Preventing Pulmonary Complications in Surgical Patients at Risk of COVID-19

Study Overview
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Brief Summary
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The aim of this study is to reduce pulmonary complications in adult patients undergoing abdominal or thoracic surgery in COVID-19 exposed hospital environments. A Trial in Low and Middle Income Countries (LMICs)

Detailed Description
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This trial has an adaptive platform design to identify at the earliest opportunity intervention arms which are showing benefit, drop arms which have a clear lack of benefit, and rapidly introduce new therapeutic options to the platform. This will enable rapid feedback of results to clinicians, allowing the standard of care to be modified as the pandemic progresses. Regular and frequent monitoring of results will be guided by an experienced, independent DMC. Eligible patients will be randomised at the level of the individual in a 1:1 ratio between: A. Control (normal practice) B. RESP301 6ml mixture of 150mM sodium nitrate, 50mM mannitol and 100mM citric acid, buffered at pH 5.4, three times per day (at least 4 hours apart), for 7 days or until discharge, whichever occurs first

Official Title
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Preventing Pulmonary Complications in Surgical Patients at Risk of COVID-19

Conditions
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Pulmonary Complications in Surgical Patients, COVID, Severe Acute Respiratory Syndrome

Intervention / Treatment
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* Drug: RESP301


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 years and over. (This criteria MUST be made country-specific) Planned to undergo abdominal or thoracic elective or emergency inpatient surgery requiring general anaesthesia. Asymptomatic of COVID-19, including patients with: those not tested, negative test results, positive test but no symptoms (to be monitored post-surgery for symptoms) Informed patient consent. Able to operate a vibrating mesh nebuliser, as assessed by the recruiting physician Exclusion Criteria: Procedures under local anaesthesia Known history of adverse reaction/contraindication to trial drug Pregnancy and/or lactating patients (including patients undergoing caesarean section) History of methaemoglobinaemia Patients receiving any type of prescribed nitric oxide-donating agents (e.g. Nitroprusside, Isosorbide dinitrate, Isosorbide mononitrate, Naproxcinod, Molsidomine and Linsidomine) Unable to tolerate use of a nebuliser and/or deemed unlikely to be able to adhere to protocol in view of investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The trial uses a Bayesian adaptive platform design, allowing for termination of arms if their superiority to standard care is established, and addition of new treatment arms. Patients will be randomised 1:1 to (A) Control (normal practice), (B) RESP301
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control (normal practice)<br>Treatment without the trial intervention. Patients will be treated as per hospital routine practice. The control arm may change over the course of the trial and will be monitored by the TMG and DMC | |
| Experimental: RESP301<br>RESP301 is administered quickly (8-10 minutes) via an easy-to-use, vibrating mesh nebuliser. The recommended nebulisers used to administer this intervention are available in all participating countries. The intervention will be administered using a nebuliser according to standard local practice; where permitted for patients to self-administer, a member of the clinical team will ensure that the patient has viewed the intervention administration training video, and will also oversee the patient for the first trial dose to ensure proper administration. | Drug: RESP301<br>* RESP301 is a formulation consisting of three agents already used in clinical practice: mannitol, sodium nitrite and citric acid. Delivered by a vibrating mesh nebuliser three times per day (TID) (at least 4 hours apart), for 7 days. Each dose of RESP301 is a 6ml admixture of 150mM NaNO2, 50mM mannitol and 100mM citric acid, buffered at pH 5.4.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pneumonia free survival; acute respiratory distress syndrome (ARDS) free survival; or death | The primary outcome is any one of the following, inpatient, postoperative pulmonary complications: Pneumonia Acute respiratory distress syndrome (ARDS) Death | From randomisation until discharge from hospital, average less than 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pneumonia | Pneumonia will be presented and analysed separately as a secondary outcome measure as well as within the composite primary outcome measure. | From randomisation until discharge from hospital, average less than 30 days | 
| Rate of ARDs | ARDs will be presented and analysed separately as a secondary outcome measure | From randomisation until discharge from hospital, average less than 30 days | 
| Death rate | Death will be presented and analysed separately as a secondary outcome measure | From randomisation until discharge from hospital, average less than 30 days | 
| Rate of unexpected ventilation | Unexpected inability to extubate and wean patient from ventilation after general anaesthesia, or reintubation and ventilation by 30 days after surgery | From operation until 30 days post operation | 
| COVID-19 pulmonary complications | Postoperative diagnosis of proven COVID-19 pulmonary complications | 30 days post-surgery | 
| Duration of hospital stay | Duration of hospital stay (including time spent in intensive care, time ventilated) | 30 days post-surgery | 
| Pulmonary function | Pulmonary function in keeping with the World Health Organisation (WHO) Solidarity Trial outcome scale | 30 days post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surgery, Pneumonia, COVID 19, COVID, SARS-Cov-2, SARS