How Ivermectin Trials Were Designed to Fail

The use of ivermectin to treat COVID-19 is an ongoing debate. The central conflict is that while many doctors have reported success in using ivermectin, some studies published in major journals suggest it is in fact ineffective.

Even as the FDA recently has been removing misinformation it posted about ivermectin, the agency has maintained its original position regarding its effectiveness, namely that there isn’t evidence.

People who trust ivermectin claim the studies showing ineffectiveness are fraudulent, while people who are skeptical of its use for treating COVID-19 view it as an anti-science conspiracy theory.

As a professional with decades of research experience conducting dozens of clinical trials on antiviral drugs, I decided to dive deep into the studies purporting ivermectin’s ineffectiveness. What I found shocked me.

Legacy Media Report Ineffectiveness

Numerous preclinical studies have found that ivermectin has a broad range of effects on COVID-19, spanning from its initial impact on viral infection to the pathological changes the virus causes in our bodies.

Ivermectin inhibits the entire life cycle of SARS-CoV-2 in our cells from attachment, spreading, and replication (1, 2, 3).

Moreover, ivermectin is anti-inflammatory and organ-protective, which can potentially protect against severe COVID-related lung damage and acute respiratory distress syndrome, heart-related complications, and blood clots.

Ivermectin exceeds the approved antiviral effects of other medications, including Paxlovid, molnupiravir and remdesivir, which only target the virus and lack anti-inflammatory and organ-protective effects. Monoclonal antibodies have to be constructed specific to each variant and are very expensive.

In the pharmaceutical industry, clinical trials are commonly used to evaluate the efficacy and safety of drugs once their mechanism is demonstrated. There are two types of clinical trials: observational and interventional.

Observational studies are often conducted by doctors in clinical, hospital, or community settings to analyze the effects of drugs. The data is collected as observed in clinical practice with minimal interference.

Many doctors have observed the positive effects of ivermectin on their patients. An observational study conducted in Brazil with over 88,000 patients showed that ivermectin reduced the rates of infection, mortality, and hospitalization by 49 percent, 92 percent, and 100 percent, respectively, compared to nonusers.

Pharmaceutical companies are required to conduct interventional studies that meet the approval standards set by the U.S. Food and Drug Administration (FDA). Randomized clinical trials (RCTs) are frequently utilized to fulfill these requirements. This type of study is considered the gold standard and involves randomly assigning one group of patients to receive a specific drug while the other group does not receive it, then comparing the outcomes.

Legally and medically, ivermectin can be prescribed off-label to treat COVID-19 since it has already been approved by the FDA for other diseases.

Although many doctors have observed the positive effects of ivermectin in treating their patients, the media has specifically highlighted data from a few selected RCTs that have concluded it is ineffective in treating COVID-19.

However, some critical aspects were overlooked in those RCTs.

Improper Dosing

A drug’s therapeutic effects can only be observed when it reaches the appropriate concentration in the body and remains there for a few days, allowing sufficient time to work.

Improper dosing was a major issue in the RCTs that found ivermectin ineffective.

According to Merck’s package insert for ivermectin (brand name Stromectol), a single oral dose of 0.2 mg/kg was officially recommended for treating parasitic diseases. There is no official dose for COVID-19.

The recommended dosage of ivermectin for treating COVID-19 is based on the clinical experiences of physicians worldwide.

The Front Line COVID-19 Critical Care Alliance (FLCCC) guidelines recommend taking 0.4 mg/kg of ivermectin daily, immediately after exposure. Once a cumulative dose in excess of 200 mg is reached, the risk of acquiring COVID-19 has been shown to be nearly zero.

It is common for a drug with multiple indications to have different doses for different diseases.

Moreover, ivermectin should be given with food, as it has a 2.6-fold higher bioavailability when taken with food rather than on an empty stomach. The Merck package insert (revised May 2022) also supports this and states: “Administration of 30 mg ivermectin following a high-fat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration of 30 mg ivermectin in the fasted state.”

FLCCC guidelines also recommend taking ivermectin “with or just following a meal for greater absorption.”

