Clinical trial NCT04858451
Conditions: COPD Bronchiectasis
Sponsor: Thirty Respiratory Limited
Start date: 2021-03-01; Completion date: 2023-02-08
Enrollment: 88 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:

Arms: arm 1: 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.
Interventions: intervention 1: RESP301
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
 
Protocol Title: 
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) 
Short Title:  
COmmunity patients at Risk of Viral Infections 
including SARS-CoV-2 (CORVIS) 
Compound: 
RESP301 
Indication: 
COPD and bronchiectasis 
Study Sponsor: 
Thirty Respiratory Limited 
1 Red Place, London, W1K 6PL, United 
Kingdom  
Chief Investigator: 
Professor 
, Newcastle 
Hospitals, UK 
Protocol Number: 
RESP301-005 
Study Phase: 
Phase 2 
IRAS ID: 
290709 
EudraCT No: 
2020-004951-34 
Approval Date of Current Version: 
18 November 2021 
Dates and Versions of Previous 
Protocols: 
v.2.0 07DEC20; v.3.0 08FEB21; v.4.0 26JUL21 


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PROTOCOL SIGNATURE PAGE 
 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Chief Investigator agrees to conduct the trial in compliance with the approved protocol 
and will adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) 
Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) and any subsequent 
amendments of the clinical trial regulations, GCP guidelines, the Sponsor’s (and any other 
relevant) SOPs, and other regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used 
for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
I also confirm that I will make the findings of the trial publically available through 
publication or other dissemination tools without any unnecessary delay and that an honest 
accurate and transparent account of the trial will be given; and that any discrepancies and 
serious breaches of GCP from the trial as planned in this protocol will be explained. 
 
Chief Investigator: 
 
 
Sponsor Signatory: 
 
 
 


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Key Trial Contacts 
 
Chief Investigator 
 
 
 
Trial Manager/Coordinator 
 
Thirty Respiratory Limited 
1 Red Place, London, W1K 6PL, UK 
 
 
Sponsor and Funder 
Thirty Respiratory Limited 
1 Red Place, London, W1K 6PL, UK 
Email: corvis@30.technology 
Phone: 01235 431 200 
Statistician 
 
Imperial College London 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Version 
Date 
Original Protocol 
Version 1.0 
20NOV20 
Protocol v.2.0 (safety 
information added 
 
 
Version 2.0 
07DEC20 
Protocol v.3.0 (exclusion 
criteria 
 
 clarified 
; 
spirometry requirements 
clarified in 
 
 clarified the 
conditions for continuing 
diaries post treatment in 
 
Version 3.0 
08FEB21 


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DOCUMENT HISTORY 
Document 
Version 
Date 
Protocol v.4.0 (changes in 
relation to 
 Dose 
Finding Phase: 
 
 
 
 
 
 
 minor 
clarifications to 
 
exclusion criteria; 
 
 
 
 
; new 
safety data added; 
 
 
 
 other 
minor clarifications) 
Version 4.0 
26JUL21 
Protocol v. 5.0 
Changes in relation to 
 Part 1 
and 
 
 
 
specifying bronchodilator 
dose and requirement for 
using it with a spacer device 
Version 5.0 
18NOV21 
 
 
 
 
 


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Table of Contents 
PROTOCOL SIGNATURE PAGE ........................................................................................ 2 
KEY TRIAL CONTACTS ...................................................................................................... 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................ 4 
TABLE OF CONTENTS ........................................................................................................ 6 
1 
STUDY SYNOPSIS ....................................................................................................... 10 
2 
ABBREVIATIONS ........................................................................................................ 19 
3 
INTRODUCTION .......................................................................................................... 20 
3.1 
Background ............................................................................................................................................ 20 
3.2 
Benefit/Risk assessment ........................................................................................................................ 25 
3.2.1 
Risk assessment .................................................................................................................................. 25 
3.2.2 
Benefit assessment .............................................................................................................................. 27 
3.2.3 
Overall Benefit: Risk Conclusion ....................................................................................................... 28 
4 
OBJECTIVES AND ENDPOINTS .............................................................................. 28 
5 
STUDY DESIGN ............................................................................................................ 31 
5.1 
Overall design ........................................................................................................................................ 31 
5.2 
Scientific Rationale for Study Design .................................................................................................. 36 
5.3 
Justification for Dose ............................................................................................................................. 37 
5.4 
End of Study Definition ........................................................................................................................ 37 
6 
STUDY POPULATION AND RECRUITMENT ....................................................... 37 
6.1 
Study Rationale ..................................................................................................................................... 38 
6.2 
Inclusion Criteria .................................................................................................................................. 39 
6.3 
Exclusion Criteria .................................................................................................................................. 39 
6.4 
Lifestyle Considerations ........................................................................................................................ 40 
6.5 
Screen Failures ...................................................................................................................................... 40 
6.6 
Screening and Enrollment Log and Participant Identification Numbers ........................................ 40 


