Nitric Oxide Nasal Spray (NONS) To Treat and Prevent the Exacerbation of Infection in Individuals With Mild COVID-19
Condition: SARS-CoV-2 Infection
MeSH terms: Infections; COVID-19
Study type: Interventional
Phase: Phase 3

Summary: 
      Primary:

      The primary objective of this study is to evaluate the efficacy of Nitric Oxide Nasal Spray
      combined with standard supportive care compared with standard supportive care alone in adult
      subjects with COVID-19 not requiring hospitalization

      Secondary:

      The secondary objective is to evaluate the safety and tolerability of Nitric Oxide Nasal
      Spray combined with standard supportive care compared with standard supportive care alone in
      adult subjects with COVID-19 not requiring hospitalization.
    

Detailed description: 
      This is a randomized, double-blind, multi-center, parallel arm, clinical study evaluating the
      efficacy and safety of Nitric Oxide Nasal Spray with standard supportive care vs standard
      supportive care alone in patients with COVID-19 not requiring hospitalization.

      306 eligible patients will be randomized in a 1:1 ratio into 2 groups: one group will receive
      Nitric Oxide Nasal Spray (NONS) along with standard supportive care and the control group
      will receive standard supportive care along with placebo of NONS. Standard supportive care
      will be provided in accordance with latest guidelines issued by Ministry of Health and family
      welfare; Government of India. Treatment duration is 7 days (up to Day 8 visit) and the total
      study duration will be maximum for 18 days from randomization (up to Day 19 visit). Viral
      load will be estimated on Day 1 (baseline), Day 2 (post-24 hours of dosing), Day 3 (post 48
      hours of dosing), Day 4 (post 72 hours of dosing) and Day 8. Patients may be detained in a
      facility to facilitate protocol assessments for first 7 days or may be treated at home based
      on investigator discretion. Subjects who are treated at home will visit the study center on
      Day 1, 4, and 8 for study assessments and Day 2 visit (and swab sample collection for visit
      2) will be conducted at home. Day 3 will be laboratory visit only for collection of swab from
      both sides in the nose for RT-PCR. If subjects are not able to visit the study center on any
      of the days, telephonic or video-conference and home based assessments can be conducted.

      On Day 1 (screening and randomization), written informed consent will be obtained from
      subjects with symptoms of COVID-19 and having symptom onset within 48 hours before consent.
      After informed consent, following activities will be conducted: detailed clinical history and
      physical examination, vaccination status, vital signs, SpO2 measurement, 12-lead ECG, chest
      x-ray, eligibility assessment and blood and urine collection for laboratory assessments
      (including C-Reactive Protein). Rapid positive result for COVID-19 antigen will be
      randomized. Subjects with negative result for COVID-19 antigen will be considered as screen
      failure. Only swab from both sides in the nose will be taken as per the standard procedure
      for quantitative and qualitative RT-PCR assessments. If the result of qualitative RT-PCR of
      swab sample collected during screening is negative, subject will be withdrawn from the study.
      After screening procedures subjects will be randomized to one of the two treatment arms and
      investigational product (IP) will be dispensed. After training on nasal spray administration,
      first dose will be self-administered under supervision. Standard supportive care will be
      provided to all the subjects during the study.

      On Day 2, 3 and 4 swab from both sides in the nose will be taken for quantitative and
      qualitative RT-PCR. On Day 2 and 4 following study procedures will be conducted: adverse
      event review, concomitant medication review, IP compliance review, SpO2, vital signs. On Day
      4 a chest x-ray or CT scan will be done (choice between x-ray and CT scan at Day 4 will be
      based on investigator discretion). Only for subjects who are not able to visit the site can
      conduct chest x-ray or CT scan at nearby facility. Day 3 will be a Laboratory visit during
      which swab will be collected from nose for RT-PCR. On Day 8 subject will visit the study site
      and following activities will be performed: adverse event review, concomitant medication
      review, IP compliance review, SpO2, vital signs, physical examination, 12-lead ECG, blood and
      urine collection for laboratory assessments. Swab from both sides in the nose will be taken
      for qualitative and quantitative RT-PCR assessment, and IP will be retrieved. Qualitative and
      quantitative RT-PCR assessments will be done in all subjects on days 2, 3 and 4, irrespective
      of RT-PCR result (positive or negative) on days 2 and 3. Subjects who have negative result of
      qualitative RT-PCR (RT-PCR negative) at Day 4, RT-PCR (both qualitative and quantitative)
      will not be done on Day 8 and rest of the assessments as per visit schedule for Day 8 will be
      conducted. Visit 5 will be conducted on Day 19 ± 2 days or any time between Day 8 and Day 19,
      if the subject's COVID-19 symptom status and RT-PCR result becomes negative. Visit 5 will be
      a telephonic visit or clinic visit. During visit 5, history of adverse events and concomitant
      medication will be taken and in case of adverse event a clinic visit can be performed based
      on investigator's discretion for detailed assessments or additional tests. For subjects who
      are RT-PCR positive on Day 8, standard of care will be continued and swab from both sides in
      the nose will be collected at visit 5 for qualitative RT-PCR assessment. On Day 1, 2, 4, and
      8; and at visit 5 information about immediate contacts and their COVID-19 status will be
      collected. During the study, following events will be recorded: first time use of high flow
      supplemental oxygen, hospitalization for treatment purposes (COVID-19 related), non-invasive
      ventilation, mechanical ventilation, and extracorporeal membrane oxygenation and symptom
      scales. Methemoglobin will be measured non-invasively in a subset of patients on Day 1
      [before randomization (baseline), and 5 minutes after administration of first dose of NONS],
      Day 2, Day 4 and Day 8. Subject diary will be used to record information related to adverse
      events, use of concomitant medications and study drug compliance. Subject diary will be
      dispensed at screening/randomization visit (visit 1) and retrieved at Day 8 (visit 4).
      Subjects will record their health status and COVID-19 related symptoms daily during the study
      participation using the subject diary. Investigator will record the score on the WHO
      Progression Scale at visits 1, 2, 3, 4 and 5. After Day 8 visit, additional qualitative
      RT-PCR tests can be conducted as unscheduled investigations in subjects who are RT-PCR
      positive on Day 8. Subjects whose baseline COVID-19 symptoms have resolved by Day 8 and whose
      RT-PCR is negative by Day 8, will not undergo any further assessment (including visit 5) and
      their study participation will be considered as complete. For subjects whose baseline
      COVID-19 symptoms are present at Day 8 and/or whose RT-PCR is positive at Day 8 will be
      continued in the study till maximum of Day 19. Between Day 8 and Day 19 on or after the day
      the subject becomes RT-PCR negative and has baseline COVID-19 symptoms resolved, visit 5 can
      be conducted and subject's study participation can be considered complete. All subjects study
      participation, irrespective of RT-PCR and symptom status will end on maximum of Day 19±2 days
      (visit 5).
    

Intervention name(s): Nitric Oxide
Intervention type(s): Drug
Intervention description(s): The Sponsor designed a dual chamber nasal spray bottle for NORS administration. Components are mixed from two chambers to create the final NO-producing formulation. The liquid contains NO at 0.11 ppm*hour, which acts as a viricidal agent. Instructions for storing, preparing, and administering the study treatment will be provided to participants.
Other intervention name(s): Nasal Spray
Intervention MeSH terms: Nitric Oxide
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The primary objective of this study is to evaluate the efficacy of Nitric Oxide Nasal Spray combined with standard supportive care compared with standard supportive care alone in adult subjects with COVID-19 not requiring hospitalization
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention