brain cancer. A brief summary of the study reads:

This phase I trial studies the side effects and best dose of combination chemotherapy in treating patients with glioblastoma multiforme after radiation therapy. Drugs used in chemotherapy, such as temozolomide, memantine hydrochloride, and metformin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing them or stopping them from dividing. 

Mefloquine may help temozolomide, memantine hydrochloride, and metformin hydrochloride kill more cancer cells by making tumor cells more sensitive to the drug. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Temozolomide, Memantine Hydrochloride, Mefloquine, and Metformin Hydrochloride in Treating Patients With Glioblastoma Multiforme After Radiation Therapy

https://clinicaltrials.gov/ct2/show/NCT01430351?term=mefloquine&draw=2&rank=28

Worth A Look

Whenever we make decisions that will have an effect on our health, be it going on a diet or taking a prescription medication, it’s always best to have access to as much information as possible in order to make the correct decision. These databases contain a great deal of valuable information and I would encourage everyone to utilize these valuable tools.

Remember, stay informed and stay healthy.