Evaluating the Safety and Efficacy of PNMR as Treatment for Long COVID

Phase II, Proof of Concept, Open-Label, Randomized-Controlled Trial Evaluating the Efficacy and Safety of PARAGON Novel Metabolic Regulator Formula (PNMR) in the Management of Long COVID

This will be a six-week, randomized, parallel, two group, open-label design. Patients will be treated with Paragon Novel Metabolic Regulator (PNMR) + standard of care (SOC) or SOC alone for 6 weeks for the treatment of Long COVID. All patients will also be provided with with Dietary & Lifestyle recommendations specifically designed to enhance immune system function and reduce viral proliferation.

Patients will be assessed in the clinic at screening/baseline, 3 and 6 weeks while on treatment, and by telephone at 4 weeks post-treatment.

All patients will be asked to fill in a diary to record their daily treatment dosage when being treated with PNMR + SOC or with SOC alone. Primary objective: To evaluate the efficacy of PNMR + (SOC) vs. SOC in the treatment and management of patients with long COVID.

Because:

• A) ~ 55% of patients have healed from long COVID, but have only been cured via a gradual, natural restoration of that patient's previously depleted endogenous mitochondrial and immune system function, and that
• B) a fully-functioning immune system comprises the only known comprehensive system of cellular-driven mechanisms which make it capable of: neutralizing almost any pathogen(s); metabolizing and clearing systemic necrotic and fibrotic tissues occurring from injury; then healing those tissues and organs; and restoring normal signaling within the body's cells; to reverse as many as 300 different chronic symptoms that can affect a patient with long COVID,

And because metabolic research shows:

