NIH Starts HCQ + AZM Trial May 14 Update

NIH news release today NIH begins clinical trial of hydroxychloroquine and azithromycin to treat COVID-19.  Excerpts in italics with my bolds.

Study enrolling adults with mild to moderate COVID-19 in the United States.

A clinical trial has begun to evaluate whether the malaria drug hydroxychloroquine, given together with the antibiotic azithromycin, can prevent hospitalization and death from coronavirus disease 2019 (COVID-19). The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is sponsoring the trial, which is being conducted by the NIAID-funded AIDS Clinical Trials Group (ACTG). Teva Pharmaceuticals is donating medications for the study.

Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.NIAID

The Phase 2b trial will enroll approximately 2,000 adults at participating ACTG sites(link is external) across the United States. Study participants must have confirmed infection with SARS-CoV-2, the virus that causes COVID-19, and be experiencing fever, cough and/or shortness of breath. The investigators anticipate that many of those enrolled will be 60 years of age or older or have a comorbidity associated with developing serious complications from COVID-19, such as cardiovascular disease or diabetes. Participants will be randomly assigned to receive short-term treatment with either hydroxychloroquine and azithromycin or matching placebos. People living with HIV and pregnant and breastfeeding women also are eligible to participate in the study. The first participant enrolled today in San Diego, California.

We urgently need a safe and effective treatment for COVID-19. Repurposing existing drugs is an attractive option because these medications have undergone extensive testing, allowing them to move quickly into clinical trials and accelerating their potential approval for COVID-19 treatment,” said NIAID Director Anthony S. Fauci, M.D. “Although there is anecdotal evidence that hydroxychloroquine and azithromycin may benefit people with COVID-19, we need solid data from a large randomized, controlled clinical trial to determine whether this experimental treatment is safe and can improve clinical outcomes.”

On March 28, FDA issued an Emergency Use Authorization (link) (EUA) to allow hydroxychloroquine and medical-grade chloroquine to be distributed from the Strategic National Stockpile and prescribed by doctors to hospitalized adolescents and adults with COVID-19, as appropriate, when a clinical trial is not available or feasible.

Participants in the ACTG study, called A5395, will receive oral medications to take at home. Those randomly assigned to the experimental treatment group will take 400 milligrams (mg) of hydroxychloroquine twice on the first day and 200 mg twice daily for an additional six days. They also will take 500 mg of azithromycin on the first day and 250 mg daily for an additional four days. The control group will receive equivalent numbers of placebo pills. Neither the participants nor the study team will know who received experimental treatment or placebo until the end of the trial.

Participants will record their symptoms, adherence to treatment, and major events such as hospitalizations in a diary for 20 days. Study staff will follow up with participants by telephone during this period. When possible, participants will come to the clinical research site for an in-person visit at day 20. Additional follow-ups will be conducted by telephone three and six months after treatment starts.

The main objective of the study is to determine whether hydroxychloroquine and azithromycin can prevent hospitalization and death due to COVID-19. Additionally, investigators will evaluate the safety and tolerability of the experimental treatment for people with SARS-CoV-2 infection.

“This study will provide key data to aid responses to the COVID-19 pandemic,” said ACTG Chair Judith Currier, M.D., of the University of California, Los Angeles. “We are pleased to be able to leverage ACTG’s existing infrastructure for HIV treatment clinical trials to quickly implement this important study.”

The study description at ClinicalTrials.gov is here. The program started May 1 and with a primary completion date of October 9, 2020.

Why This Matters

There was mention above of “anecdotal” evidence regarding HCQ in fighting Covid 19.  The most recent example is a study reported at medRxiv Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients

  • Researchers at NYU Grossman School of Medicine looked at 932 coronavirus patients hospitalized between March 2 and April 5
  • Half were given a combination of hydroxychloroquine, azithromycin and zinc sulfate and the other half did not receive zinc
  • Patients receiving the triple drug combination were 1.5 times more likely to recover enough to be discharged and 44% less likely to die
  • The team believes hydroxychloroquine helps zinc, which has antiviral properties, get into infected cells

