Alpha-1 Adrenergic Receptor Antagonism to Prevent Cytokine Storm Syndrome and Severe COVID-19: A Pragmatic Randomized, Double-Blind Phase 2 Study Comparing the Efficacy of Doxazosin vs. Placebo for SARS-CoV-2 infection.

Protocol No: SLS-JHM-02

Title: Alpha-1 Adrenergic Receptor Antagonism to Prevent Cytokine Storm Syndrome and Severe COVID-19: A Pragmatic Randomized, Double-Blind Phase 2 Study Comparing the Efficacy of  Doxazosin vs. Placebo for SARS-CoV-2 infection.

Study Sponsor: Johns Hopkins University, School of Medicine

Study Type: Interventional, multicentric

Study sites: 10 sites

Total number of subjects: 300

Study Arms: 2 (Arm 1: Doxazosin and standard of care, Arm 2: Placebo and standard of care)

Study Population:

1. Subjects must be 45 years of age or older 2. Subjects have symptoms of COVID-19 and have Mild disease 3. Subjects have an approved positive test for SARS-CoV-2 and symptom onset within 6 days of start of treatment 4. Subject must have indicated interest in participating in the clinical trial and provided informed consent to participate in the CALM-COVID trial specifically.

Study Duration:

June 01, 2021 to December 31, 2022. The total duration of treatment with doxazosin will be 2 weeks (14 days) from initial dose or until deterioration of COVID-19 symptoms to Moderate/Severe, whichever comes first. Patients will be followed by tele-consultation for 14 days after starting treatment if in home isolation or, if hospitalized, until the end of hospitalization, whichever comes later, and also post completion at 28 days, 3 months, and 6 months.

Study Design:

This randomized, double-blind, placebo-controlled phase 2 trial will assess the efficacy of doxazosin (Arm 1) vs. placebo (Arm 2) to prevent Moderate/Severe disease in patients with positive SARS-CoV-2 testing who have Mild disease. The Site Investigator and Site Management Team will engage incoming patients with symptoms of COVID-19, screen for eligibility, obtain informed consent, and – if applicable – enroll patients according to the inclusion criteria and exclusion criteria for the study population (as defined in sections 3.1 and 3.2, respectively). Adults between 45 and 85 years of age who meet these criteria and provide informed consent may participate. A total of 300 eligible subjects will be randomized in a 1:1 ratio to receive either doxazosin 1 mg by mouth daily (with dose escalation to 4 mg daily as defined in section 2.3.6) plus standard of care as compared to placebo plus standard of care for the duration of the study. Drug or placebo will be provided to the patient in accordance with their randomization status. Patients will be followed longitudinally via regular tele-consultations conducted by the Site Management Team.

Randomization:

Randomization will be done by block randomization in random blocks of 4 and 6. The following will be assessed in all subjects after approved SARS-CoV-2 testing that resulted positive:

â— Safety and efficacy: Scheduled tele-consultation evaluations at day 0 (baseline) and from day 1 until day 14. Additional tele-consultation check-ins may be triggered based on symptoms and/or blood pressure measurements as outlined in section 4.5. All assessments will be performed by tele-consultations or in person by the Site

Management Team.

Primary Efficacy Objective:

Evaluate the efficacy of treatment with doxazosin (given for at least 2 doses) versus placebo to prevent deterioration of COVID-19 to Moderate/Severe disease in subjects testing positive for SARS-CoV-2 and presenting with Mild disease at the time of enrollment.

Secondary Objectives:

1. Assessing shift in the ordinal scale of clinical status (scores 1-9) to less severe disease 3 among those randomized to doxazosin plus standard of care as compared to placebo plus standard of care. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day [Time Frame: Baseline (day 0), evaluated up to day 14 or until discharge from hospitalization whichever is later, and day 28]. 2. Time to meaningful recovery [Time Frame: 14 days and day 28]: Clinical ordinal scale progression improved by one category and sustained for at least 2 consecutive days. 3. COVID-19 symptom severity based on patient-reported Daily Symptom Scale [Time 4 Frame: Baseline (day 0), evaluated for 14 days or until deterioration of COVID-19 symptoms to Moderate/Severe which is earlier and day 28]: Maximum numeric score of COVID-19 symptoms defined by adding the symptom score for each individual symptom of the symptom scale from prior to starting treatment (day 0) until the end of the study (day 14) and on day 28. 4. Time to resolution of COVID-19 symptoms [Time Frame: Baseline (day 0), evaluated for 14 days or until deterioration of COVID-19 symptoms to Moderate/Severe whichever is earlier and day 28]: Difference in time to resolution of COVID-19 symptoms for each individual symptom of the symptom scale between the treatment arm and the control arm. Resolution of a symptom is defined as when a symptom previously scored ≥1 on the scale is scored as 0 for at least 2 consecutive days. 5. Frequency and severity of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) [Time 5 Frame: months 3 and 6]: PASC or long COVID-19 will be assessed in frequency and severity using a PASC questionnaire to measure functional status of the study subjects from the two arms.