AT1001 for the Treatment of Long COVID

Phase 2a Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Larazotide (AT1001) for the Treatment of Long COVID in Children and Young Adults

The primary objective of this study is to evaluate the safety and efficacy of Larazotide (AT1001) versus placebo in children and young adults 7 to ≤21 years of age who present with symptoms of Long COVID in the presence of SARS-CoV-2 antigenemia. AT1001 (n=32) or placebo (n=16) will be administered orally four times a day (QID) for 21 days.

This is a Phase 2a randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of AT1001 for use in children and young adults with symptoms of Long COVID in the setting of SARS-CoV-2 antigenemia. Eligible participants (N= 48) will be treated with AT1001 (n= 32) or matching placebo (n= 16) orally four times a day (QID) for 21 days. The study will consist of three phases: I. Baseline Screening Visit After obtaining informed consent and before starting treatment with Larazotide or placebo, an initial study visit will be conducted in person to confirm subject eligibility. Subjects will be asked complete a baseline Symptom Burden Questionnaire™ for Long COVID (SBQ™-LC) to assess organ involvement and symptom severity. During this screening visit, a venous blood sample will be obtained to, among other things, assess for Spike antigenemia and confirm subject eligibility. Additional study procedures occurring during the baseline/screening phase of this study are outlined in Section 6 of this protocol. Candidates who are found not to meet inclusion criteria, or those who meet ≥1 exclusion criteria will be terminated from the study and will therefore not be treated with AT1001 or placebo. II. Treatment phase Patients who meet inclusion criteria as stated in Section 4 of this protocol will be treated with AT1001 or matching placebo at a dose of 250 μg or 500 μg for 21 days. Drug dose will be determined by weight: patients <25.0 kg will receive 250 μg of Larazotide or Placebo, and patients ≥25.0 kg will receive 500 μg of Larazotide or Placebo. Randomization and initial dosing will occur on Visit 1 (Day 1). Visits will then occur on a weekly basis during the treatment phase and will consist of data and/or specimen collection. Visit 2 (Week 1) and Visit 3 (Week 2) will take place virtually and will not involve sample collection. Once the subject has completed 21 days of dosing, Visit 4 (Week 3) will take place in person and require the collection of blood, stool and nasal swabs. Further detail of study procedures during the treatment phase is provided in Section 6 of this protocol. III. Follow-up phase Patients will have two additional virtual follow-up visits after completing their 21-day course of treatment with the study drug. The first follow up visit will occur one week after completing the study drug (ie. at week 4), and the second will occur one month later (ie. at week 8). Week 8 visit will serve as the end of study visit. Biospecimens will not be collected during the follow-up phase. Safety monitoring, including physical examination, vitals, and clinical laboratory testing will be performed during the screening phase and after completion of treatment. Adverse events and concomitant medications will be recorded during the entire study. Total duration of the participants' participation in the study is approximately 8 weeks (with 21 days treatment period). Total duration of the study is projected to be 12-36 months, dependent on enrollment timeline.

Drug arm Placebo arm Subjects <25.0 kg will receive 250 µg of AT1001 or placebo, and subjects ≥25.0 kg will receive 500 µg of AT1001 or placebo

Subjects will receive 250 or 500 µg of Larazotide Acetate orally four times a day (QID) for 21 days. Subjects <25.0 kg will receive 250 µg dose of Larazotide Acetate (AT1001), and subjects ≥25.0 kg will receive 500 µg dose of Larazotide Acetate (AT1001).

Subjects will receive 250 or 500 µg of placebo orally four times a day (QID) for 21 days. Subjects <25.0 kg will receive 250 µg dose of placebo and subjects ≥25.0 kg will receive 500 µg dose of placebo.

AT1001 (Larazotide) is a locally acting, non-systemic, octapeptide inhibitor of the zonulin receptor that has shown efficacy in a large variety of animal models of inflammation. The effectiveness of AT1001 in controlling paracellular permeability as a tight junction regulator has been widely demonstrated in animal models both in vitro and in vivo. In MIS-C, prolonged presence of SARS-CoV-2 in the GI tract leads to release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation (Yonker, et. al. 2021). Five children treated with AT1001 (through an Emergency Investigational New Drug request authorized by the FDA) displayed a decrease in plasma SARS-CoV-2 Spike antigen levels, inflammatory markers, and symptom improvement superior to that achieved with the current standard of treatment for MIS-C (ie. immunoglobulin, systemic steroids) (Yonker, et. al. 2021) (Yonker, et. al. 2022)

Matching placebo will be administered orally four times a day (QID) to participants in the placebo arm.

The primary objective of this study is to evaluate the safety and efficacy of Larazotide (AT1001) versus placebo in children and young adults 7 to ≤21 years of age who present with symptoms of Long COVID in the presence of SARS-CoV-2 antigenemia. Safety will be assessed by means of adverse event monitoring, and efficacy will be evaluated using the Symptom Burden Questionnaire™ for Long COVID (SBQ™-LC) survey (excluding questions regarding reproductive health). The surveys will be used to monitor symptoms, quality of life and limitation of activities before, during and after treatment with Larazotide or Placebo.

The secondary objective of this study is to characterize the inflammatory response observed in children and young adults 7 to ≤21 years of age with Long COVID and SARS-CoV-2 antigenemia. To assess inflammatory responses, blood, stool and nasal epithelial specimens will be obtained at baseline prior to treatment with Larazotide or Placebo, and at completion of the study's treatment phase (21 days). Inflammatory responses will be evaluated by means of antigen testing, cytokine profiling, among others.

Inclusion Criteria: Age 7 to ≤21 years History of SARS-CoV-2 infection, documented by positive PCR and/or antigen test SARS-CoV-2 Antigenemia, defined as any detectable presence of full-length spike protein and/or Spike S1 subunit in plasma Ongoing, worsening, new, or recurrent symptoms present ≥4 weeks after SARS-CoV-2 infection.Symptoms include but are not limited to fatigue, malaise, headache, cognitive impairment, neuropsychiatric symptoms, decreased exercise tolerance, post exertional malaise, dyspnea, cough, chest pain, palpitations, tachycardia, gastrointestinal symptoms, musculoskeletal symptoms, fever, lightheadedness, insomnia and other sleep disturbances, anosmia or dysgeusia, pain, paresthesia, menstrual cycle irregularities, erectile dysfunction. Exclusion Criteria: Age ≤6 years or >22 years at time of enrollment Pregnancy and/or lactation Female participant of childbearing age unwilling to use an acceptable method of birth control for the duration of the study Inability to tolerate drug Unstable medical conditions or significant co-morbid disease that, by the investigator's determination would make the participant unsuitable for enrollment Participation in any other clinical investigation using an experimental drug within 30 days prior to screening Intent to participate in another clinical study while participating in this clinical trial Blood/plasma donation and or blood loss greater than 400 mL within 90 days, or greater than 200 mL within 30 days prior to screening Known hypersensitivity to any of the formulation components of AT1001. Abnormal baseline liver function as indicated by AST or ALT ≥3 times the upper limit of normal (ULN), or direct bilirubin ≥2x ULN for age Abnormal baseline renal function, defined as glomerular filtration rate ≤50 mL/min/1.73m2