Yet this important dosing information is not reflected in the commonly used drug prescribing resource known as the Prescribers’ Digital Reference or PDR which states: “Take the number of tablets your doctor has prescribed all at the same time with water on an empty stomach. Do not eat any food within two hours before or after taking the tablets.”

So if a person takes the dose while fasting, they are getting only 40 percent of the recommended dose. For patients with a higher body weight, the effects of underdosing could be even more significant.

RCT Studies Used Inappropriate Dosing

In the most recent PRINCIPLE trial published in March, ivermectin was used at 0.3 mg/kg for only three days. Moreover, it was designed to dose the ivermectin without food: “Participants were advised not to eat two hours before or after taking ivermectin.”

In another RCT ACTIV-6 published in JAMA in October 2022, ivermectin was dosed in a fasting status, as the protocol stated: “Ivermectin should be taken on an empty stomach with water (30 minutes before a meal or 2 hours after a meal).”

Ivermectin was reported as dosed at 0.4 mg/kg for three days—a much shorter time period than it should be. However, in the protocol Table 4 in Appendix 16.3.3, the precise dosing was as low as 0.269 mg/kg, and 0.4 mg/kg is actually only the upper dose limit—not the real dose.

According to the worldwide recognized study guideline ICH Good Clinical Practice, clinical trials must adhere to ethical principles. Failure to do so would be considered study misconduct or fraud and would violate the principle of integrity.

Another JAMA study published in March 2021 repeated the same mistake in mild COVID-19 patients by suggesting they take 0.3 mg/kg for five days on an empty stomach.

An RCT study known as TOGETHER, published in March 2022 in the New England Journal of Medicine, underdosed ivermectin with 0.4 mg/kg for only three days and did not mention dosing with food.

Nevertheless, even at this low dose, the ivermectin still reduced hospitalization rates, death, and the need for mechanical ventilation compared to a placebo.

Clinical Improvement Despite Underdosing

It is inappropriate to conclude that ivermectin was ineffective based on these RCT studies with major design flaws.

Despite the poor study design, ivermectin showed clinical benefits and saved lives.

In the PRINCIPLE study, self-reported recovery was shorter in the ivermectin group than usual care, with a median decrease of 2.06 days. The statistical analysis showed that it met the predefined superiority criteria.

Furthermore, the analysis showed that ivermectin effectively reduced COVID-19-related hospitalizations and deaths. Only 1.6 percent of 2,157 patients in the ivermectin group experienced hospitalizations or deaths, compared to 4.4 percent of 3,256 patients in the usual care group.

Even a low dose of ivermectin has demonstrated the potential to save lives. However, the authors concluded, “Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes.”

Meanwhile, the report’s appendix includes dozens of recorded clinical benefits in patients treated with ivermectin, such as the time it took to alleviate all symptoms, general unwellness, muscle aches, and headaches. The improvement of symptoms was also sustained, and the severity was reduced. Surprisingly, the source PDF was removed from the website during the writing of this article.

There are additional examples. Although the previously mentioned 2021 JAMA study underdosed patients, treatment with ivermectin reduced recovery time by two days. In the ACTIV-6 study, only one venous blood clot event was reported in 817 ivermectin-treated patients, compared to five events in 774 placebo-treated patients.

Statistical Failures

It is important to note that the definition of treatment effects in an RCT can differ from those discussed in real-life observational studies.

Sometimes, even if the results of a clinical trial demonstrate a clear effect, the conclusion may still be interpreted as ineffective due to the statistical definition of effectiveness.

Interpreting statistics can be challenging as they usually involve complicated mathematical models and numerical data that can be manipulated to support a specific agenda. Nevertheless, for the purpose of this discussion, let’s presume that all research is carried out conscientiously and without manipulative intent.

In a randomized, double-blind, placebo-controlled clinical trial with mild to moderate COVID-19 patients, none of the 55 patients in the ivermectin group died, whereas four of 57 in the placebo group died. This resulted in a comparison of zero percent versus 7 percent. Moreover, only 1.8 percent of ivermectin-treated patients needed invasive ventilation compared to 8.8 percent in the placebo group.

In other words, ivermectin reduced the risk of death by 100 percent and the need for ventilators by 80 percent.

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