The Playground

    Quote from interested observer

    This site used to be dominated by discussions about Rossi. Very little to do with LENR, but at least entertaining. Now it’s mostly a place for nonsense about Covid as if there needs to be more channels for that. Oh well. Sorry to intrude.

    Keeping everyone happy is a juggling act. We found out the hard way the forum can't be all science, and all serious. We learned we have to have an outlet for a little fun too, along with the serious stuff. And that is what the Playground is for.


    On the positive side, and to our credit...staff and members alike, most of what we discuss here on the forum is LENR, and related. The forums mix of work/play seems to be working, as we have a very healthy website, large membership, and have become an integral and influential part of the LENR community. And we keep getting better and better each year.


    We will be around for a long time I suspect.

    Ivermectin Fails to Shorten COVID Recovery Time in NIH Sponsored ACTIV-6 Study But Study Underdoses Ivermectin


    Ivermectin Fails to Shorten COVID Recovery Time in NIH Sponsored ACTIV-6 Study But Study Underdoses Ivermectin
    Abstract NIH’s Active-6 investigators randomized mild to moderately ill COVID outpatients to placebo or ivermectin 0.4 mg/kg for 3 days in an attempt to…
    www.trialsitenews.com


    Abstract

    NIH’s Active-6 investigators randomized mild to moderately ill COVID outpatients to placebo or ivermectin 0.4 mg/kg for 3 days in an attempt to see if ivermectin was effective for early COVID. The dose used was felt to be acceptable by all for the alpha variant which was dominant at the time study planning began. The study ultimately treated a patient population heavily infected with delta (70%) for which the ivermectin dose was much too low, however, the study investigators never changed the dose or added another arm with a higher dose.


    It was clear prior to enrolling any patients that ACTIV-6 would treat patients mostly infected with the delta variant, which was far more virulent. The appropriate dose for delta was unknown. ACTIV-6 was aware that soon the results of the TOGETHER study which wound up treating the more virulent gamma variant using the same dose as ACTIV-6 would be announced.


    Instead of waiting to make sure the study team had established an acceptable dose, on 6/23/21 ACTIV-6 opted to commence enrolling patients using the dose of ivermectin which they had planned to use for alpha. We have no idea how ACTIV-6 decided that 0.4 mg/kg for 3 days was an appropriate dose for delta.


    ACTIV-6 knew that if that dose failed TOGETHER and/or if it became clear that a higher dose was needed, they would not stop and restart the study to increase the dose. They could have started with or added a higher dose arm at any time but consciously opted to not do so.


    Six weeks later, not unexpectedly on 8/6/21, the study investigators knew that their dose had failed to show statistically significant benefit in TOGETHER and the US now had approximately 80% delta variant circulation.


    By then, the Front Line COVID-19 Critical Care (FLCCC) Alliance, based on reports from all over the world, recommended a significantly higher dose, 0.4-0.6 mg/kg for a minimum of five (5) days. Two months after that, the ACTIV-6 team was notified that the FLCCC Alliance recommended 0.6 mg/kg with food for 5 days, a cumulative dose 2.5 times higher than what ACTIV-6 was using yet the Duke University-led, National Institutes of Health (NIH)-sponsored trial leadership opted to not add another arm with higher dosing even though there was no end in sight for delta.


    The regimen used did not show overall benefit in the trial which included alpha, delta, and omicron patients, leaving open the issue of whether a higher dose of ivermectin might have been effective in the study. The dose was increased significantly in February 2022 when we had all omicron, and the study continues.


    The investigators reported the results in a preprint, and those who were interviewed by the media, in this author’s opinion, pretended that they had performed a fair study of ivermectin, and it had failed. They were judicious with their words not to outright lie, but their comments were extremely disingenuous.


    The ACTIV-6 Ivermectin Study

    On April 17, 2020, the National Institutes of Health (NIH) announced the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership to develop a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines.


    The NIH stated, “In the outpatient setting, repurposed drug studies have been challenged by small sample sizes, designs with significant limitations, and variable results, limiting the impact on clinical practice.”


    The 6th ACTIV study, ACTIV-6 study was first posted on clinicaltrials.gov on 5/13/21 with a placebo arm and 3 treatment arms, ivermectin 0.3-0.4 mg/kg for 3 days, fluvoxamine 50 mg twice a day for 10 days and inhaled fluticasone 200 mcg. daily for 14 days.


    The ACTIV-6 study results for ivermectin were released on preprint server MedRxiv 6/13/22. See the link: ACTIV-6 Ivermectin Study


    The massive ACTIV-6 study, which involved 93 centers, randomized 1591 patients to placebo or 0.4 mg/kg of ivermectin for 3 days given an average of 6 days into symptoms which is long by today’s standards although the timing of dosing made no difference. Patients were at least 30 years old (average 48) with at least two COVID symptoms and needed to be symptomatic 7 days or less. 47% were vaccinated.


    Ivermectin had no effect on hospital admissions. There was no difference in ER visits. Only one patient died (ivermectin group). It shortened the time to sustained recovery by about one-half day and also showed benefit in the 90 patients (6%) who presented with severe illness. Neither was statistically significant.


    Of the 1591 people enrolled in the trial, only 19 were hospitalized, 10 ivermectin, 9 placebo. 6% needed the ICU.


    The conclusions stated: “Thus, ACTIV-6 adds to the growing evidence that there is not a clinically relevant treatment effect of ivermectin at this dose and duration. While those with severe symptoms at baseline appeared to have beneficial treatment effect with ivermectin as compared with placebo, this subgroup was small, thus these findings should be considered exploratory.”