• that long COVID patients are depleted of key nutrient metabolites enabling immune system and mitochondrial function, thereby making them unable to mount a properly regulated immune response,
• and that COVID-19 and long COVID patients are depleted of specific amino acids and other metabolites compared to those fully recovered from COVID-19, whose metabolite levels have recovered to normal levels,
• therefore: without the necessary balance of metabolites to rapidly and fully activate that patient's mitochondrial and immune system metabolism, many COVID-19 and long COVID patients cannot fully recover.
• Further metabolic research also shows:
• human cell systems maintain significant cellular storage levels of a wide range of essential nutrient metabolites supporting enzymes driving mitochondrial and immune system function and healing, all of which can be depleted by serious illness, and/or excessive exposure to any other toxic pathogens (whether industrial or environmental contaminants, pesticides, excess exposure to blue light, other harmful radiation, alcohol, drugs, certain Rx, lack of sleep, exercise stress, work stress, processed foods, refined sugars, nutritional imbalances, malnutrition, etc., and/or any combinations of the above), and that,
• Affected cell systems and components (including the cytosol, mitochondria, associated metabolic pathways within cells, the lymphatic system, white blood cells, antibodies, antimicrobial peptides, defensins, and other compounds) require specific concentrations and ratios of specific amino and fatty acids - and corresponding concentrations and ratios of a wide range of specific metabolites - that together enable their continuous enzyme-driven metabolism within those cell systems.
• This is possible because those enzyme systems are operating at speeds up to a million X faster than typical random chemical reaction. Further, the 1500-4000 interdependent enzymes found within each cell type all work together to supply byproduct from one enzyme reaction as input substrate to another in high-speed harmony to drive the metabolism of each cell type.
• Therefore, anything disrupting the inflow of enzyme activators or substrates necessarily negatively impacts the flow of enzyme chemical byproduct output, and can seriously disrupt or dysregulate the entire enzyme matrix within the cell, and various organs, tissues and/or other physiological systems affected.
• And therefore, when the body is subjected to excess pathogenic microbes or any other type of toxin listed above, the body's mitochondria and immune system cells have to work longer and harder to neutralize pathogens, detoxify and rebuild tissues,
• and therefore, to maintain homeostasis, the body must consume higher levels of essential nutrient metabolites and other co-enzyme factors supporting this critical enzyme activity. If any of the essential nutrient metabolites supporting that enzyme activity is deficient or depleted, the proteome (net sum of enzymes in the body) supporting mitochondrial and immune system function can be significantly and negatively impacted.
• Therefore: the PNMR was specifically designed to replenish those intracellular reserves of nutrient metabolites supporting this comprehensive endogenous mitochondrial and immune system function described above:
• The PNMR capsules (provided in 1 - 6 packets per day, based on a patient's individual deficiency symptoms and needs) are designed to quickly restore optimum and balanced intracellular storage levels of those essential metabolites driving the balanced intracellular enzyme activity and metabolism required to maintain mitochondrial and immune system function, healing, and homeostatic regulation.
• Further, this specific trial design is somewhat unusual - and is necessary - because there has never been a disease in modern human history like long COVID:
• which is continuing to have unprecedented detrimental effects on human health and all national economies around the world,
• is being driven by variants at least 12 X more infectious than the original Wuhan virus,
• which results in viral persistence within tissues in those with even mild long COVID, which continues to mutate new COVID-19 variants in the entire global population with long COVID (and those with acute COVID-19), with the mutation rate measured to be ~ 1 mutation every 5 days in one long COVID patient in isolation in Germany,
• with research showing repeat COVID-19 infections increase the probability of developing long COVID,
• which is causing long COVID to spread quickly to all parts of the world, and is now estimated to have affected as many as 36% of all people who have had COVID-19, with just under half who contracted it who are not healing.
• with no simple, approved testing method to quickly diagnose long COVID,
• and based on Nov 2024 research from Harvard/Mass General Brigham (which used AI to help identify signs of long COVID, track symptom manifestation over time, and eliminate alternative explanations for 300,000 patients' symptoms) the data suggests that 22.8% of that population experience long COVID symptoms, a figure that may paint a more realistic picture of the pandemic's long-term toll and global reach.
• And as most patients infected with long COVID globally have milder symptoms, and are not aware of their infection and its potential to cause serious clotting disorders, as well as other serious complications, or that they are actively mutating new COVID-19 variants - some which may mutate to a COVID-19 variant of concern (VOC) via convergent evolution,
• and therefore, if the PNMR is proven to be successful reversing long COVID disease, as well as the mutation of new COVID variant mutations within such long COVID patients,
• and therefore, if the world's goal is to reduce the current global levels of COVID-19 VOC transmission - then it's estimated that 75-85% of the 20-35% of the global population with long COVID will need to receive the PNMR treatment, to achieve the global herd immunity necessary to finally eradicate 75-85% of long COVID globally, which would thereby eradicate the vast majority of the rampant current mutation and transmission of new COVID-19 VOC from within long COVID patients globally, and thereby, very dramatically reduce global COVID-19 VOC transmission. When 75% - 85% of the world's population are immune to COVID viral infection, it may be possible to finally eradicate the transmission of COVID-19 virus, and ultimately eradicate the COVID-19 strains of virus.
• Therefore, the critical importance of all factors above makes it equally important to design a PNMR Phase II trial that:
• 1) clearly demonstrates the PNMR is essential to a rapid cure of chronic, systemic long COVID disease and tissue damage,
• 2) while also demonstrating the combination of confounding dietary & lifestyle factors that enable an even more rapid reversal - to demonstrate to the world the most effective use of this new class of medicine to most rapidly reverse disease.

This is why the Dietary and Lifestyle Recommendations, which have been demonstrated by peer-reviewed research to benefit those with chronic viral infections causing mitochondrial & immune system dysfunction, are being provided to both the control & treatment groups in the trial. This gives both patient groups in the trial potential mechanisms for healing.

And while initial medical case studies indicate the ingredients in the PNMR potentially represent a powerful curative treatment for the chronic tissue & organ damage many long COVID patients have, effective dietary & lifestyle measures are critical to further accelerating this healing process.

