Remdesivir Data from NIAID Trial Published

“Not a panacea” or a “cure-all,” expert cautions

https://www.medpagetoday.com/infectiousdisease/covid19/86670

Peer-reviewed findings were published late Friday from one of the key trials of remdesivir, perhaps the most promising antiviral agent for COVID-19, confirming and extending topline results announced a month ago via press release.

Hospitalized patients with COVID-19 who received remdesivir had a median recovery time of 11 days versus 15 days with placebo (rate ratio for recovery 1.32, 95% CI 1.12-1.55, P<0.001), reported John Beigel, MD, of the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues.

Mortality estimates by 14 days were lower for the remdesivir group compared to placebo, but non-significant (HR for death 0.70, 95% CI 0.47-1.04), the authors wrote in the New England Journal of Medicine.

Interestingly, when researchers examined outcomes on an 8-point ordinal scale, they found patients with a baseline ordinal score of 5 had a rate ratio for recovery of 1.47 (95% CI 1.17-1.84), while patients with a baseline score of 7 had a rate ratio for recovery of 0.95 (95% CI 0.64-1.42).

Some of these data were released by the NIAID on April 29, but without further details such as 95% confidence intervals. On May 1, the FDA agreed to let remdesivir be used clinically under an emergency use authorization. Since then, however, clinicians and other researchers have clamored for a fuller report, to help guide their clinical practice. For example, questions were raised as to whether particular subgroups got more benefit from the drug than others.

David Aronoff, MD, of Vanderbilt University Medical Center in Nashville, who was not involved in the research, noted the drug seemed more effective when given to patients who weren’t as severely ill, earlier in the course of disease. He added this wasn’t surprising, given remdesivir’s mechanism of action as an antiviral, which works by blocking the virus from replicating.

“The drug doesn’t affect the host, it only affects the virus. What seems to cause major problems late in the course of disease is the inflammatory response to the initial damage the virus causes,” he told MedPage Today.

Aronoff likened the virus to an arsonist setting fires, and antivirals like remdesivir as the police trying to catch the arsonist before they set more fires.

“But once the building is on fire, it doesn’t matter where the arsonist is,” he noted.

This is why combining a drug to address the viral response with a drug to address the host response may be critical to treating the virus. Aronoff cited the NIAID’s ACTT-2 trial in progress, which will examine combination therapy with remdesivir and anti-inflammatory drug, baricitinib, versus remdesivir alone.

In Aranoff’s analogy, the anti-inflammatory would be akin to the firefighters putting out the fires the arsonist set.

Study Details

The Adaptive Covid-19 Treatment Trial (ACTT-1) was comprised of 60 trial sites, including 45 sites in the U.S., along with sites in Europe and Asia. Participants hospitalized with COVID-19 with evidence of lower respiratory involvement were randomized to either intravenous remdesivir or placebo for up to 10 days. Primary outcome was time to recovery, meaning either hospitalization for infection control purposes only or discharge from the hospital.

An independent data and safety monitoring board recommended unblinding the results based on preliminary data from 1,059 patients — 538 assigned to remdesivir and 521 to placebo. As of April 28, only 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29 (either recovered or died).

Patients were a mean age of 59, and almost two-thirds were men, 53% were white, 23% were Hispanic or Latino and 21% were black. About 80% were enrolled at sites in North America. Half of patients had two or more pre-existing conditions, including half with hypertension, 37% with obesity and 30% with diabetes mellitus.

Beigel and colleagues included 33-day Kaplan-Meier curves for recovery among subgroups categorized by oxygen need. The greatest separation between the remdesivir and placebo groups (i.e., the greatest drug benefit) was seen for patients receiving oxygen but not at high flow or with noninvasive mechanical ventilation. There was no advantage for remdesivir in recovery rates among patients on high-flow oxygen or those on mechanical ventilation or extracorporeal membrane oxidation.

Among patients not receiving oxygen, a trend toward benefit with remdesivir was evident, but it did not reach statistical significance, probably because more than 80% of the placebo group in this category recovered.