    Said USA Today, “Preliminary results from a trial funded by the National Institutes of Health adds to a mountain of evidence showing ivermectin is not effective at treating COVID-19. The randomized, double-blind, placebo-controlled trial – the gold standard for determining effectiveness of drugs – is the largest of its kind studying the controversial antiparasitic. In the eight-month study conducted during the delta and omicron waves, authors found no statistical difference in recovery time. Patients given ivermectin recovered in about 11 days on average, while patients given the placebo recovered in about 11.5 days.”


    Study lead Dr. Adrian Hernandez, executive director of the Duke Clinical Research Institute, said "At this point, we’re not surprised. Given these results, there does not appear to be a role for ivermectin outside of a clinical trial setting."


    Dr. David Boulware, University of Minnesota infectious disease researcher, has been heavily involved in studying repurposed drugs for COVID. He oversaw the design of ACTIV-6 as co-chair of its protocol committee and was heavily involved in running the University of Minnesota’s COVID-OUT study which investigated ivermectin, fluvoxamine and metformin. He was involved in two trials of hydroxychloroquine at University of Minnesota and is widely quoted on COVID therapies.


    Boulware said he “expects ivermectin proponents to dismiss the latest results because of the lower dosage, but that they are "moving the goalpost" because he consulted with some of them at the outset of ACTIV-6 in early 2021 and they supported the dosage at that time.”- Star Tribune


    Study Purpose

    Clinicaltrials.gov-ACTIV-6 “The purpose of this study(ACTIV-6) is to evaluate the effectiveness of repurposed medications (study drug(s)(In this case ivermectin) in reducing symptoms of non-hospitalized participants with mild to moderate COVID-19.”- clinicaltrials.gov.


    The purpose of the study should not have been “to add to the growing evidence that there was not a clinically relevant treatment effect of ivermectin at this dose and duration” if “ivermectin at this dose and duration” were known to be ineffective in another large trial reported 6 weeks after the start of ACTIV-6 and 2.5 times cumulatively lower than the dose recommended by some of the world’s leading ivermectin experts for the virulent delta variant which affected about 70% of the patients treated in the study.


    Comparison to Prior Ivermectin Studies

    The results of the ACTIV-6 ivermectin study were no surprise since a higher cumulative dose, 1.5 mg/kg was found to be ineffective in 478 patients averaging 37 years old in the Lopez-Medina study from Colombia reported in JAMA 3/4/21.


    Ivermectin lowered risk of admission by one third and intubation 48% which did not reach statistical significance in an Argentinian study (IVERCOR) of 501 patients averaging 42 years old when given in the doses based on weight which averaged a very low of 0.15 mg/kg for 2 days which was based on ivermectin’s use for parasites.


    0.4 mg/kg without food for 3 days did not show statistical benefit in admissions or death at the same dose ACTIV-6 used in higher risk patients in the TOGETHER trial in patients there mostly infected with the gamma P.1 variant. The results were announced 8/6/21, six weeks after the first patient was enrolled in ACTIV-6. The final results were published in the New England Journal of Medicine 3/30/22. There were serious criticisms of the study, the most obvious of which was that the dose was inappropriately low.


    The I-TECH study of 490 patients was performed concurrently with ACTIV-6, 5/25-10/31/21, during a period when the delta variant dominated the world. In Malaysian high-risk patients averaging 62 years old, reported 2/18/22 in JAMA, 0.4 mg/kg with food for 5 days did not lower progression to severe disease (needing oxygen) which affected about 19% of the patients which was the main outcome measure of the trial. It lowered risk of intubation 70% (10 to 3), need for ICU 25% (8 to 6) and death 70% (10 to 3) which were not statistically significant.


    IVERCOR and I-TECH have been widely referenced as showing no benefit of ivermectin. This is a common problem with studies of COVID therapies. Studies evidenced benefit however, they were underpowered to reach statistical significance. The discussion section of ITECH said “Our findings are consistent with the results of the IVERCOR-COVID19 trial, which found that ivermectin was ineffective in reducing the risk of hospitalization.”


    Had IVERCOR had 1591 patients like ACTIV-6 with the same proportion of events, it would have shown statistical benefit for admissions and intubation.


    If I-TECH had done likewise there would have been 32 intubations and 32 deaths in the placebo arm and 10 intubations and 10 deaths in the ivermectin arm which would have shown statistical significance.


    Government Healthcare Agencies and Repurposed Drugs For COVID

    If proven to be of significant benefit in low-risk patients in shortening the duration of illness, ivermectin would have gotten an emergency use authorization (EUA) to treat that enormous group of patients but probably not those at high risk since there weren’t enough of them in the study. It would thus not be a competitor for the drugs for which the FDA has granted emergency use authorization for high-risk patients, paxlovid, molnupiravir, remdesivir and bebtelovimab.


    Public health authorities in Uttar Pradesh, India with over 200 million people reported great success against COVID with an ivermectin and doxycycline and supplement regimen which they started using heavily in early August 2020. By December 2020, their mortality rate was 0.26 per 100,000, 9% of the US.


    In 22 million people in Mexico City admissions were lowered 50-75% with ivermectin in a population-wide public health initiative.


    These programs were chronicled by TrialSite News to which individuals from various regulatory and health and human services agencies subscribe including the NIH, FDA, and CDC.


    Many think that ivermectin should have been in widespread use in the United States by at the latest January 2021. Unfortunately, the media has not reported anything about Uttar Pradesh or Mexico City or for that matter any study or initiative with positive outcomes.


    The media has been guilty of providing misinformation to the public about ivermectin. Here is Dr. Jennifer Ashton of ABC news with three false statements about ivermectin.


    1) It has not been widely used in India


    2) She emphasized that it is not an antiviral. It is a 3CL protease inhibitor among other things.


