Investigation of Safety and Efficacy of CARDIO Softgels in Former Smokers and Asthma Patients With COVID-19 Infection
کلید واژه ها
خلاصه
شرح
SARS-CoV-2, a plus-sense single-stranded RNA virus, is the etiologic agent of COVID-19. After an incubation period, which typically lasts for 5-6 days, COVID-19 patients present with a mild illness that lasts for a few days. Common symptoms are reminiscent of the flu, and include fever, dry cough and dyspnea. A large percentage of patients resolve the infection whereas others progress onto adult respiratory distress syndrome (ARDS) which impedes gas exchange between the alveolar space and the bloodstream and creates the need for assisted respiration. Acute eosinophilic pneumonia (AEP) is an acute respiratory illness of varying severity that includes presentation as ARDS with fatal outcomes. AEP pathology results from an uncontrolled inflammatory response characterized by excessive recruitment of lung eosinophils and production of inflammatory cytokines. Former smokers are at a particularly high risk for developing ARDS and constitute a disproportionately higher burden for scarce intensive care unit (ICU) beds. At first glance, several studies from China and the US CDC show a low smoker prevalence among hospitalized COVID-19 patients. However, parsing of the smoker subset for example from the CDC, shows that former smokers actually constitute a significantly higher percentage of patients moving from "Hospitalized non-ICU" to "Hospitalized ICU" status (73%) as compared to other single underlying condition (44%) patients, and a much higher percentage than Current Smokers (22%). Possible explanations for former smokers being at much greater risk of ARDS disease progression than current smokers include:
1. The continued presence of nicotine in current smokers and its known anti-inflammatory protection
2. Ongoing smoking down-regulates angiotensin converting enzyme 2 (ACE2), which the SARS-CoV-2 uses to invade host cells.
3. In inflamed airways due to allergy or infection, cigarette smoke significantly attenuates inflammatory eosinophilia, eosinophil trafficking and activation of B cells in the bronchoalveolar lavage.
Changes in smoking pattern triggers interstitial injury patterns mediated via recruitment and inappropriate persistence of myeloid and other immune cells, including eosinophils, especially after cessation of smoking. The adjacent image shows a Computed Tomographic (CT) of the lungs of a former smoker 2 weeks after resuming smoking following several years of abstinence. It is surprisingly similar in presenting the same bilateral patchy ground-glass opacities seen in COVID-19 patients.
Uncontrolled eosinophil production in lung epithelial cells plays a critical role in the destruction of the respiratory epithelium and rapid development of ARDS, particularly in former smoker patients. The pulmonary inflammation leads to cardiac impairment and intravascular coagulation, kidney insufficiency and liver damage. The scope, intensity and rapidity of the host COVID-19 response in former smoker patients strongly advocates for a therapeutic strategy that aims to prevent rather than reverse progression from mild to severe disease. It is estimated that between 5-10% of asthma patients do not respond to steroid-based therapies and require higher doses of medication to achieve control of their disease, or have asthma exacerbations, persistent symptoms and airway obstruction despite greater medication use. These steroid-resistant asthmatics typically have greater morbidity and disproportionately require 50-80% of asthma-related health care costs. Similar to former smoker patients, eosinophil presence in the lung is believed to be a major pro-inflammatory effector cell in the pathogenesis of asthma. Further, in the United States, chronic lung disease (primarily asthma) was the second most prevalent underlying condition in those admitted to hospital for COVID-19 infection in adults ages 18-49.
CARDIO is a safe, natural, salmon oil based, eosinophil effector function (EEF) reducing, softgel formulation. Fish oil, inclusive of salmon oil, or marine-derived omega-3 supplements have been established as cardioprotective. CARDIO has been studied in human clinical studies for the treatment of cardiovascular disease, and as an antioxidant, with an excellent safety record. CARDIO has demonstrated therapeutic potential for the treatment of allergic and inflammatory conditions, particularly those involving eosinophil effector functions. Specifically, CARDIO at 100 ug/ml inhibited eosinophil response to chemoattractant CCL11 in a Shape Change assay; inhibited eosinophil response to chemoattractant CCL11 in an integrin (CD11b) surface upregulation assay; and significantly enhanced apoptosis, in eosinophils sourced from immuno-modulated individuals.