The main finding of this study is that after adjusting for the timing of zinc therapy, we found that the addition of zinc sulfate to hydroxychloroquine and azithromycin was found to associate with a decrease in mortality or transition to hospice among patients who did not require ICU level of care, but this association was not significant in patients who were treated in the ICU. This result may be reflective of the proposed mechanism of action of zinc sulfate in COVID-19. Zinc has been shown to reduce SARS-CoV RNA dependent RNA polymerase activity in vitro [13]. As such, zinc may have a role in preventing the virus from progressing to severe disease, but once the aberrant production of systemic immune mediators is initiated, known as the cytokine storm, the addition of zinc may no longer be effective [17]. Our findings suggest a potential therapeutic synergistic mechanism of zinc sulfate with hydroxychloroquine, if used early on in presentation with COVID-19. However, our findings do not suggest a prophylactic benefit of zinc sulfate in the absence of a zinc ionophore, despite interest in this therapy for prevention. A prophylactic strategy of zinc sulfate should be evaluated to help answer this question.

Background: Previous Post  Preemptive Coronavirus Therapy

University of Minnesota is leading an important HCQ clinical trial, including collaboration with McGill University Montreal, University of Manitoba and University of Alberta. The initiative is called Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2 (COVID-19 PEP) at ClinicalTrials.gov.  Excerpts in italics with my bolds. H/T Don Monfort

Study Objective:

  1. To test if post-exposure prophylaxis with hydroxychloroquine can prevent symptomatic COVID-19 disease after known exposure to the SARS-CoV-2 coronavirus.
  2. To test if early preemptive hydroxychloroquine therapy can prevent disease progression in persons with known symptomatic COVID-19 disease, decreasing hospitalizations and symptom severity.

The Intervention Drug is Hydroxychloroquine. 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days  Other Name: Plaquenil

This is the April 22, 2020: Second Interim Analysis Update

On April 22, 2020, the independent Data and Safety Monitoring Board (DSMB) for the COVID-19 post-exposure prophylaxis trial has reviewed the cumulative safety data from 783 participants in the ongoing hydroxychloroquine prevention trial. The DSMB has identified no safety concerns or efficacy concerns at this time. We congratulate the study investigators on their enrollment thus far, and we will continue to provide oversight for the trial as specified in the DSMB charter.

Based on the event rate of COVID-19 illness observed in the control group, the sample size can be reduced by approximately one-third with approximately 200 more research participants needed to complete the trial to demonstrate conclusively whether or not there is a 50% reduction in symptomatic illness with a 5-day course of hydroxychloroquine after a high-risk exposure to someone with COIVD-19. The next interim analysis is scheduled for May 6, 2020. Ongoing U.S. enrollment is occurring at http://www.covidpep.umn.edu and in Canada at: http://www.covid-19research.ca

What Theory of the Disease Covid19 Suggests this Intervention?

A plain language explanation comes from WebMD by way of the Daily Star Bangladesh Chloroquine, zinc tested to treat COVID-19 infection

In the United States and Europe, a handful of clinical trials have begun to test ways to keep healthcare workers and other vulnerable people safe from coronavirus disease (COVID-19).

Most are testing drugs called chloroquine or hydroxychloroquine that have long been used to prevent and treat malaria, and also as a therapy against rheumatoid arthritis and lupus. The hope is that, given before infection or early in the course of the disease, the drugs will protect someone against infection and illness from the virus, or, if they do, will ensure that their case is mild. But whether these drugs will help, hurt or do nothing remains an open question.

The virus that causes COVID-19 uses a backdoor to enter the cell. As it enters, it is exposed to an acidic, vinegar-like environment, which is actually needed for the virus to get all the way inside. Hydroxychloroquine, metaphorically keeps the cap on the vinegar, Greene says, preventing acidification. Thus, there is a scientific rationale for how this drug might exert an antiviral effect.

Mahir Ozmen, a professor of surgery at the Istinye University, School of Medicine in Istanbul, Turkey, says he thinks the best way to use chloroquine is in combination with zinc and vitamins C and D. He is running a clinical trial, testing to see whether this combination protects health care workers and their immediate families – including his own.