    3) It is not safe to use in humans for COVID


    NIH had been in no hurry to study ivermectin. ACTIV 1-5 had studied 29 branded therapies and no repurposed drugs for early COVID. Dr. Boulware said he had submitted 10 applications to NIH to study repurposed drugs which were turned down. Clearly some sort of bias was present.


    Had ivermectin been in widespread use and showed significant benefit in the US in January 2021, it would have hurt the vaccine rollout by increasing vaccine hesitancy.


    Hydroxychloroquine, about which there is much controversy, is the most commonly used COVID drug in the world. (Ivermectin is second).


    Dr. Boulware participated in two studies involving hydroxychloroquine which found the anti-malarial drug failed to improve recovery time, but his studies were in low-risk patients making it impossible for hydroxychloroquine to show statistical benefit in the most important endpoints, admissions, and death.


    On the other hand, Yale epidemiologist Harvey Rich MD, PhD states “Every one of the now 10 studies of high-risk outpatient hydroxychloroquine (HCQ) use have shown risk reduction for hospitalization or mortality. A meta-analysis demonstrates


    44% reduction in hospitalization and 75% reduction in mortality.”


    It appears that failure to shorten duration of illness in low-risk patients does not preclude benefit in high-risk patients.


    Hydroxychloroquine’s emergency use authorization (EUA) was rescinded by the FDA in June 2020 who said that because it didn’t work in hospitalized patients it shouldn’t be used for early COVID in outpatients even though treating early COVID mainly involves killing the virus and in hospitalized treatment involves treating inflammation.


    The government has gone on to deny an emergency use authorization application for generic fluvoxamine for which Dr. Boulware filed. He sent a strong rebuttal letter to the FDA after it turned down fluvoxamine’s EUA request. Its efficacy data in 1497 patients in a large, randomized trial was equal to Merck’s molnupiravir which received an EUA. Merck has gone on to sell billions worth of products now.


    There is evidence that mast cell activation is a significant factor in causing the inflammation in COVID. Famotidine blocks H2 histamine receptors on mast cells. Famotidine and mast cell stabilizers like quercetin had enormous potential for benefit. The recently deceased Dr. Vladimir “Zev” Zelenko found quercetin was beneficial along with hydroxychloroquine, ivermectin, zinc and other generic and over the counter drugs in over 7000 patients he treated with only 3 deaths.


    Dr. Cliff Lane, NIAID deputy chairman, acknowledged that the ACTIV committee chose not to study famotidine. The American Academy of Asthma Allergy and Immunology (AAAAI) showed great interest in mast cell activation and famotidine but since consulting with the coronavirus taskforce has done nothing.


    ACTIV-6 Strategy

    ACTIV-6 designed their trial to study low risk patients. The trial specifics were posted on clinical trials.gov 5/13/21. If benefits were shown in that group, it would have had major implications for the vast majority of patients in the world with early COVID, all of whom want to get better more quickly.


    I-TECH in Malaysia was already studying high risk patients. TOGETHER was studying patients with one risk factor mostly in a more virulent variant. Those patients turned out to have moderate to high risk. COVID-OUT was studying patients with obesity, a big risk factor. PRINCIPLE studied those aged 18 to 64 years with some underlying health conditions or shortness of breath from Covid-19, or those aged above 65 years. ACTIV-6 was the only study looking at low risk patients.


    Ivermectin Dosing

    Dosing in ACTIV-6 was crucial. Using too low a dose would prevent the study from showing benefit of ivermectin and randomize patients to placebo or an ineffective dose of ivermectin. It was well known that there is no significant toxicity from higher doses of ivermectin and thus no reason to risk underdosing ivermectin in the trial.


    Complicating choosing a correct dose was the fact that starting in February 2021, the delta variant had swept through India causing devastation. ACTIV-6 had to be concerned that by the time they started to enroll patients, that delta would be the dominant variant. and that it might be hard to treat.


    The results of a large multicenter trial of ivermectin for early COVID had never been announced let alone published. The results of the TOGETHER study which used the same dose but predominantly against the gamma variant were going to be announced soon and knowledge of the results should have helped ACTIV-6 greatly with choosing a dose. It is likely ACTIV-6 could have gotten preliminary results early.


    ACTIV-6’s efforts initially were put into treating the alpha variant which was dominant in the US at the time planning began. The correct dose of ivermectin for the alpha variant was not universally agreed upon since many different doses had been used against different variants and shown variable results.


    Ivermectin is lipophilic and has been shown, based on blood levels, to be better absorbed with food in three studies by 18%, 25% and 2.6 times. ACTIV-6’s preprint and protocol on clinical trials.gov does not specify taking it with or without food.


    If 0.4 mg/kg for 3 days worked in TOGETHER, it might have worked against the less virulent alpha variant, but it was uncertain to be an appropriate dose for delta.


    If the dose failed in TOGETHER, it seemed unreasonable to use the same dose for delta. It turns out delta is more virulent than gamma per a Canadian study from October 2021 but that was unknown at the time.


    Dr. Boulware sought the opinion of many in choosing a dose for ivermectin for ACTIV-6 for alpha. He asked Dr. Pierre Kory of the FLCCC Alliance in February 2021 if 0.4 mg/kg for 3 days was a reasonable dose. Dr. Kory said yes. The ACTIV-6 study participants were given fluvoxamine for 10 days and inhaled fluticasone for 14 days.


    A white paper 4 months earlier from Mumbai, India 10/18/20 from numerous authors suggested ivermectin needed a significantly higher dose for the variants prior to delta. “Ivermectin in the dose of 12 mg BD(twice a day) alone or in combination with other therapy for 5 to 7 days may be considered as a safe therapeutic option for mild, moderate or severe cases of Covid-19 infection. It is cost effective especially when the other drugs are very costly & not easily available.”


