European Clinical Research Alliance on Infectious Diseases – primary care adaptive platform trial for pandemics and epidemics (ECRAID-Prime)

The primary objective of this study is to evaluate the **efficacy** of the investigational product (IP) compared to a control in the context of COVID-19 and COVID-like illness. This will be assessed through two main outcomes: the time to first self-report of feeling recovered from symptoms, and **viral clearance**. These outcomes are crucial for understanding the potential of the IP to expedite recovery and reduce viral load, which are significant factors in managing the spread and impact of the disease.

Secondary objectives include:

• Sustained recovery, defined as participants' reported recovery maintained until 28 days.
• Assessment of the presence, duration, and severity of individual respiratory symptoms.
• Participant-reported overall wellbeing.
• Evaluation of the overall safety of the IP by monitoring adverse events and adverse drug reactions.
• Occurrence of complications such as hospitalization and death.
• Impact on usual daily activities and healthcare utilization.
• Long-term consequences of COVID-19 or COVID-like illness up to 6 months.
• Incidence of COVID-19 and COVID-like illness in household members.
• Exploratory assessments of mutations in causative pathogens and experiences of researchers, healthcare professionals, and patients involved in the trial.
• Time to first self-report of return to usual daily activity and viral clearance for different phases of evaluation.
• Use of additional antiviral and other medications for respiratory infection.
• Key secondary outcome of early sustained recovery, defined as recovery by day 14, sustained until day 28.

The clinical trial involves a total of **143 participants** who are being studied for conditions related to **COVID-19** and COVID-like illnesses. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on the presence of at least two symptoms suggestive of COVID-19 or COVID-like illness, with one being respiratory and the other systemic. The trial does not focus on a vulnerable population, and participants are required to have the onset of symptoms within a specified timeframe. The selection criteria ensure that participants are willing and able to comply with all trial procedures, including the storage of self-collected swabs at home. The study does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include the ability to provide informed consent and, for women of childbearing potential, the use of effective contraception or abstinence. The trial does not provide additional information on the general health status of the participants beyond the specified criteria.

The clinical trial is designed to evaluate the efficacy and safety of **nitric oxide** nasal spray compared to a **saline nasal spray** in the treatment of **COVID-19** and COVID-like illness. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment is being administered, thus minimizing bias. The trial is expected to commence on May 1, 2024, and conclude by November 30, 2024, with a maximum treatment period of 7 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), presence of specific symptoms, and ability to comply with trial procedures. Following the screening, participants will be randomly assigned to receive either the nitric oxide nasal spray or the saline nasal spray. The primary endpoint is the time to first self-report of feeling recovered from symptoms, while secondary endpoints include viral clearance and the impact on biomarkers of illness severity.

Study visits will include baseline assessments and follow-up visits on days 4, 7, and 14 to monitor recovery and collect data on viral clearance and symptom severity. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted. Participants are expected to be involved in the study for approximately 28 days, including the treatment and follow-up periods.

Conditions that may lead to early termination from the study include the participant's inability to comply with trial procedures, withdrawal of consent, or any adverse events that necessitate discontinuation of the investigational product. The trial aims to provide valuable insights into the potential therapeutic benefits of nitric oxide nasal spray in managing COVID-19 and related illnesses.

The clinical trial involves the administration of two **nasal spray** formulations. The first treatment is the **SALINE NASAL SPRAY (0.9% NACL)**, which contains **sodium chloride solution 0.9%** as the active substance. This product is manufactured by the University Medical Center Utrecht and is presented in the form of a nasal spray. The maximum daily dose is 0.45 ml, with a total maximum dose of 3.15 ml over a treatment period of 7 days. The administration route is intranasal, and the product is not a pediatric formulation. The saline nasal spray serves as a comparator in the trial.

The second treatment is the **Nitric Oxide Nasal Spray (NONS)**, which contains **nitric oxide** as the active ingredient. This product is also produced by the University Medical Center Utrecht and is delivered via a nasal spray. Similar to the saline nasal spray, the maximum daily dose is 0.45 ml, with a total maximum dose of 3.15 ml over a 7-day treatment period. The administration route is intranasal, and it is not formulated for pediatric use. The Nitric Oxide Nasal Spray is the test product in this clinical trial.

Both treatments are administered as solutions, and participant compliance is monitored to ensure adherence to the dosing schedule. The trial aims to evaluate the efficacy of the test product compared to the comparator in terms of time to recovery from symptoms of COVID-19 or COVID-like illness, as well as viral clearance and potential impacts on biomarkers.

The efficacy of the investigational products in the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the **time to first self-report of feeling recovered** from symptoms related to COVID-19 or COVID-like illness, and **viral clearance**, with potential impacts on biomarkers of illness severity. These assessments will be conducted at baseline and on days 4, 7, and 14, or as specified in the intervention-specific appendix.

Secondary endpoints encompass a range of patient-reported outcomes and clinical measures. These include the time to first self-report of return to usual daily activity, the presence, duration, and severity of individual respiratory symptoms, and participant-reported overall wellbeing on a scale of 0-10. Additionally, the impact on usual daily activities, complications such as hospitalization, healthcare utilization, and long-term consequences of COVID-19 or COVID-like illness will be evaluated. Exploratory endpoints will investigate the emergence of mutations in causative pathogens, experiences of researchers and healthcare professionals, and patient views on trial participation and interventions.

The efficacy assessments will utilize patient diaries and self-collected swabs, with data collection scheduled at specified time points throughout the trial. The analysis will focus on both the immediate and sustained recovery of participants, with key secondary outcomes including early sustained recovery by day 14, maintained until day 28. Overall safety and the incidence of adverse drug reactions will also be monitored as part of the trial's comprehensive evaluation of the investigational products' efficacy and safety.