There was no subgroup in which placebo clearly outperformed remdesivir. Many groups (such as racial minorities) didn’t have enough patients to show meaningful differences.

Notably, however, patients with symptom duration greater than 10 days benefited from remdesivir just as much as those with shorter duration.

Serious adverse events occurred in 21% of patients in the remdesivir group and 27% of patients in the placebo group, and two in each group were judged to be related to the study drug. Anemia or decreased hemoglobin was the most common adverse event in the remdesivir group (7.9% vs 9.0% in the placebo group). Pyrexia and hyperglycemia also occurred more often in the remdesivir group.

Aronoff said more will be known once final results from the study are released in a few weeks, but they will likely confirm the current report.

When asked if it would be appropriate to use this medication outside of a clinical trial setting, he noted there are reasons to hesitate, namely remdesivir’s availability, the optimal duration of therapy, and that it can only be given intravenously.

“It’s hard to implement it really early when you’re at a nursing home or somebody’s house,” Aronoff said. “It’s not a panacea and it’s not a cure-all. It has some barriers to widespread implementation.”

Remdesivir’s manufacturer Gilead Sciences is conducting two trials of its own with remdesivir, one of which includes a placebo control. Results from that trial are expected soon.

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https://youtu.be/eLMZoXfnY_I

COVID-19 getting back to normal with control plans

Nobody should resume their work, going back to school, or reopening without a written control plan.

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TENN: KENT MORRELL FOR SENATE 2020

https://www.kentmorrell2020.com/

Why I’m Running for Senate

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  https://www.amazon.com/Pain-Warriors-Tina-Petrova/dp/B084WPJW9L

I just finished previewing- the long awaited and soon to be released ( May 25th)  film (pain-warriors) by Tina Petrova & Eugene Weis

It is abt 80 minutes long and I normally – because of my ADD/ADHD – have trouble sitting and focusing on something that long – but I remained transfixed until the end.

This is a new perspective on the war on pts, caregivers and prescribers.

From a grader schooler dealing with chemo for 4 years to be cured to be left with lingering chronic pain.

To a empathetic prescriber who ends up being the target of the state medical board and DEA for treating chronic pain pts and ends up practicing medicine in a totally different path.

Unfortunately, two pts are never able to get their health issues and pain under control and end up ending their lives.

The DVD/Blu-Ray can be pre-ordered from Amazon on the link below

https://www.amazon.com/Pain-Warriors-Tina-Petrova/dp/B084WPJW9L

Pain Warriors by Tina Petrova & Eugene Weis
https://itunes.apple.com/ca/movie/pain-warriors/id1506122098

http://www.tinapetrova.com

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CDC Opioid Guideline Mobile App

https://www.cdc.gov/drugoverdose/prescribing/app.html

*MME Calculator Disclaimer: This calculator is not intended to replace clinical judgement or to guide opioid dosing for patients receiving active cancer treatment, palliative care, end-of-life care, or for patients younger than 18.

The application is not intended to provide guidance on dosing of opioids as part of medication-assisted treatment for opioid use disorder. Conversion factors for drugs prescribed or provided as part of medication-assisted treatment for opioid use disorder should not be used to benchmark against MME dosage thresholds meant for opioids prescribed for pain. The calculator does not account for incomplete cross-tolerance between opioids and should not be used to guide opioid rotation or conversion between different opioids. This is especially important for fentanyl and methadone conversions. Equianalgesic dose ratios are approximations and do not account for interactions between opioids and other drugs, patient weight, hepatic or renal insufficiency, genetic factors, and other factors affecting pharmacokinetics. Additional clinical guidance, including opioid prescribing for acute pain, may be available through manufacturers’ full prescribing information or consultation with other clinicians with expertise and experience in pain management.

Prescribe with Confidence

CDC’s Opioid Guideline App can help providers apply the recommendations of CDC’s Guideline for Prescribing Opioids for Chronic Pain in clinical practice by putting the entire guideline, tools, and resources in the palm of their hand. Managing chronic pain is complex, but accessing prescribing guidance has never been easier.