    The delta variant was first discovered in India in late December and had started raising havoc there in February. By early June it was 91% of the cases in the UK. It first appeared in the US in February.


    “Prevalence of the SARS-CoV-2 Delta variant rose quickly in the US between May and June 2021, with the variant achieving dominance by late June 2021, and accounting for over 90% of all SARS-CoV-2 infections for an extended period from late July to early December 2021”


    An analysis of genetic sequencing data as of June 27, 4 days after ACTIV-6 enrolled it first patient, showed that the Delta strain, also known as B.1.617.2, made up about 40% of positive COVID-19 test samples in the US, according to Helix, a population genomics company that collects and analyzes test samples from several U.S. states.


    As far as we knew, delta was here to stay. Getting the dosage right in the study was crucial. Before enrolling its first patient, 6/23/21, it was clear that ACTIV-6 would mainly be treating delta and needed to figure out an appropriate dose for it. The delta variant wound up being about 70% of all those treated in the study, over 90% for several months until it was supplanted by omicron in mid-December.


    Choosing an appropriate dose was not simple. Because of the recommendations against its use by the FDA and the Infectious Disease Society of America (IDSA), few academic centers in the US used ivermectin for any of the variants. In the US because delta was new, there was little experience.


    There were many experts in India and elsewhere who had experience with it. Most of the physicians treating COVID belonging to the 17,000-member Global COVID Summit regularly used ivermectin, many in areas with delta. They would have loved to have helped with deciding on dosing.


    In this 8/11/21 video of the weekly FLCCC Alliance webcast the dosing of ivermectin for delta is discussed. Listed in their protocol was a dose for delta of 0.4-0.6 mg/kg for 5 days.


    In April 2022, an in vitro study showed that ivermectin was beneficial against all COVID-19 strains and better than chloroquine or remdesivir


    8/6/21 TOGETHER announced that 0.4 mg/kg for 3 days on an empty stomach showed a statistically insignificant benefit in ivermectin treated patients. By then the US had 80% delta. The FLCCC Alliance was recommending a much higher dose as were experts all over the world. It should have been obvious to the ACTIV-6 investigators that ivermectin needed to be using a much higher dose of ivermectin. ACTIV-6 did not stop the trial and restart with an appropriate dose even though they knew the trial would fail to show benefit. They could have added a higher dose arm yet did not do so.


    The similarly sized TOGETHER study evaluated patients with at least one risk factor, thus at higher risk. They wound up treating a more virulent variant. They were of similar age, 49, but as it turned out were of far higher risk. In the TOGETHER ivermectin trial patients were treated at an average of 3.8 days as opposed to 6 days in ACTIV-6. There were 211 primary outcome events with 171 needing hospitalization as opposed to 19 hospitalized in ACTIV-6. 45 died in TOGETHER as opposed to 1 in ACTIV-6. Had a higher dose of ivermectin been used in TOGETHER and been effective the benefit would have shown up in admissions and deaths.


    Dr. Kory says he would never have approved of 0.4 mg/kg for 3 days for delta, but his opinion about dosing for delta was not solicited by ACTIV-6. The FLCCC Alliance wound up recommending 0.6 mg/kg with food for 5 days for delta.


    On 10/18/21 the ACTIVE-6 team was emailed about those recommendations. Dr. Cliff Lane acknowledged receiving it and said ACTIV-6 was working on it. ACTIV-6 could have added another arm with a higher dose of ivermectin but didn’t and continued with the same dose.


    All four major randomized trials, TOGETHER, ACTIV-6, COVID-OUT and PRINCIPLE gave ivermectin 0.47 mg/kg or less for 3 days. That dose appears to have been too low in TOGETHER for gamma patients and too low for delta patients in the ACTIV-6. COVID-OUT and PRINCIPLE have not reported their results.


    ACTIV-6 Made a Mistake Not Waiting for The TOGETHER Results

    ACTIV-6 could and should have waited for the results of TOGETHER which came 6 weeks after the ACTIV-6 study started, showing a small, statistically insignificant benefit from 0.4 mg/kg for 3 days in significantly higher risk patients in a more virulent variant than alpha.


    ACTIV-6 will say they had no way to know when the TOGETHER results would be out, but it is very likely that Dr. Edward Mills who ran TOGETHER would have shared the preliminary results with ACTIV-6 earlier. He had to know early on that at best it had shown mild benefit.


    ACTIV-6 knew they would never stop the trial except for obvious benefit or futility, meaning they would be using 0.4 mg/kg for 3 days until the end of the trial.


    When the NY Times reported on the New England Journal of Medicine article with the official results of TOGETHER on 3/30/22, they quoted Dr. Boulware “There’s really no sign of any benefit,” said Dr. David Boulware, an infectious-disease expert at the University of Minnesota.


    “Now that people can dive into the details and the data, hopefully that will steer the majority of doctors away from ivermectin towards other therapies,” Dr. Boulware said.


    This author believes that Dr. Boulware’s comments were disingenuous. He knew that ivermectin advocates had numerous legitimate issues with the trial, including that the dose that was used was too low, the fact that ivermectin was available over the counter in that area of Brazil and the particular placebo group to which ivermectin was compared had a lower event rate than the other placebo groups.


    Any doctor knows that if a particular dose shows some benefit, but it is statistically insignificant in a study, that a higher dose or larger study may show statistically significant benefit. That was clearly the case in TOGETHER. It’s interesting that no one in the infectious disease community or the media came out with that very obvious idea. It appears that that idea also didn’t make its way to the ACTIV-6 investigators. Why the entire US infectious disease community wants ivermectin to fail is inexplicable.