In vitro and animal dosing studies have been completed for therapeutic dose determination for an accelerated Phase 2 trial application. It is hypothesized that CARDIO may reduce morbidity and mortality in former smoker patients by protecting respiratory epithelium and alveolar pneumocytes from eosinophil-mediated damage. In light of the mechanism of action outlined above, it is possible that CARDIO could be used as a therapeutic for COVID-19, particularly in former smoker patients with mild illness, with the goal of preventing progression into severe disease.
The population being investigated are hospitalized former smokers or steroid-resistant asthmatics diagnosed with mild to moderate respiratory distress due to COVID-19. The former smoker definition is from the National Health Interview Survey from the Center for Disease Control (CDC). Though the age and BMI have a reasonably wide range to facilitate recruitment, the exclusions in place provide the required guidance measures to ensure patient safety and address associated comorbidities. Individuals most prone to SARS-CoV-2 and hospitalization as a result of SARS-CoV-2 infection are those with co-morbidities such as older age, cancer, cardiovascular disease and hypertension, type I or II diabetes, chronic obstructive pulmonary disease, obesity and on immunosuppressive treatments. Therefore, participants with the above co-morbidities will comprise the population of interest. However, in this context, each participant will be assessed on a case-by-case basis by the Qualified Investigator to ensure all inclusions and none of the exclusions are met, and that the safety of their participation in the study is critically evaluated. The requirement of mild to moderate respiratory disease is determined by applying the National Early Warning Score (NEWS) of ≤6, which is indicative of not requiring critical care. The NEWS score is a standardized tool developed by the Royal College of Physicians to assess disease severity and monitoring of patients in hospital. An aggregate score of respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness and temperature and the score is increased if supplemental oxygen is required. The use of these physiological screening tools is relevant to the former smoker and steroid-resistant asthma COVID-19 population of interest as this tool addresses signs and symptoms of COVID-19. The safety of patients will be assessed at each assessment day, a Data and Safety Monitoring Board will be established, and an interim analysis is planned to guide safe continuation of the study.
The objectives of this randomized, open-label, parallel study is to investigate the safety and efficacy of CARDIO plus best standard-of-care in reducing the need for mechanical respiratory support, alleviating respiratory symptoms and reducing mortality in hospitalized former smoker and steroid-resistant asthma patients with COVID-19 infection.
تاریخ
| آخرین تأیید شده: | 06/30/2020 |
| اولین ارسال: | 07/07/2020 |
| ثبت نام تخمینی ارسال شد: | 07/08/2020 |
| اولین ارسال: | 07/09/2020 |
| آخرین بروزرسانی ارسال شده: | 07/08/2020 |
| آخرین به روزرسانی ارسال شده: | 07/09/2020 |
| تاریخ شروع مطالعه واقعی: | 08/30/2020 |
| تاریخ تخمین اولیه اولیه: | 08/30/2021 |
| تاریخ برآورد مطالعه: | 08/30/2021 |
شرایط یا بیماری
مداخله / درمان
Dietary Supplement: Best Standard of Care + CARDIO
Dietary Supplement: Best Standard of Care
فاز
گروههای بازو
| بازو | مداخله / درمان |
|---|---|
| Active Comparator: Best Standard of Care + CARDIO Combination of CARDIO and Best Standard of Care | Dietary Supplement: Best Standard of Care + CARDIO Combination of dietary supplement with clinical care |
| Placebo Comparator: Best Standard of Care Placebo and Best Standard of Care | Dietary Supplement: Best Standard of Care Combination of placebo with clinical care |
معیارهای صلاحیت
| سنین واجد شرایط تحصیل | 18 Years به 18 Years |
| جنسیت واجد شرایط مطالعه | All |
| داوطلبان سالم را می پذیرد | آره |
| شاخص | Inclusion Criteria: 1. Former smoker, defined as anyone who has stopped smoking for 3 months prior to enrollment and who had smoked at least 100 cigarettes in their lifetime and/or patients with steroid-resistant asthma 2. Patients with signs and symptoms corresponding to COVID-19 viral infection admitted to hospital and who have been initiated with BSC treatment 3. Secondary laboratory confirmation of COVID-19 infection by reverse-transcription polymerase chain reaction (RT-PCR) or comparable methodology used by the hospital from any diagnostic sampling - source for analysis and recovery 4. Mild to moderate disease (National Early Warning Score of ≤ 6) 5. Males and females between 18 and 75 years of age, inclusive 6. BMI between 18.5 to 34.9 kg/m2, inclusive 7. Absolute neutrophil count (ANC) ≥ 0.6 ×109 cells/L 8. Female patient is not of child-bearing potential, defined as females who have undergone a sterilization procedure (e.g. hysterectomy, bilateral oophorectomy, bilateral tubal ligation, complete endometrial ablation) or have been post-menopausal for at least 1 year prior to screening Or, Females of child-bearing potential must have a negative baseline urine pregnancy test and agree to use a medically approved method of birth control for the duration of the study. All hormonal birth control must have been in use for a minimum of three months. Acceptable methods of birth control include: - Hormonal contraceptives including oral contraceptives, hormone birth control patch (Ortho Evra), vaginal contraceptive ring (NuvaRing), injectable contraceptives (Depo-Provera, Lunelle), or hormone implant (Norplant System) - Double-barrier method - Intrauterine devices - Non-heterosexual lifestyle or agrees to use contraception if planning on changing to heterosexual partner(s) - Vasectomy of partner at least 6 months prior to screening 9. Willingness to complete assessments, questionnaires and records associated with the study 10. Provided voluntary, written, informed consent to participate in the study. Exclusion Criteria: 1. Women who are pregnant, breast feeding, or planning to become pregnant during the study 2. Inability to take medications orally 3. Individuals with a known fish allergy or hypersensitivity reaction 4. Current use of antiretroviral agents 5. Individuals with requirement of supplemental oxygen to maintain oxygen saturations >94% 6. Individuals with uncontrolled hypotension (systolic blood pressure < 90 mmHg) or need for vasopressor/inotropic medication 7. Individuals with renal impairment (increase of creatinine by 50% from baseline, glomerular filtration rate reduction by >25% from baseline or urine output of <0.5 ml/kg for 6 hours) 8. Individuals with gastrointestinal symptoms that require hospitalization (e.g. severe nausea, vomiting, diarrhea or/and abdominal pain) 9. Any other condition, that, in the opinion of the QI, may adversely affect the patient's ability to complete the study or its measures or pose significant risk to the patient |
نتیجه
اقدامات اولیه
1. Oxygenation requirements during hospital stay (oxygen saturation rates) [On day of discharge if earlier than 28 days from baseline, then 28 days from baseline]
2. Oxygenation requirements during hospital stay (supplemental Oxygen) [On day of discharge if earlier than 28 days from baseline, then 28 days from baseline]
3. Oxygenation requirements during hospital stay (ventilator support) [On day of discharge if earlier than 28 days from baseline, then 28 days from baseline]
اقدامات ثانویه
1. Clinical improvement [Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
2. Clinical status [Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
3. Serial chest CT or X-ray findings [Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
4. Time to clinical recovery [Day 28 from baseline or day of discharge]
5. Time to improvement in oxygenation for at least 48 hours [Day 28 from baseline or day of discharge]
6. Hospitalization period [Day 28 from baseline or day of discharge]
7. Amount of time on Ventilator [Day 28 from baseline or day of discharge]
8. Intensive Care stay [Day 28 from baseline or day of discharge]
9. Quality of life (QoL) [Day1, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
10. All-cause mortality [Day 28 from baseline or day of discharge]
11. Temperature measurements [Day 28 from baseline or day of discharge]
12. Oxygen saturation measurements [Day 28 from baseline or day of discharge]
13. COVID-19 QoL measurements [Day 28 from baseline or day of discharge]
سایر اقدامات نتیجه
1. Adverse Events [During 15 days of supplementation or until day of discharge and during home follow up]
2. Blood pressure [From baseline to 28 days thereafter]
3. Heart rate [Everyday From baseline to 28 days thereafter]
4. Abnormality in laboratory tests [Day 28 from baseline or day of discharge]
5. Body mass Index (BMI) [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
6. Complete blood count (CBC) [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
7. Aspartate transaminase (AST) [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
8. Alanine transaminase (ALT) [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
9. Alkaline phosphatase (ALP) [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
10. Bilirubin [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
11. Sodium ion [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
12. Potassium ion [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
13. Chloride ion [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
14. Creatinine [Daily From baseline to 28 days thereafter]
15. eGFR [Daily From baseline to 28 days thereafter]
16. HbA1c [Daily From baseline to 28 days thereafter]
17. Glucose [Day 0, Day 10, Day 14, from baseline, Day 28 from baseline or day of discharge]
18. C-Reactive protein (CRP) [Baseline only]