The application includes a Morphine Milligram Equivalent (MME) calculator*, summaries of key recommendations, a link to the full Guideline, and an interactive motivational interviewing feature to help providers practice effective communications skills and prescribe with confidence.

Free Download

The CDC Opioid Guideline App is available for free on Google Playexternal icon (Android devices) and in the Apple Storeexternal icon (iOS devices).

I have not had the time to play with this app… but may be useful for some pts to show their prescribers what the real rules are when they are “quoting the law about opiate prescribing”

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Remdesivir Safety Forecast: Watch the Liver, Kidneys

https://www.medpagetoday.com/infectiousdisease/covid19/86582

The adverse event profile for remdesivir as a treatment for COVID-19 remains murky, although liver and kidney risks are emerging.

“Because we’re kind of moving at warp speed, the reporting on that has some unusual aspects,” noted Barbara Young, PharmD, of the American Society of Health-System Pharmacists (ASHP). “We’re getting emerging information, but it’s certainly not what we’re used to getting from clinical trials on most drugs that go through the FDA approval process.”

The first human safety data for remdesivir came from the Ebola virus treatment setting, where the nucleotide analogue and polymerase inhibitor drug had what one review called “an acceptable safety profile,” although it wasn’t more effective than other experimental options tried in the PALM trial.

The only adverse events reported in that trial were deaths, and the only one adjudicated as possibly related to remdesivir was one case of hypotension followed rapidly by cardiac arrest.

Hypotension and other infusion reactions would not be a surprise for an IV drug, noted Young, who is editor of ASHP patient medication information.

However, the event could just as easily have been from the underlying fulminant Ebola virus disease itself, the researchers cautioned in the New England Journal of Medicine paper.

Infusion-related reactions were noted as potential side effects, along with increased liver enzymes in the FDA’s announcement May 1 of emergency use authorization of the antiviral drug for severe COVID-19.

“It was surprising when these came out; it had a very short side effect list. It’s either the safest drug there is or…,” Young said, trailing off. “But my caution is I just think it hasn’t been used widely enough for all the reporting.”

That authorization was based on the only two published datasets with remdesivir, and some highly anticipated data described in press releases so far, suggesting clinical benefit in COVID-19 from the NIH ACTT randomized trial and from Gilead’s phase III SIMPLE randomized trial. A second SIMPLE trial in moderate-severity COVID-19 is expected out at the end of the month.

Liver Risks

Adverse event risk involving the liver has been one of the clearest potential risks from remdesivir.

Liver enzyme increases in the SIMPLE trial included 7% of patients with grade 3 or higher alanine aminotransferase elevations and 3% who stopped the drug over elevated liver enzymes.

Compassionate use data on 61 severe COVID-19 cases treated with the drug, published in the New England Journal of Medicine in April, showed that hepatic enzyme increases were by far the most common adverse event, occurring in 23% of patients. Hypotension was seen in 8%.

However, in the randomized trial from China, stopped early at an enrollment of 237 patients and published in The Lancet, elevated aspartate aminotransferase was actually less common in the remdesivir group than with placebo (5% vs 12%). Alanine aminotransferase elevation led to treatment discontinuation in one patient and acute kidney injury (AKI) prompted it in another.

Early antiviral agents developed for HIV often had issues with mitochondrial damage that could lead to liver failure, noted Matthew Spinelli, MD, an infectious diseases specialist at the University of California San Francisco, which has dosed remdesivir as part of blinded randomized studies.

“Most of the modern antivirals and antiretrovirals for HIV don’t have too much liver toxicity,” he said. “It’s possible to design antivirals that don’t have serious side effects.”

“The really challenging thing is that severe COVID-19 disease, as well as sepsis from pretty much any pathogen, including viruses, can result in damage to the liver,” he cautioned. He called the Chinese trial data somewhat reassuring, but “without more randomized, controlled trial data it’s hard to know exactly how much we need to worry about the liver toxicity issue.”

The FDA’s professional information sheet, which is akin to the prescribing information that would come with an approved drug, called for hepatic laboratory testing on all patients prior to starting remdesivir and daily while receiving it.