    Possible Strategies For ACTIV-6

    ACTIV-6 may claim there was urgency to find a drug to treat COVID and needed to start as soon as possible. NIH had waited 4 months from the time Dr. Kory presented to the senate to start designing a study. Then the results weren’t available for 14 months.


    If ACTIV-6 was going to start the trial without knowing the results of TOGETHER as it did 6/23/21, the least they needed was a plan on how to treat delta which already represented a significant proportion of new infections in the US.


    The easiest strategy was to initially start with two ivermectin arms, the 0.4 mg/kg for 3 days and a higher dose arm. ACTIV-6 chose to start only with the low dose for alpha.


    The knowledge 6 weeks later that the same dose they were using had failed in TOGETHER and that we now had 80% delta again should have prompted a change in strategy.


    At that point, the plan which would have made it most likely to fairly test ivermectin and make it least likely to randomize patients to placebo or an ineffective dose of ivermectin would have been to stop the trial and start all over with placebo vs. a higher dose of ivermectin, something that is almost never done once a study has started. ACTIV-6 did not do that.


    Another option which would still have had some patients randomized to treatment taking an ineffective dose of ivermectin would have been to add another arm with a higher dose of ivermectin. Failing to offer any patients a higher dose of ivermectin would guarantee the study would fail. Randomizing any patients to placebo or 0.4 mg/kg for 3 days which was very likely to be ineffective was unethical but that is what ACTIV-6 did and continued that dose for another 6 months. ACTIV-6 eventually increased the dose to 0.6 mg/kg for 6 days in February when we had all omicron.


    ACTIV-6 Increases Ivermectin Dose to 0.6 mg/kg for 6 days for Omicron

    When omicron appeared and it was clear it would become the dominant variant, ACTIV-6 chose to finish enrollment and then increase the dose to 0.6 mg/kg for 6 days in February 2022. By then we had almost all omicron which are less virulent, and it meant that they were enrolling patients at even lower risk than in the initial trial in which only 1.2% of the patients were admitted despite 70% having the virulent delta.


    Hospitalization and death would be even less common, and ACTIV-6 would have to rely almost exclusively on shortening the duration of illness in those who were still symptomatic and were able to receive and take their medications at an average 6 days into their illness which is late for an antiviral.


    It’s possible the time to treatment will be shorter in the higher dose study and more consistent with what is happening during the antiviral drug era when patients know they have to get treatment early. Unlike with the lower dose of ivermectin which was ineffective whenever it was given, the timing of high dose ivermectin may make a big difference.


    Had ACTIV-6 chosen to change the enrollment criteria and use high dose ivermectin in high-risk patients, those who needed ivermectin the most would eventually find out if ivermectin would help them. If it worked in high-risk patients, not only could it have helped those who are unvaccinated who benefit most from paxlovid but may especially have helped those at high risk and are vaccinated who are less likely to benefit from paxlovid, like Dr. Fauci. Patients would have had a cheap, safe alternative to paxlovid, molnupiravir, remdesivir and bebtelovimab.


    4 months into the present higher dose trial the data safety monitoring committee should have an idea of whether high dose ivermectin is beneficial in these patients. If ivermectin is not showing benefit at the higher dose, ACTIV-6 should be planning a study of high dose ivermectin in high-risk patients.


    Discussion

    NIH’s ACTIV group waited as long as possible to start a study of ivermectin which had shown benefit on a very large scale in Uttar Pradesh by 10 months before then it took a year for the results of their trial to be announced. When they finally did a study, they chose to see if low risk patients would get better more quickly. It was reasonable. Others were studying higher risk patients. Showing benefit in low-risk patients would have wound up shortening the illness of many millions and prevented some of the severe illness and death which can happen unpredictably in these patients.


    On the other hand, showing benefit in low-risk patients may not have been sufficient for the FDA to approve it for high-risk patients. It would have been reasonable to study high risk patients who make up most of the serious illness and death.


    As it turned out, TOGETHER used too low a dose to show benefit and I-TECH wasn’t large enough to show statistical benefit in higher risk patients so the issue of whether ivermectin is beneficial in that group is unanswered. As a result, the only drugs recommended for treatment are the branded products which have EUAs for high-risk patients, paxlovid, molnupiravir, remdesivir and bebtelovimab.


    In their trial ACTIV-6 inexplicably treated delta patients with a dose which had almost no chance to work and failed to add a higher dose arm when it became obvious, they needed one. Is it possible that ACTIV-6 accidentally messed up and didn’t realize it? If they didn’t realize it, why did they eventually change to a higher dose? We don’t know if they did it because they realized their mistake and wanted to rectify it or felt they could not get away with any slighter of hand.


    COVID Analysis had issues with the analysis of the data, feeling it showed investigator bias.


    Statements by Dr. Boulware after the results of TOGETHER were published in the NY Times showed bias. Statements by Drs. Boulware and Hernandez were deceptive after the ACTIV-6 preprint was published.


    Dr. Boulware said he “expects ivermectin proponents to dismiss the latest results because of the lower dosage, but that they are "moving the goalpost" because he consulted with some of them at the outset of ACTIV-6 in early 2021 and they supported the dosage at that time.”


    Nature moved the goalposts from alpha to delta, not the ivermectin proponents, and ACTIV-6 could have “adapted” in their “adaptive trial” but didn’t.


    The TOGETHER study had had the same dilemma as ACTIV-6. They planned for alpha. They wound up with a more virulent variant, gamma. They could have added a higher dose arm. They didn’t and the study failed to show benefit mainly because the dose was too low. It was a blueprint for ACTIV-6 to follow.


    ACTIV-6 should have delayed starting the trial until they were certain of the proper dose for ivermectin or started with two doses of ivermectin. They had multiple opportunities during the study to at the least add a higher dose arm which should have been allowable under the study protocol, but they didn’t do it. It was ACTIV-6’s job to test a dose of ivermectin that might work against whatever variant was dominant in the US at the time. They didn’t do it.


