Evaluating the Impact of EnteraGam In People With COVID-19

Background: Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), emerged as a potentially life-threatening disease in Wuhan, China, at the end of 2019. Since then, it has spread to almost 200 countries and infection rates are rapidly accelerating. Overactivation of T cells resulting in immune dysfunction, dysfunction of the renin angiotensin system, and antibody-dependent enhancement are thought to contribute to the cytokine storm that results in acute respiratory distress syndrome (ARDS), culminating in death. In addition to causing respiratory symptoms, SARS-CoV-2 can cause diarrhea and has been isolated from the stool. SARS-CoV-2 binds to Angiotensin-converting enzyme 2 (ACE2) on lung alveolar type 2 cells, but ACE2 is also expressed in the absorptive enterocytes from the ileum and colon. The diarrhea may be caused by increased intestinal permeability due to binding of these receptors by the SARS-CoV-2. Thus, an intervention to attenuate this cytokine storm may improve clinical outcomes in people with COVID-19. One such intervention is oral administration of serum bovine immunoglobulins, which decreases interleukin-6 (IL-6) levels safely with minimal side effects. Animal and human clinical studies have shown dietary supplementation with oral immunoglobulins improves mucosal immunity, specifically respiratory/pulmonary and GI mucosa, and decreases systemic inflammation, reducing the symptoms and severity of pulmonary inflammation and viral infections. Hypothesis: Dietary supplementation with EnteraGam® will decrease IL-6 levels and prevent disease progression in SARS-CoV-2 infected individuals. Objectives: To evaluate the effectiveness of the oral nutritional therapy EnteraGam® (serum-derived bovine immunoglobulin/protein isolate) to prevent disease progression of COVID-19 and to decrease IL-6 levels as compared to standard of care in subjects with COVID-19. Methods: Randomized open-label clinical study evaluating the effectiveness of EnteraGam® 10.0 g BID (every 12 hours) added to standard of care, as compared to standard of care alone, in subjects with COVID-19.

Subject population: Outpatient and inpatient male and non-pregnant females ≥18 years old, diagnosed with COVID-19 in the emergency department or admitted to the hospital but not requiring invasive mechanical ventilation or in the ICU. Approximately 420 subjects will be randomized (2:1 ratio), 280 in the EnteraGam® arm and 140 in the control (standard of care) arm. Nutritional intervention: ImmunoLin is the active ingredient in EnteraGam®, a medical food developed and marketed by Entera Health in the US since 2013. ImmunoLin is an edible bovine plasma-derived immunoglobulin concentrate developed in 2001 as an immunoglobulin enriched plasma preparation for the human dietary supplement market. ImmunoLin is Generally Regarded as Safe (GRAS) following a letter of no objection from the US FDA in 2008. Physicians have prescribed EnteraGam® for patients with a variety of GI-related conditions. Statistical methodology: Efficacy: Based on per protocol analysis. Subjects lacking an assessment at Week 2 will be included in the analysis using the last available post-baseline data. Three pre-specified secondary analyses will be performed: 1) restricted to subjects with a comorbidity considered a major risk factor for hospitalization and disease severity (diabetes, cardiovascular disease, chronic lung disease, chronic renal disease, immunocompromised state); 2) restricted to age ≥ 50 years; 3) by inpatient only and outpatient only subgroups. Additional analysis of covariance models with adjustment for Baseline characteristics and interactions may be examined in supportive or exploratory analyses. Safety: All safety analyses will be based on all subjects who are randomized to EnteraGam and subsequently receive at least 1 packet of investigational product. Safety assessments will be analyzed by frequency of events/abnormalities for categorical values or summarized using descriptive statistics (mean, standard deviation, median, range, and number of observations).