How the drug works in people with liver problems hasn’t been tested. “It is not known if dosage adjustment is needed in patients with hepatic impairment and remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk,” the information sheet said.

The European Medicines Agency summary warned against use in patients with liver enzymes five or more times the upper limit of normal.

Kidney Risks

Remdesivir has some structural and functional similarities with the antiviral drug tenofovir (Vemlidy, Viread) used in HIV and hepatitis B infection, Spinelli noted, and “we know that that drug has issues with the kidneys.”

Rat model studies showed low-level injury to the kidney cortical tubules from remdesivir.

In humans, remdesivir appears to be cleared largely by the kidneys, which could lead to accumulation of the drug in those with poor renal function, Young noted. “Certainly someone who already had compromised renal function is going to be affected differently.”

The published compassionate use study showed AKI in 6% of remdesivir-treated patients and serious such cases in 4%. One patient had to discontinue the drug due to worsening of preexisting renal failure. The Chinese trial showed a 1% rate of AKI.

The FDA emergency use authorization called for liver function testing on all patients before dosing. “Remdesivir is not recommended in adult and pediatric patients (>28 days old) with eGFR less than 30 mL/min or in full-term neonates (≥7 days to ≤28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk.”

“We’re certainly willing to tolerate some toxicity in people who are at such high risk of death if the drug continues to appear effective in studies,” Spinelli concluded.

Of course, severe COVID-19 itself also has a known risk of AKI.

“You’re not sure what’s an effect of the disease progression versus the drug being used, and they’re also often using combinations of medications,” Young noted. “It’s a very complex situation.”

Other Concerns

Cardiovascular adverse effects haven’t loomed large as with the prior frontrunner for COVID-19 treatment, hydroxychloroquine.

For remdesivir, one review in the American Journal of Emergency Medicine cited concern about cardiac arrhythmias, but another in Cardiovascular Research called CV effects and toxicities unknown. Preclinical monkey studies suggested no effect on cardiovascular parameters.

Lower grade GI adverse effects like nausea and diarrhea have also been reported in the 3% to 5% range in data so far, but again can be a symptom of COVID-19 as well.

The true rate of events and less common risks will become clear as remdesivir is used more widely, Young predicted. “The populations it has been studied for have really been small in the world of drug approvals.”

Remdesivir was rushed along due to infectious diseases outbreaks and not expected to have a huge market, so a lot of the pharmacokinetics and pharmacodynamics studies typical for a drug headed to market have not been done in humans.

“There’s really no information here even on drug interactions, which as a pharmacist is something we always look for,” Young said. “This is a really unusual situation for a drug to be used outside of the routine drug approval process, and there’s just less information available and able to be reported at this time.”

Some of the drugs being tried for COVID-19 have been problematic for interactions, like lopinavir/ritonavir.

Early on, it looked like remdesivir might have CYP3A4-mediated drug interactions, but that hasn’t been borne out so far clinically, wrote Daniel Streetman, PharmD, of the University of Michigan in Flint, on the Wolters Kluwer site. Still, “pharmacokinetic interactions cannot be completely ruled out without more specific data, and it seems prudent to minimize the concurrent use of any nonessential medications whenever possible.”

Everyone is expressing their concerned about the safety of  hydroxychloroquine being prescribed for treating COVID-19 and yet here is this “new med” that many are pushing to treat COVID-19 and in reading about this med – it is not all that safe.

As I have said before, all meds have some sort of problem… everything with medications is risks vs benefits.

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Government Waging War on Doctors with Prosecutorial Tricks

https://aapsonline.org/government-waging-war-on-doctors-with-prosecutorial-tricks/

Under the U.S. Constitution, the federal government has jurisdiction over only three crimes: treason, counterfeiting, and piracy,

writes Association of American Physicians and Surgeons (AAPS) General Counsel Andrew Schlafly in the summer issue of the Journal of American Physicians and Surgeons. “The Founders would be shocked at the degree to which the federal government is pursuing prosecutions of physicians and others, and the tactics employed to attain convictions.”