    It would have taken about a month to choose a new dose and restart the study with a higher dose. There was no rush. As it was, it took a year to announce the results.


    The decision making on the part of the ACTIV-6 investigators was inexplicable. At every step of the way they chose not to use a dose of ivermectin which may have been effective for those with delta who had been randomized to therapy. We don’t know how those decisions were made or who made them.


    Either they did not acknowledge that delta would dominate or that they did plan for it but that they thought the dose they used was appropriate for delta. Neither idea is believable.


    There is no possible argument that prior to enrolling the first patient that ACTIV-6 didn’t know they would predominantly be treating delta. It will be interesting to see if they can find physicians to perjure themselves and say that ACTIV-6’s dosing was appropriate.


    Unfortunately, the investigators failed to acknowledge their very obvious underdosing of delta patients which caused the study to fail, wasted millions of dollars, wasted the effort of 93 centers and the time of patients who were randomized to placebo or a dose of ivermectin which had almost no chance to be effective.


    It is hard to believe that experienced investigators could have so obviously botched the trial then pretend nothing had been done wrong and expect no one would notice.


    Expect ACTIV-6 to do everything in their power to try to deflect blame. That’s what doctors do when they get caught doing something they shouldn’t have. They will come up with clever excuses as to why the low dosing of ivermectin was not their fault. They may even claim the dosing wasn’t low. ACTIV-6 may claim they weren’t sure that delta would dominate. They may say that “experts” advised them that delta didn’t need a higher dose.


    They may say that they were unaware of the FLCCC’s recommendations for dosing. They may say the FLCCC is not objective when it comes to ivermectin, and others have different opinions about it. It’s interesting that FLCCC’s opinion was important enough to solicit for alpha but not for delta.


    They may say that the failure of ivermectin at the same dose in TOGETHER was not an indication to use a higher dose or add a higher dose arm. They may say the safety of higher dose ivermectin was uncertain. They may say that the protocol did not allow for a new arm. They may say they had no money for another arm. It’s all absurd.


    The failure of any patient in ACTIVE-6 to receive a dose of ivermectin which had a reasonable chance to work should never have happened and could not have happened without investigator misconduct.


    Consequences of ACTIV-6’s Strategy

    Had a higher dose of ivermectin been used at the start of ACTIV-6 and been effective enough in the study to have the study stopped prematurely for evidence of efficacy prior to omicron taking over, it would have been difficult for the FDA to not quickly give it emergency use authorization even though they would have hated to do it. Ivermectin would have continued to have been used during omicron and perhaps had a profound beneficial effect all over the world. Maybe US hospitals would stop taking families to court to prevent their loved ones from receiving it. The strategy of ACTIV-6 precludes those possibilities.

    The strategy also meant that the 817 patients randomized to ivermectin received a dose which was far less likely to be effective than a dose they should have received.

    Had omicron not replaced delta the study would have wasted at least 8 months in finding out if ivermectin was beneficial at higher doses.

    To their credit, ACTIV-6 has chosen to rectify the problem in their ongoing trial of the less virulent omicron variant by using a large, appropriate dose of ivermectin. Has it been planned that if the study shows benefit that the results will be released just before the midterms with the democrats and Dr. Fauci taking credit for it?

    Conclusions

    Thousands of physicians regularly see quick and consistently excellent results from ivermectin. Completely discounting their experience makes no sense. Bringing them before medical review boards to discipline them for using ivermectin to help sick patients makes even less sense and seems unjust if not criminal.


    Discounting the massive benefit of ivermectin seen in hundreds of millions of people in multiple countries makes doesn’t make any sense either. The media failing to report on the topic while major medical organizations failed to acknowledge the trend makes even less sense.


    The randomized double blind controlled drug trial is not a “gold standard” because of the many things which can and do go wrong with them, including wrongdoing and investigator bias. ACTIV-6 is a good example. Relying on large, randomized trials exclusively to evaluate drugs for COVID so far has failed.


    So far, in the four 1500 patient randomized trials which were supposed to finally answer the question of whether ivermectin is effective for early COVID, TOGETHER appears to have underdosed ivermectin for gamma and ACTIV-6 underdosed it for delta. COVID-OUT and PRINCIPLE are pending but also appear to have underdosed for delta variant of concern. How did all four ivermectin trials wind up using a regimen inappropriately low for the dominant variant in their trial?


    With the decreasing benefit of the vaccines, the approval of the VRBPAC committee this week of the next Pfizer vaccine having no serious efficacy or safety testing for omicron, the ability of BA.4 and 5 to infect those who are vaccinated or have natural immunity, the lower benefit of paxlovid in vaccinated high-risk patients and younger immune patients, populations need economical, safe, effective drugs. It’s truly a shame that it would appear that the ACTIV-6 study team designed the ivermectin study so as to not show any benefit.


    Prior ivermectin trials conducted outside the US have been discounted for not being up to US standards. It appears those standards were a lot higher than those in ACTIV-6. Previous studies within the US such as the ICON study published in CHEST showed great promise, although it wasn’t a randomized controlled trial.


    Unfortunately, the track record appears clear: the ACTIV-6 operation prevented any possibility of ivermectin demonstrating benefit. Positive results could have helped many hundreds of millions around the world. How could human beings do anything worse?


    NIH and FDA have no love for ivermectin. That’s been clear in information propaganda wars. They and ACTIV-6 knew exactly what they were doing. All involved need to be held accountable


    Here a print of our vaccination/hospital cases. You can clearly see that with BA.5 the curve for the vaccinated grows much faster than for unvaxx /blue bottom). 37 people have been going to hospital the last week/each day in average that have had vaccination and 6 had none. so the ratio is 6:1 or more than double the real vaxx::unvxx ratio. "unbekannt" means the vaccine type or number of vaccines not known.


