Damian Sendler: As a result of more than two decades of random, double-blind clinical studies, the effectiveness and safety of ivermectin as an early therapy for COVID-19 have been shown. The authors, who have worked on Helicobacter pylori combination medicines, now offer a COVID-19 therapy combination that has been shown to be extremely successful in clinical studies. Methods and patients: On average, the authors gave this new combination of ivermectin and doxycycline with zinc, as well as vitamins D and C, to 24 COVID-19 patients who refused hospitalization because of their high-risk characteristics, such as hypoxia. After 24 hours, all of the patients had improved from 87.4 percent to 93.1 percent in oxygen saturation (p = 0.001). No one was admitted to the hospital or died in this study, which was conducted in accordance with the background-matched CDC database controls. Even in outpatients with moderate to severe symptoms, triple combination treatment is safe and effective.
Damian Jacob Sendler: Currently, there are no viable therapies for COVID-19 individuals who are ambulatory or in the early stages of the disease. Patients who have been diagnosed as HIV positive are sent home to quarantine themselves. But there is a growing body of data that some repurposed medications, given early, may dramatically enhance outcomes and even eliminate or postpone the need for immune-modulators, antiplatelet/antithrombotic treatment, and the provision of oxygen [1].
Dr. Sendler: Ivermectin (IVM), a medication that has been used safely in 3.7 billion doses globally since 1987, is one of the most widely investigated COVID-19 treatments. According to a recent assessment by Nobel Prize co-winner Dr. Satoshi Omura on IVM activity against COVID-19, the data shows that it is effective [4]. Many randomized, controlled studies (RCTs) have examined IVM alone for the treatment of COVID-19, with statistically significant therapeutic benefits in almost all of them and a 62 percent decrease in mortality risks on average [5]. IVM therapy for COVID-19 has recently been the subject of five studies published in high-quality medical publications, all of which found substantial therapeutic advantages for IVM compared to controls, the majority of which were statistically significant (p 0.002) [6–10]. IVM has been used in RCTs for COVID-19 therapy at cumulative doses of 1500 g/kg [13,14] and 3000 g/kg [15,16] over 4 or 5 days without or with moderate and temporary side effects. IVM is widely used in non-Western nations to prevent and treat COVID-19, especially in the early stages of the illness.
Damian Sendler
Despite the fact that the COVID-19 study found a link between IVM therapy and improved clinical outcomes, there has been some disagreement over the best way to treat acute infections due to the use of different therapeutic regimens, particularly those that include broad-spectrum antibiotics and zinc. While early multidrug therapies, which claimed an 87 percent and 75 percent reduction in hospitalizations, both with a p-value of 0.01 in 869 high-risk subjects, left the optimal management strategy ambiguous due to IVM and hydroxychloroquine (HCQ) usage, [15] it was unclear what the best course of action was. Based on the best available evidence, there is an urgent need for an effective, safe, and practical combination treatment formulation.
IVM interferes with cytoplasmic-nucleus communication, generating a hostile environment for viral aggregation while lowering cytokine-mediated inflammation at the cellular level. To prevent further infection with the COVID-19 virus, IVM blocks the spike protein’s binding to ACE2 receptor, which in turn suppresses pathogenesis. Finally, positive modifications in cellular innate immunity have been linked to IVM [16].
An antiviral medicine combination developed by the authors’ group has been demonstrated to be especially beneficial as a co-therapy for treatment early in COVID-19 to reduce symptom duration and avoid hospitalization. Only when used in conjunction with other treatments can IVM be considered curative [1,6,17]. Thus, the scientists picked a combination of safe and widely accessible drugs, licensed for various uses and without drug–drug interactions or QT prolongation, as well as one that slows intracellular viral multiplication and has some anti-inflammatory characteristics for their study.
A single component of combination treatments for intracellular viral diseases such as hepatitis B and C has seldom proven curative and has been used effectively to treat TB, H. pylori infections, leprosy, and leprosy, as well as leprosy for intracellular bacterial infections. Even when many antiviral medicines are combined, they cannot entirely cure but only decrease the viral burden [18]. With a high cure rate and little medication resistance when used in combination, IVM is best recognized for its broad-spectrum effectiveness against parasite infections. IVM by itself is not a “magic bullet,” despite its value. Combinations may help lessen individual dosages while also reducing negative effects.. IVM was mixed with doxycycline and zinc as active components and vitamins D and C as substitute ‘excipients’ provided to augment prevalent clinical deficits in elderly patients to cover all age groups.
Coagulation treatment with oxygen supplementation (SpO2) levels as low as 70 percent was used in patients who refused to be sent to the hospital and insisted on being treated on an outpatient basis, according to the results of this research. Participants in a clinical study named Combination Therapy to Treat COVID-19 Infection received treatment from an experienced clinical trials staff.
Damian Jacob Markiewicz Sendler: Patients in Los Angeles, Ventura County, California, and other parts of the United States were referred to the study by their doctors or via word of mouth. NCT04482686 is the clinicaltrial.gov identifier for the clinical studies that these individuals were recommended to enroll in (which is a double-blind RCT). Some patients, whose SpO2 was less than 90%, were judged too ill to participate in a placebo-controlled experiment and were so excluded from this study. For a variety of reasons, including the fear of dying in a hospital, the participants declined hospitalization. During the months of August 2020 and February 2021, participants who were disqualified from other trials and refused to travel to the hospital were treated off-label via telemedicine. This open-label study was approved by the Institutional Review Board (IRB) after a swab reverse transcription quantitative real time PCR (RT-qPCR) diagnostic was made. To be eligible, participants had to test positive on a PCR for COVID-19, provide informed permission, be under the age of 18, and agree to use two highly effective methods of pregnancy control if they were of reproductive potential themselves Allergies or pharmacological interactions with the combination treatment components, as well as any of the specified comorbidities, such as seizure risk, and pregnancy, were all grounds for exclusion from the study.
Damian Jacob Sendler
Within 72 hours of patients arriving at Ventura Clinical Trials, treatment started. All participants who passed the screening process were recruited sequentially. As part of the “IVM Combination Therapy” (ICT), patients received oral doxycycline (100 mg twice daily), IVM (12 mg on days 1, 4, and 8), zinc (25mg twice daily), vitamin D3 (1500 IU twice daily), and vitamin C for 10 days as part of a “IVM combination therapy” (1500 mg twice a day). Only 10 days of ICT classes were offered.
There were two patients (#10 and #23) whose SpO2 levels were so low that they got 36 mg IVM (rather than 12 mg) as their first dose of IVM on day 1.
A daily diary (Supplementary Figure 1) was kept by each participant for the first 10 days of the study. EKGs, blood pressure, temperature (in °F), and oxygen saturation (SpO2) were measured using medical equipment that was supplied to the patient at home. Pathology received swabs from participants on days 1, 5, 10, and 30 for testing of SARS-CoV-2. According to the guidelines, pregnancy tests were carried out.
SARS-CoV-2 negative PCR, symptom remission, progression to hospitalization and patient survival were the end goals of this study.
Damien Sendler: COVID-19’s open-label study with an untreated control arm was unable to recruit high-risk, extremely hypoxic patients, thus the treated group’s survival was compared to the general population’s survival rate. From the CDC database of COVID-19 participants, an externally controlled trial (ECT), or synthetic control arm, was constructed [20]. Information available includes the age range, the existence of any chronic disease (COVID-19 vulnerability or otherwise, conditions not indicated), date of infection and if the COVID-19 diagnosis has been confirmed in the laboratory. The researchers drew on the records of all patients who satisfied the following criteria: were 50 years or older, had a laboratory-confirmed diagnosis of COVID-19, had death/survival, race/sex, and infection dates prior to March 2021, and had any concomitant conditions. It was done after the authors had gathered their own data to better match their individuals, all of whom had some comorbidity and the majority were over the age of 50. This synthetic control arm data selection CSViewer version 1.3 was used to examine the CDC database.
They describe for the first time an outpatient ICT that averted hospitalization and resulted in a 100 percent survival and cure in COVID-19 patients with hypoxia who were not chosen. In quest of a treatment for COVID-19, the authors, who have developed combination therapies for H. pylori, tested numerous other IVM-based combinations on ambulatory COVID-19 patients and discovered that the aforementioned combination was very beneficial as a therapy. It was necessary for certain patients to use HCQ or additional components, similar to how H. pylori resistant to triple treatment occasionally required quadruple therapy. They admit that they couldn’t examine every possible combination of substances in this research, but such investigations may be valuable for future refining. IVM may be applied using weight-based dosing [22], but it may also be necessary to provide the correct amounts to cover all COVID-19 strains.
It has been shown that COVID-19 mortality is influenced by hypoxia. As an example, oximetry revealed that some of these individuals presented with levels of hypoxia ranging from as low as 73% to as high as 84% and even as high as 85%. In several patients, the recovery began within 12 hours and the mean SpO2 rose from 86.5 to 93.1 in the first 24 hours of therapy. The symptoms, including the disappearance of cough, fever, and weariness, all improved at the same time. It also took around 11.5 1.6 days after starting therapy for the first negative PCR to occur. ICT was used to treat critically sick patients who would normally have been admitted to the hospital, but none of them were and none died as a result of it.
