COmmunity Patients at Risk of Viral Infections Including SARS-CoV-2

Study Overview
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Brief Summary
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Patients with a respiratory disease are at higher risk of poor outcomes due to worsening of symptoms caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and other respiratory infections. New therapies are needed for treating high risk patients at early stages of an infection. This study will assess the safety, tolerability and feasibility of using an inhaled nitric oxide generating solution, RESP301, as a self-administered treatment following flare-up of symptoms. RESP301 is a liquid solution which produces nitric oxide in the lungs when inhaled using a nebuliser. The components of RESP301 are already used in clinical practice and inhaled nitric oxide is used as a treatment for newborns and patients with Chronic Obstructive Pulmonary Disease (COPD). In a laboratory setting, RESP301 has been shown to be effective against respiratory viruses, including SARS-CoV-2. This study will first determine the maximum tolerated dose of RESP301 in up to 48 adult patients with COPD or bronchiectasis in the United Kingdom (UK) (Part 1a; Dose Finding Phase). Once the Maximum Tolerated Dose (MTD) has been determined in Part 1a, a cohort of 8 patients will be recruited and RESP301 administered at the MTD but these patients will in addition receive a single dose of a short acting bronchodilator 10 minutes preceding administration of RESP301. After completion of Part 1, approximately 150 patients will be recruited into Part 2 of the trial (Expansion Phase). A minimum of 50 participants will receive a test dose of RESP301 during a screening visit. Response to the test dose will be monitored. Participants who tolerate the test dose will continue in the study and should contact the study team if they experience exacerbation symptoms in the next 52 weeks. Following a call with the site team to discuss symptoms, participants will receive RESP301 delivered to their home to self-administer for 7 days. The study duration for each participant will be at most 57 weeks, including the study visit and monthly calls. Participants who start the course of study treatment, will receive daily calls during the treatment period and will also be followed up after they complete the treatment.

Official Title
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Community Participants With COPD or Bronchiectasis and at Risk of Respiratory Viral Infections Including SARS-CoV-2: An Open-label, Multicentre Feasibility Study of an Inhaled Nitric Oxide Generating Solution (RESP301)

Conditions
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COPD, Bronchiectasis

Intervention / Treatment
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* Drug: RESP301


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female of non-childbearing potential or male ≥35 years of age, at the time of signing the informed consent Able and willing to provide informed consent Spirometry-confirmed diagnosis of COPD (FEV1/FVC<0.7 post-bronchodilator) or computerised tomography (CT) proven bronchiectasis Part 1 only: FEV1 ≥50% predicted at screen 1 (i.e. FEV1 prior to any in-clinic administered short acting bronchodilator) Exclusion Criteria: Unable to safely use a nebuliser as required by the study according to Investigator's opinion Severe COPD or bronchiectasis defined as FEV1 <20% or requiring non-invasive ventilation History of methaemoglobinaemia Baseline methaemoglobin concentration (using fingertip sensor) > 2% Uncontrolled or severe asthma or history of severe bronchospasm Presence of tracheostomy/inability to provide spirometry or contraindication for performing spirometry Allergy to any of the components of the study intervention Participation in other clinical investigations utilising investigational treatment within the last 30 days / 5 half lives whichever is longer Deemed unlikely to be able to adhere to protocol in view of investigator Any subject who in the opinion of the investigator would not be best served by participating in this clinical trial Any unstable, uncontrolled or severe medical condition which in the opinion of the investigator would make the patient unsuitable for the trial Participant lives at home with no other adults in the household (Part 2 only) On long-term non-invasive ventilation and/or at higher risk of bronchospasm Prescribed Nitric Oxide donating agent (Nitroprusside, Isosorbide dinitrate, Isosorbide mononitrate, Naproxcinod, Molsidomine and Linsidomine) Female of childbearing potential Clinical diagnosis of COPD but Screening Visit spirometry at study centre excludes COPD (i.e. FEV1/FVC post bronchodilator ratio is not <0.7)

Ages Eligible for Study
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Minimum Age: 35 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: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Part 1a: Dose Finding Phase Up to 48 eligible participants will be administered single ascending doses of RESP301 to determine the maximum tolerated dose, according to the following schedule: 8 participants to receive RESP301 at a dose of 1 ml 8 participants to receive RESP301 at a dose of 2 ml 8 participants to receive RESP301 at a dose of 3 ml 8 participants to receive RESP301 at a dose of 4 ml 8 participants to receive RESP301 at a dose of 5 ml 8 participants to receive RESP301 at a dose of 6 ml Part 1b: Concomitant Medication Expansion Phase • 8 participants to receive RESP301 at MTD with short-acting bronchodilator administered 10min prior to RESP301 Part 2: Expansion Phase A minimum of 150 patients will be enrolled in to the Expansion Phase. These may include eligible participants from Part 1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All participants<br>In Part 1a, up to 48 patients will be administered single ascending doses of RESP301 (1-6ml; 8 patients per dose cohort). Provided that individual stopping criteria are not met in ≥3 participants, and there are no serious adverse events that are at least possibly related to RESP301, the next dose cohort can be enrolled. Patients can be enrolled into more than one dose cohort provided they did not meet individual stopping criteria. In Part 1b, 8 participants will receive RESP301 at MTD determined in Part 1a, with short-acting bronchodilator administered 10min prior to RESP301. In Part 2, a minimum of 150 patients will be enrolled. This may include patients who took part in Part 1. At least the first 50 patients will receive a test dose of RESP301 before enrolment into the dormant phase. Patients who experience flare-up symptoms while in the dormant phase, may proceed to the treatment phase where they will self-administer RESP301 at home for 7 days. | Drug: RESP301<br>* A single RESP301 dose administered at a study site to assess tolerability. In patients who experience a flare-up during the study period, self-administered RESP301 treatment for 7 days, 3 times a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients tolerating RESP301 at each dose level in Part 1 | Defined as percentage of participants able to tolerate the test dose, i.e. able to complete the test dose without any of the following: Troublesome cough, chest pain or tightness, bronchospasm or dyspnoea that is deemed unacceptable by the patient methaemoglobin >5% during or >3% post dose (60 mins) any treatment-related AE that led to participant not being able to complete the test dose >20% reduction in FEV1 pre dose to post dose at 60min if additionally reporting troublesome cough, chest pain or tightness, bronchospasm or dyspnoea that is deemed unacceptable by the patient | Screening Visit | 
| Feasibility of self-administering RESP301 treatment in terms of commencing treatment | Defined as percentage of patients who, having experienced and correctly reported an exacerbation, commence self-administration of the treatment on the day the treatment is delivered | 1 day | 
| Feasibility of self-administering RESP301 treatment in terms of treatment compliance | For those participants commencing treatment, the percentage of total doses taken | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of RESP301 (in Part 1a, Part 1b, and Part 2) | Defined as percentage of participants able to tolerate the test dose, i.e. able to complete the test dose without any of the following: Troublesome cough, chest pain or tightness, bronchospasm or dyspnoea that is deemed unacceptable by the patient methaemoglobin >5% during or >3% post dose (60 mins) any treatment-related AE that led to participant not being able to complete the test dose, and/or be suitable to be enrolled into the dormant phase in the Investigator's opinion for the first 50 patients who will undergo pre spirometry, >20% reduction in FEV1 from pre test dose to post test dose with symptoms (patients with >20% reduction in FEV1 without symptoms would be offered the option to continue in the study) | Screening Visit | 
| Safety of RESP301 in terms of Adverse Events | Defined as total counts and cumulative incidence of Adverse Events (AEs) | Screening Visit; Treatment phase + follow-up period (7 + 28 days) | 
| Safety of RESP301 in terms of Serious Adverse Events | Defined as total counts and cumulative incidence of Serious Adverse Events (SAEs) | Screening Visit; Treatment phase + follow-up period (7 + 28 days) | 
| Safety of RESP301 in terms of Suspected Unexpected Serious Adverse Reactions | Defined as total counts and cumulative incidence of Suspected Unexpected Serious Adverse Reactions (SUSARs) | Screening Visit; Treatment phase + follow-up period (7 + 28 days) | 
| Safety of RESP301 in terms of Severe AEs | Defined as total counts and cumulative incidence of Severe AEs | Screening Visit; Treatment phase + follow-up period (7 + 28 days) | 
| Safety of RESP301 in terms of treatment-related AEs and SAEs | Defined as total counts and cumulative incidence of treatment-related AEs and SAEs | Screening Visit; Treatment phase + follow-up period (7 + 28 days) | 
| Efficacy of RESP301 in terms of percentage of patients recovered by Day 7 | Defined as percentage of participants recovered by Day 7 post starting treatment, where recovery is defined as patient feels all their symptoms are back to their usual baseline (all symptom Visual Analogue Scores are 0 on a scale from 0 to 10, where 0 is same as usual and 10 is much more than usual) | 7 days | 
| Efficacy of RESP301 in terms of percentage of patients recovered by Day 14 | Defined as percentage of participants recovered by Day 14 post starting treatment, where recovery is defined as patient feels all their symptoms are back to their usual baseline (all symptom Visual Analogue Scores are 0 on a scale from 0 to 10, where 0 is same as usual and 10 is much more than usual) | 7 days | 
| Efficacy of RESP301 in terms of time to recovery | Defined as days to recovery, where recovery is defined as patient feels all their symptoms are back to their usual baseline (all symptom Visual Analogue Scores are 0 on a scale from 0 to 10, where 0 is same as usual and 10 is much more than Defined as percentage of participants recovered by Day 14 post starting treatment, where recovery is defined as patient feels all their symptoms are back to their usual baseline (all symptom Visual Analogue Scores are 0 on a scale from 0 to 10, where 0 is same as usual and 10 is much more than usual) | 21 days | 
| Efficacy of RESP301 in terms of preventing exacerbation-related hospitalisation and/or death | Number of patients with exacerbation-related hospitalisation and/or death | 7 days | 
| Efficacy of RESP301 in terms of patient-reported symptoms | Change in Clinical COPD Questionnaire (CCQ) score from Day 1 to Day 7, where the minimum score is 0 (very good health status) and maximum score is 6 (extremely poor health status) | 7 days | 
| Feasibility of self-administering RESP301 treatment in terms of receiving treatment | Defined as percentage of patients who, having experienced and correctly reported an exacerbation, receive the treatment within 48 hours of reporting their exacerbation | 2 days |