    So vaccination today is a big big risk factor to end up in hospital!! Here we do not even talk of the 5x increased excess data rate we see in some places among vaxx people.

    Quote from interested observer

    This site used to be dominated by discussions about Rossi. Very little to do with LENR, but at least entertaining. Now it’s mostly a place for nonsense about Covid as if there needs to be more channels for that. Oh well. Sorry to intrude.

    @Admins, please please please, I kindly ask you to reopen the covid dedicated thread! Covid stuff is too much to be afforded by a general thread discussion. Even if I'm not understanding why threads like BLP etc (clearly scams as the AR one) are still around and having their own dedicated threads, AR's funny news can confortably sit in playground channel but not overflodded by insane covid fans. Thanks in advance

    Quote from miles

    @Admins, please please please, I kindly ask you to reopen the covid dedicated thread! Covid stuff is too much to be afforded by a general thread discussion. Even if I'm not understanding why threads like BLP etc (clearly scams as the AR one) are still around and having their own dedicated threads, AR's funny news can confortably sit in playground channel but not overflodded by insane covid fans. Thanks in adva

    Hi -I have flagged your post up for discussion by the team, but it will take awhile. BTW, I thought the topic would be passé by now. But Covid is the gift that keeps on giving....

    Interesting from 2002


    Abstract

    The nuclear fusion reactions and have been measured at projectile energies between 5 and 60 keV using deuteron-implanted solid targets (C, Al, Zr and Ta). An exponential-like enhancement of the reaction cross-section compared to the bare nuclei fusion could be observed for energies below 20 keV. This effect may be interpreted as a result of the electron screening of the Coulomb barrier between reacting deuterons and described by a screening energy Ue. The experimentally determined Ue values show a clear target-material dependence and reach for heavier materials values being one order of magnitude larger than the value achieved in a gas target experiment and significantly larger than the theoretical predictions. Specific solid-state contributions to the enhancement of the fusion cross-sections arising from the channeling of projectiles in the crystal lattice and some other related effects will be discussed.

    Solid-state effects in d+d fusion reactions
    The nuclear fusion reactions 2H(d,p)3H and 2H(d,n)3He have been measured at projectile energies between 5 and 60 keV using deuteron-implanted solid ta…
    www.sciencedirect.com

    This comes as no surprise, it was just a matter of when. Canada's Health Minister has just said the following :


    "... it is essential that Canadians remain up to date with their vaccines. And what does being up-to-date mean? Being up-to-date with your vaccination means that you received your last dose during the last nine months. "


    The question is if it will get to the stage of being mandated by government. Or perhaps the government will be content in allowing companies to get away with firing those employees who are not 'up-to-date'.


    My hope is that more and more previously compliant Canadians will say no.


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    Zephir,


    I'm glad you posted this again, because I know you like to understand stuff and will appreciate what I am about to say (again).


    Comparing risks from vaccines in a trial quantitatively with COVID risks from the same trial makes no sense (without a large adjustment factor).


    Obviously, the risks from the trial depends on the trial length and the COVID rate. By this standard none of the childhood vaccines would pass, because the viruses they protect against are (now) rare. The COVID vaccine trials were very short - designed to be minimum length because this was an emergency deployment. Therefore few people on them ever caught COVID.


    The correct comparison is vaccine risk (per jab) against the difference in risk, if you catch covid, between being vaccinated and unvaccinated, since we know almost everyone ended up catching COVID and since the advent of delta (let alone omicron) it was pretty obvious that would happen.


    The comparison made here would rate a vaccine 10X better just because it was conducted at a time and place when the local COVID rate was 10X higher. That can't be right!


    This is so obviously (to anyone thinking about it seriously) wrong it counts as antivaxxer rhetoric. Anyone making this argument is either very naive and being misled by others, or deliberately misleading people.


    THH

    Quote from Alan Smith

    Hi -I have flagged your post up for discussion by the team, but it will take awhile. BTW, I thought the topic would be passé by now. But Covid is the gift that keeps on giving....

    It has mostly turned into an interesting review and rebuttal of antivaxxer memes - which as you say keep on coming.


    Maybe not interesting to many, but I like thinking about this stuff. I think the "best" way to deal with antivaxxers, like trolls, is to ignore them - because by showing the clear mistakes in their arguments you are legitimising them. And antivaxxer-followers do so for real emotional reasons that need to be addressed through understanding - intellectual arguments do not help. Weird but true.


    Anyway I am not much worried about PR here. I like some others here still get satisfaction out of demolishing the rhetoric taht claims to be science occasionally - and having blocked W the signal-to-noise ratio of this thread is better!

    Quote from miles

    @Admins, please please please, I kindly ask you to reopen the covid dedicated thread! Covid stuff is too much to be afforded by a general thread discussion. Even if I'm not understanding why threads like BLP etc (clearly scams as the AR one) are still around and having their own dedicated threads, AR's funny news can confortably sit in playground channel but not overflodded by insane covid fans. Thanks in advance

    Like Alan, I will give this serious consideration at our weekly Staff meeting. We do take into consideration what our members want, and in this case they, and you, have been consistent in opinion since we consolidated threads. There are a few that will disagree, but overall, I do believe the majority want a separate COVID thread...again.


    Rossi...well he has gotten so ridiculous, the Playground is the place for him as you prefer. Even his most diehard fans would probably agree.

    I'm asking if Katsuaki Tanabe is involved with cold fusion research in Japan.