A limited sample size of patients in the’synthetic control arm’ of an ECT trial shows that ICT outperformed it statistically. Studies with this treatment group show that ICT may be used if symptoms and risk factors for COVID-19 development exist, even in instances where the PCR findings are not yet available. The use of ECT arms is on the rise, particularly in cases when the’standard-of-care’ control arm might prove lethal [23].
Combination antiviral treatment is being investigated because we’re learning that most intracellular infections, whether bacterial or viral, cannot be treated with a single medicine. Multiple medications can treat a wide range of viral infections by targeting a variety of viral replication pathways. H. pylori treatments, for example, have developed resistance to even two-drug regimens. Multidrug treatments are likely to be more successful in decreasing viral load and minimizing resistance and variation generation [24], as discussed for HIV [18]. This is particularly true when employing three or more different drugs at once. When treating scabies, nematodes, strongyloidesis, microfilaridermias and Onchocerca volvulus alone, resistance has already developed [17,25–28]. Diseases based on the eukaryotic organism infection, not viral, are less susceptible to mutations and hence more resistant to treatment. To avoid IVM resistance in COVID-19 and its future versions, it is necessary to prevent IVM resistance in these disorders on a regular basis. We cannot allow IVM resistance to develop clinically and be shown experimentally before it is addressed because of the present condition of the pandemic. The IVM in COVID-19 is not a monotherapy but should be used in conjunction with other medications, particularly with increasing reports of vaccination breakthrough infections caused by mutant strains. ‘No replication, no mutation’ may be possible with combination treatment, allowing for faster cures, resistance avoidance, and the overcoming of mutant strain emergence.
Intracellular coronavirus replication needs a combination of antiviral medications in order to stop the virus from reactivating. Even though other alternatives have been suggested, the authors chose the aforementioned combination because of its effectiveness, component safety profiles, affordability, and absence of drug–drug interaction. The authors note that other candidates may also block coronavirus replication independently. Although doxycycline is not considered effective on its own, the combination of IVM and doxycycline has been shown to be somewhat effective for COVID-19 [7], potentially (statistical trend) more effective than the HCQ and azithromycin combination [29], and mechanistically theorized as synergistic [30]. As zinc is a fundamental component of antiviral action, it would work well with the ionophores (IVM and doxycycline) to enhance zinc’s intracellular concentration and speed up viral clearance. There have been no reports of medication interactions between zinc, IVM, and doxycycline [35]. Azithromycin has been linked to QT prolongation, but none of the other medications on this list has that problem [22,36–38].
For patients with COVID-19, a 10-day combined treatment of IVM, doxycycline and zinc is recommended to alleviate symptoms [6,7]. For COVID-19 treatments, the authors have selected a safe IVM dosage of 36 mg over 10 days, which has been recommended for parasites [39]. Staggered IVM dosing over ten days is recommended because of the long plasma half-life (up to 66 hours) of the medication [40]. Zinc entrance into cells would be made easier if IVM at plasma levels were readily available for the length of the experiment. It follows that a multimodal regimen is more likely to treat COVID-19 than IVM alone, as several publications have previously shown [41].
There were no biases in the selection of participants for this research, which recruited successive volunteers (i.e., when subjects came forward, they were enrolled and none were turned away). ICT activity seems to have quickly restored SpO2 and reversed other symptoms, which cannot be explained solely by the development of immunity. According to the study’s authors, the study’s limited sample size (n = 24 participants who agreed to therapy) may restrict its applicability. The initial group of patients to present to Ventura Clinical Trials included these people, and more data is being gathered. Some very sick individuals may be reluctant to participate in a clinical study that is less well-known. Extending the sample size, testing other IVM doses, and investigating the microbiome’s mechanistic contribution to IVM’s success in COVID-19 will be the focus of future investigations by the authors.
There is no way to conduct an RCT with severe COVID-19 without simultaneously enrolling a control group. It was concluded that “Placebo-controlled studies of ivermectin therapy among patients with COVID-19 infection are no longer ethical and active placebo-controlled trials should be stopped” because of the consequences found in the two participants who denied treatment and did not live. It is because of this that this research relied on an experimental control group known as an ECT or’synthetic’ control arm [23]. It’s time for IRBs to authorize synthetic arm research and reject COVID-19 experiments that include a control arm, according to Lawrie.
Dr. Damian Jacob Sendler and his media team provided the content for this article.