• Further, because there is no treatment yet approved for long COVID, there is no approved standard of care (SOC) for long COVID:
• therefore, the trial's design, and patient evaluations performed at Day 0 upon screening, Day 21 (end of week 3) midway through treatment, and at Day 42 (end of week 6) upon termination of treatment, allow the evaluation of 3 distinct levels of treatment on a long COVID patient's physical and mental function:
• A) SOC (no treatment) prior to the trial: On Day 0, upon screening, up to 82 patients who've not received any long COVID treatment will be evaluated, establishing a baseline for patients without treatment,
• Then upon evaluation, those up to 82 patients will then be randomly split into 2 groups:
• B) Group 1 of up to 41 patients will receive PNMR treatment + SOC + Dietary & Lifestyle Recommendations and be evaluated at the end of 3 & 6 weeks, establishing potential for improvement with PNMR + Dietary and Lifestyle Recommendations,
• C) Group 2 of up to 41 patients will receive SOC + Dietary & Lifestyle Recommendations and be evaluated at 3 & 6 weeks, establishing potential for improvement with Dietary & Lifestyle Recommendations alone.
• Therefore, this trial design will evaluate whether:
• the group receiving the Dietary and Lifestyle Recommendations alone sees some improvement over no treatment, or SOC alone,
• the group receiving the PNMR + the Dietary and Lifestyle Recommendations sees an even greater improvement over no treatment, or SOC alone.

Inclusion Criteria: The patient must meet all the following criteria to be enrolled in the study:

1. ≥19 years of age.

2. Negative COVID-19 test for a minimum of four (4) weeks prior to enrollment in the study.

3. Confirmed COVID-19 diagnosis by Polymerase chain reaction (PCR) test, antibody test, or clinical diagnosis more than four (4) weeks prior to enrollment in the study.

4. Long COVID diagnosis according to the WHO criteria, specifically the continuation or development of new symptoms three months after the initial SARS-COV-2 infection, with these symptoms lasting for more than two months with no other explanation.

5. For women of childbearing potential involved in any sexual intercourse that could lead to pregnancy: Negative pregnancy test and willingness to use contraceptive (consistent with local regulations) during the study period. Approved contraceptive methods include contraceptive pills or patches, hormonal implants, intrauterine device (IUD), diaphragm or cervical cap with spermicide, and condos with spermicide.

   Note: If participant become pregnant during the study, they must stop taking the study products immediately and inform the study investigator.

6. Patient agrees to stop taking any over the counter supplements, vitamins, or natural products as well as any of the prohibited medications during the study.

7. Patient agrees not to use medications affecting directly (or potentially) the objectives of the study such as fatigue and cognitive function during the study.

8. Willing to adhere to the study diet and exercise recommendations to the best of the patient's ability.

9. Willing to complete the 6MWT.

10. Willing to complete the patient self-administered questionnaires and diaries.

11. Signed informed consent form by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representatives.

Exclusion Criteria:

1. Subject is a female who is breastfeeding or pregnant or trying to conceive.

2. Subject with a vegetarian diet or not able to follow the dietary guidelines.

3. Known hypersensitivity to PNMR or its ingredients.

4. Participating in other drug clinical trials (participation in COVID-19 antiviral trials may be permitted if approved by sponsor).

5. Any condition that in the opinion of the investigator participation in the trial increases the risk to the patient.

6. 4 weeks or more of consecutive daily supplement use of 5000 IUs Vitamin D / day and/or 50mg Zinc (without copper) / day within 4 weeks of Day 0.

7. Use of any medications or treatments for which treatment with PNMR is counter-indicated.

8. Subject is not able to swallow a larger number of capsules.

9. Any condition that in the opinion of the investigator would confound the study results or would prevent the patient to complete the study.

10. Any patient for whom vitamin D3 (cholecalciferol) is contraindicated per the following patient situations:

    1. Hypersensitivity to vitamin D, any of its analogues and derivatives or to any ingredient in the formulation
    2. Hypercalcemia and/or hypercalciuria
    3. Nephrolithiasis (renal calculi)
    4. Severe renal impairment (eGFR <30)
    5. Malabsorption syndrome
    6. Abnormal sensitivity to the toxic effects of vitamin D
    7. Sarcoidosis
    8. Hypervitaminosis D