    Description

    About the Author

    Profile: Received a B.Eng. (2001) and a M.Eng. (2003) in Chemical Engineering from University of Tokyo, and a M.S. (2005) in Applied Physics and a Ph.D. (2008) in Materials Science from California Institute of Technology. He was a project assistant professor (2008-2011) and a project associate professor (2011-2015) at Institute for Nano Quantum Information Electronics, University of Tokyo, and has been an associate professor at Department of Chemical Engineering, Kyoto University since 2015.


    Gottfried Wagener Prize, German Innovation Award (2017)

    Funai Academic Award (2016)

    Young Scientists' Prize, Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology (2015)

    IEICE Electronics Society Laser-Quantum Electronics (LQE) Young Researchers Award (2012)

    Japanese Society of Applied Physics (JSAP) Young Scientist Presentation Award (2011)

    Electronic Materials Symposium (EMS) Award (2009)

    Best Student Presentation Award, IEEE Photovoltaic Specialists Conference (PVSC) (2008)


    Google Scholar Citations: https://scholar.google.com/citations?user=-3G7btYAAAAJ


    45 page book $100

    My library might order one


    "Plasmonics for Hydrogen Energy"

    DOI: https://doi.org/10.1007/978-3-030-88275-4

    Link

    Plasmonics for Hydrogen Energy
    This book provides an overview of the fundamentals of plasmonic field enhancement phenomena and the recent advancements in the field of hydrogen energy…
    www.springerprofessional.de


    ISBN:9783030882754, 3030882756

    Tanabe, Katsuaki. Plasmonics for Hydrogen Energy. Switzerland: Springer International Publishing AG

    October 14, 2021


    This book provides an overview of the fundamentals of plasmonic field enhancement phenomena and the recent advancements in the field of hydrogen energy technologies that utilize plasmonics for their performance enhancement. Hydrogen energy is currently a representative clean energy without polluting or greenhouse emission in its use. However, industrial production of hydrogen molecules, or other usable hydrogen-containing molecules, is required for the use of hydrogen energy. It is also important to produce hydrogen in clean, renewable manners, to contribute to the solution of the environmental problems, such as atmospheric pollution and global warming, and of the depletion of energy resources. For the widespread use of hydrogen energy, technical developments particularly for hydrogen production and storage are highly sought after. Free electrons in metals, particularly around metal surfaces or interfaces with dielectric materials, exhibit a strong interaction with electromagnetic fields or light in the form of collective oscillation, named surface plasmons. The electromagnetic field intensity around subwavelength-size metal particles can be highly localized due to the coupling between the incident photons and collective oscillation of free electrons at the metal surface, resulting in focusing of electromagnetic energy density, or namely local field enhancement.

    Frontmatter

    Chapter 1. Hydrogen Energy Technology and Plasmonics

    Abstract

    The hydrogen energy is currently a representative clean energy without polluting or greenhouse emission in its use, in contrast to the conventional fossil fuels.

    Katsuaki Tanabe

    Chapter 2. Field Enhancement Around Spherical Metal Nanoparticles and Nanoshells

    Abstract

    To quantitatively discuss the plasmonic field enhancement effect, the field enhancement factor, defined as the ratio of the electromagnetic field intensity around the metal object to that in the absence of the object, or the original incident field, is calculated as follows.

    Katsuaki Tanabe

    Chapter 3. Field Enhancement on Planar Metal Surface

    Abstract

    Next, we present the calculation of the field enhancement factors on planar metal surfaces.

    Katsuaki Tanabe

    Chapter 4. Field Enhancement at Sharp Metal Tips

    Abstract

    In contrast to the plasmonic field enhancement effect on planar metal surfaces discussed in the previous chapter, it is known that surfaces with sharp curvatures allow the electromagnetic field to concentrate further.

    Katsuaki Tanabe

    Chapter 5. Field Enhancement in Metal Nanogaps

    Abstract

    In the previous chapters, we discussed the plasmonic field enhancement factors on planar and spherical surfaces and also at sharp tips of nanoparticles or nanoscale surface roughnesses of hydrogen-absorbing transition metals.

    Katsuaki Tanabe

    Chapter 6. Applications

    Source: Publisher

    This is the latest publication I could find and shows that Tanabe's group are successfully working on cold fusion!


    Spatially and temporally heterothermic kinetic model of hydrogen absorption and desorption in metals with heat transport

    Article

    • Jun 2022

    Numerical modelling of hydrogen transport is effective for designing and optimizing various energy systems, including hydrogen storage devices, fuel cells, and nuclear fusion reactors. In the present study, we propose and demonstrate a spatiotemporally heterothermic, autonomous kinetic model of hydrogen absorption and desorption in metals for preci...

    Cite
    Request full-text

    Are Omicron-Targeted Boosters Worth It?

    — Weighing the evidence to move forward


    https://www.medpagetoday.com/opinion/second-opinions/99557?xid=nl_secondopinion_2022-07-05&eun=g1346736d0r


    The FDA, following the advice of its advisory committee, is advising COVID-19 vaccine manufacturers to reformulate future booster shots to include protection against the BA.4 and BA.5 Omicron variants of SARS-CoV-2. While this decision was not surprising and may have seemed perfunctory to many people, it is worth thinking about the wider context that undergirds this decision.


    The primary driver of this recommendation is the fact that the spike protein of SARS-CoV-2 has significantly mutated away from its ancestral form, eroding the protection the vaccine affords against infection. This phenomenon became overwhelmingly obvious when the immune-evasive Omicron variants emerged, causing countless infections, including many in those who were vaccinated or had immunity from prior infection. However, though vaccine protection against infection was compromised by Omicron, the ability of the ancestral strain-directed vaccine to stave off what really matters -- severe disease, hospitalization, and death -- was durable in all except the high-risk.

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