The federal court system lacks the checks and balances that exist in the state systems, and federal prosecutors command almost unlimited resources. Unlike in state courts, where there is a reasonable chance of acquittal, federal courts acquit on all counts in less than one percent of cases that are prosecuted. Conviction on only one of dozens or hundreds of counts that prosecutors pile on results in the same sentence—often decades in prison. That is why most defendants plead guilty to get a much shorter sentence, even if they are innocent. And not a few commit suicide, Schlafly writes.

Tricks that prosecutors use include statements designed to inflame or manipulate an average person, Schlafly notes. For example, as in a recent case of Dr. Eugene Gosy, a prominent pain-management specialist in New York, they may tell the public about the doctor’s expensive cars, or trips abroad, or colleagues that pleaded guilty. They emphasize the total amount of alleged false claims, without mentioning that these may have constituted less than 1 percent of billings submitted over 5 years.

Prosecutors grab more headlines by bringing down a respected member of the community than by prosecuting real criminals, Schlafly states.

Prosecutors have no accountability for the devastating effect on the community when its “number 1 prescriber” can no longer treat patients. The indictment of Dr. Gosy stranded 8,000 to 10,000 patients in urgent need of pain medication, causing what county health commissioner Gale R. Burstein called “a public health crisis.” Schlafly observed that “other physicians are obviously terrified to treat [these patients] with the threat of decades in prison hanging over them if they do.”

“What isn’t grabbing headlines are the doctors who quietly stop prescribing pain medicine or stop treating government-insured patients, as the rules for prescribing and billing become ever more complicated, and the penalties ever more draconian,” comments AAPS executive director Jane Orient, M.D. “Those who remain in practice need to become more aware of prosecutorial traps.”

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FDA Bureaucrat Brags He Blocked Physician Prescribing of Hydroxychloroquine in Early COVID-19

https://aapsonline.org/fda-bureaucrat-brags-he-blocked-physician-prescribing-of-hydroxychloroquine-in-early-covid-19/

FDA Bureaucrat Brags On Blocking Physicians Prescribing Hydroxychloroqine in Early COVID-19

By Elizabeth Lee Vliet, M.D.

How could a cheap, effective drug, FDA-approved and in use worldwide since 1955, suddenly be restricted for outpatient use by American physicians? On March 28, 2020, as physicians worldwide were seeing striking success using hydroxychloroquine to treat COVID-19, the FDA erected bureaucratic barriers.

Rick Bright, Ph.D., is an FDA bureaucrat, vaccine researcher, and was appointed by President Obama on November 15, 2016 to head BARDA (Biomedical Advance Research and Development Authority, a sub-agency of the FDA). In an unprecedented move, Bright expanded his power and claimed credit for being the person imposing his will on all of us.

In an appalling admission, Bright said: “Specifically, and contrary to misguided directives, I limited the broad use of chloroquine and hydroxychloroquine, promoted by the administration as a panacea, but which clearly lack scientific merit.”  

Meanwhile, he promoted both remdesivir, a never-approved experimental antiviral in development by Gilead Sciences, and a vaccine for COVID-19. Early effective use of the older, safe, and  available hydroxychloroquine, whose patents had expired decades ago, would decrease demand for these new products.

Rick Bright’s dictatorial decree restricts the use of chloroquine (CQ) and hydroxychloroquine (HCQ) from the National Strategic Stockpile in COVID-19 to hospitalized patients only. States are using Bright’s fiat to impose broad restrictions limiting the drugs’ availability for physicians to use for outpatients to help them recover without hospitalization.

In other countries, early use in outpatients is changing the life-and-death equation by reducing severity and spread of illness, greatly reducing the need for hospitalization and ventilators and markedly reducing deaths.

By his own admission, Rick Bright, who is not a physician, knowingly and unilaterally countermanded Secretary of Health and Human Services Alex Azar, Admiral Giroir in charge of Public Health Service and the President of the United States, who had directed BARDA to establish a Nationwide Expanded Access Investigational New Drug (“IND”) protocol for chloroquine, which would provide significantly greater outpatient access for the drug than would an Emergency Use Authorization (EUA). Unlike an EUA, a Nationwide Expanded Access IND protocol would make the drug available for the treatment of COVID-19 outside a hospital setting at physicians’ medical discretion based on patients’ needs.