Ozmen, who is collaborating with a chest medicine specialist, an intensive care physician, and two infectious disease experts, says he intended to include only 80 participants, but 98 quickly volunteered. He began in April providing prophylactic therapy, and expects to complete the trial by July.

Ozmen says, “Hydroxychloroquine helps the zinc get inside the infected cells to destroy the virus, and vitamins A and D support immune function”. He gives volunteers a low dose of hydroxychloroquine every 3 weeks, and a vitamin tablet every day – or every other day for people prone to kidney stones. At the end of the trial, each participant will be checked for antibodies to COVID-19, suggesting an infection, whether they realised it or not.

This kind of prophylaxis will give us the time to develop a vaccine that will offer protection to everyone.

In perhaps the fastest-moving, large prophylaxis trial, researchers at Duke University are leading a US$ 50 million collaboration across hundreds of American healthcare systems, which will test 15,000 volunteers. Half the health care workers will take hydroxychloroquine, and half a placebo. Other drugs could be added to the study if they prove promising for preventing or lessening infection, says Adrian Hernandez, the trial’s principle investigator.

In France, researchers are running a trial with 1,200 healthcare workers to test prophylactic use of hydroxychloroquine or a combination of two HIV drugs, Lopinavir and Ritonavir, which failed as a treatment in people with severe COVID-19 infections but may work as prevention. It is expected to take 6 months.

In a 40,000-person trial led by the University of Oxford in England, participants in Asia will receive chloroquine or a placebo, and in Europe, hydroxychloroquine or a placebo. That trial is expected to take a year.

Footnote: A more detailed hypothesis for testing is provided by Dr. Scholz and Dr. Derwand of Leukocare in Munich (PDF here). Excerpt:

Based on the evidence of therapeutic effects of CQ/HCQ, their possible pharmacological effect as zinc ionophores and possibly underestimated specific and unspecific antiviral effects of zinc, we hypothesize that the combination of CQ/HCQ with parenteral zinc in the treatment of hospitalized COVID-19 patients may help to improve clinical outcomes and to limit the COVID-19 fatality rates.

Due to the existing substantial evidence, we propose to amend current clinical trial designs to test this hypothesis in the treatment of hospitalized COVID-19 patients by including at least one treatment arm with oral CQ or HCQ in combination with zinc. However, because of the better clinical safety profile HCQ should be preferred. To avoid interindividual differences of oral absorption rates and because of possible gastrointestinal side effects of oral zinc supplementation, it is proposed to use parenteral zinc preparations which are approved and clinically already used.

2 comments

  1. Graeme Weber · 21 Days Ago

    Ron,
    You should check out MSB’s (Mesoblast) which is listed on the Australian and NY stock exchanges, with its medical advancement drug called REMESTEMCEL-L. I think it is a game changer in stopping most deaths.
    Regards,

    Like

    • Ron Clutz · 20 Days Ago

      Thanks Graeme. That does look promising, but at the other end of the disease. The press release talks about saving patients on ventilators.
      NEW YORK, April 30, 2020 (GLOBE NEWSWIRE) — Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in cellular medicines for inflammatory diseases, today announced a Phase 2/3 randomized, placebo-controlled trial to rigorously confirm whether its allogeneic mesenchymal stem cell therapy remestemcel-L provides a survival benefit in moderate/severe acute respiratory distress syndrome (ARDS) due to COVID-19 has commenced enrollment.

      More than 20 medical centers across the United States will participate in the trial which is expected to complete enrollment within three to four months, with interim analyses planned which could result in stopping the trial early for efficacy or futility.

      Mesoblast Chief Executive Dr Silviu Itescu stated: “There are limited treatment options for ventilator-dependent patients with acute respiratory distress syndrome, the principal cause of mortality in COVID-19 infection. Based on the encouraging initial results of remestemcel-L treatment under emergency compassionate use in New York, there is an urgent need to execute this robust randomized placebo–controlled trial in order to definitively determine whether this cell therapy can reduce the mortality of patients with COVID-19 ARDS on ventilators.”

      Like

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