How does one non-physician bureaucrat have such power with impunity? How can one person brag about blocking physicians’ attempt to reduce hospitalization and deaths during a national emergency?

It is a falsehood to say that the administration promoted HCQ as a “panacea” or that this medicine “clearly lacks scientific merit.” Both statements are contradicted by video recordings of Presidential briefings, by NIH/CDC studies going back 15 years, and by U.S. and worldwide clinical outcomes studies in COVID-19.

It is unprecedented to restrict physicians from prescribing FDA-approved drugs for a newly discovered use—“off-label.” This is contrary to FDA regulations in place since World War II.

Basic science studies published in 2005 from our own CDC and NIH showed clearly that CQ and HCQ work early in SARS-CoV to block viral entry and multiplication, and suggested that they would not work as well in late-stage disease when the viral load had become huge. When SARS-CoV-1 waned and disappeared by late 2003, the drugs were not submitted for FDA-approval for this coronavirus. 

In 2019, when Chinese doctors recognized the deadly impact of SARS-CoV-2, they began trying known and available anti-viral medicines, especially CQ and HCQ, based on 15-year-old studies. They shared information with South Korea, India, Turkey, Iran, and several other countries, who also began quickly and successfully using CQ and HCQ, alone or with azithromycin. Later, Brazil, Israel, Costa Rica, Australia, and others followed, with good results .  

Based on these initial clinical reports, President Trump said, at an early press briefing, that CQ and HCQ “offered hope.”

More studies have replicated these findings. HCQ given within the first week of symptoms, especially with zinc, can prevent the virus from entering your body’s cells and taking over, much like people use locks and alarms to stop burglaries. Waiting until you are in the ICU is like installing home locks and alarm system after burglars have invaded, vandalized your home, and stolen all your valuables. The drugs cannot reliably undo the damage from the exaggerated immune response, or cytokine storm, triggered by COVID-19.

Examples from the world data on May 18, 2020, which is updated daily, show how Third-World countries are faring far better than the U.S., where entrenched bureaucrats, governors, and medical and pharmacy boards are interfering with physicians’ medical decisions.

Instead of orchestrating a war on HCQ,  the media should be asking key questions, such as:

• How does ONE person, by his own admission, block directives from his superiors to expand availability of HCQ for outpatients and nursing home patients in the U.S.?

• What is the cost in lives and economic damage resulting from one person’s decision to restrict physicians’ independent medical decision-making?

• How many nursing home deaths could have been prevented if physicians had been allowed early access to HCQ?

• Why are U.S. doctors and nurses prevented from using HCQ prophylactically when workers in China, South Korea, India, Brazil, Argentina, Israel, Australia, Turkey, France, and other countries can be protected?

• Why does the U.S. with its a much more sophisticated medical infrastructure have a much higher mortality rate than poor countries?

Bright’s disastrous bureaucratic decision may well be remembered as one of the worst preventable medical tragedies in our time. Never again should one government employee be allowed unrestrained power without oversight, and allowed to make a sweeping order interfering with the prescribing authority of front-line physicians trying to save lives.

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The Chronic Pain Patient Community led by video producer Passionate Pachyderms fires it’s first shot accross the bow in their battle to regain adequate appropriate treatment for all those suffering debilitating Chronic Pain. Grab the tissues, turn up the sound, and get ready for something truly amazingly done.

Each individual pictured is a Chronic/Intractable Pain Patient who represents 450,000 Chronic/Intractable Pain Patients suffering the effects of this crisis. They are unable to obtain appropriate adequate care and/or the long term pain medication they require to function from day to day or have any quality of life.

These Americans are pictured on both their worst days, (which make up the majority of their lives) and on their rare good days, (in most cases before their medications were severely tapered or stopped completely) leaving them in endless cycles of miserably painful days that give way to sleepless and tormented nights. WE ARE THE FACES OF PAIN.

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