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7 
STUDY INTERVENTION ............................................................................................ 41 
7.1 
Study Intervention Administered ........................................................................................................ 41 
7.1.1 
Medical Devices ................................................................................................................................. 41 
7.1.2 
Device Training .................................................................................................................................. 42 
7.2 
Preparation, Handling, Storage, and Accountability ......................................................................... 42 
7.2.1 
Preparation of Study Intervention Product ......................................................................................... 42 
7.2.2 
Storage and Accountability of Study Intervention at site ................................................................... 43 
7.2.3 
Storage of Study Intervention at home ............................................................................................... 44 
7.3 
Measures to Minimise Bias: Randomisation and Blinding ............................................................... 44 
7.4 
Study Intervention Compliance ........................................................................................................... 44 
7.5 
Concomitant Therapy ........................................................................................................................... 44 
7.5.1 
Rescue Medication ............................................................................................................................. 45 
7.6 
Intervention After the End of the Study ............................................................................................. 45 
7.7 
Stopping Criteria for Dose Finding Phase (Part 1) ............................................................................ 45 
7.7.1 
Dose Finding ...................................................................................................................................... 45 
7.7.2 
Individual Stopping Criteria ............................................................................................................... 46 
7.7.3 
Cohort Stopping Criteria .................................................................................................................... 46 
7.7.4 
Study Stopping Criteria ...................................................................................................................... 47 
7.8 
Discontinuation of Study Intervention and Participant Discontinuation ........................................ 47 
7.8.1 
Permanent Discontinuation of Study Intervention ............................................................................. 47 
7.8.2 
Temporary Discontinuation of Study Intervention ............................................................................. 48 
7.8.3 
Participant Discontinuation/Withdrawal from the Study ................................................................... 48 
7.8.4 
Loss of Participants to Follow-Up ...................................................................................................... 48 
7.9 
RESP301 Safety ..................................................................................................................................... 49 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................ 50 
8.1 
Screening Visits (Part 1 and Part 2) .................................................................................................... 58 
8.1.1 
Informed Consent ............................................................................................................................... 58 
8.1.2 
Eligibility Criteria ............................................................................................................................... 58 
8.1.3 
Demographics ..................................................................................................................................... 58 
8.1.4 
Medical history and medications ........................................................................................................ 58 
8.1.5 
Examinations and tests ....................................................................................................................... 59 
8.1.6 
RESP301 tolerability .......................................................................................................................... 60 
8.1.7 
The Clinical COPD Questionnaire (CCQ) (Part 2 only) .................................................................... 61 
8.1.8 
Instructions to participants (Part 2 only) ............................................................................................ 61 
8.1.9 
AE/SAE .............................................................................................................................................. 61 
8.2 
Dormant period ..................................................................................................................................... 61 
8.3 
Pre-treatment appointment .................................................................................................................. 62 
8.4 
Treatment period ................................................................................................................................... 62 
8.5 
Post-treatment Follow-up calls ............................................................................................................. 63 
8.6 
Early Withdrawal .................................................................................................................................. 63 


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9 
PHARMACOVIGILANCE .......................................................................................... 64 
9.1 
Adverse Events and Serious Adverse Events ...................................................................................... 64 
9.2 
Time Period and Frequency for Collecting AE and SAE Information ............................................ 64 
9.3 
Method of Detecting AEs and SAEs .................................................................................................... 64 
9.4 
Follow-up of AEs and SAEs ................................................................................................................. 64 
9.5 
Regulatory Reporting Requirements for SAE .................................................................................... 65 
9.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or SAEs (Not 
Applicable) ............................................................................................................................................................ 65 
9.7 
Adverse Events of Special Interest (Not Applicable) ......................................................................... 65 
9.8 
Medical Device Deficiencies (Not Applicable) .................................................................................... 65 
10 
STATISTICAL CONSIDERATIONS ..................................................................... 66 
10.1 
Statistical Hypothesis ............................................................................................................................ 66 
10.2 
Sample Size Determination ................................................................................................................... 66 
10.3 
Populations for Analyses ...................................................................................................................... 66 
10.4 
Statistical Analyses ................................................................................................................................ 67 
10.4.1 
General Considerations .................................................................................................................. 67 
10.4.2 
Primary Endpoint ........................................................................................................................... 67 
10.4.3 
Secondary Endpoint(s) ................................................................................................................... 68 
10.4.4 
Other Analyses ............................................................................................................................... 69 
10.5 
Interim Analyses .................................................................................................................................... 69 
10.6 
Data Monitoring Committee (DMC) ................................................................................................... 69 
11 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS
 
69 
11.1 
Regulatory and Ethical Considerations .............................................................................................. 69 
11.2 
Informed Consent Process .................................................................................................................... 70 
11.3 
Data Protection ...................................................................................................................................... 71 
11.4 
Committees Structure ........................................................................................................................... 71 
11.5 
Data Quality Assurance ........................................................................................................................ 71 
11.6 
Source Documents ................................................................................................................................. 72 
11.7 
Study and Site Start and Closure ......................................................................................................... 73 
11.8 
Publication Policy .................................................................................................................................. 73 
11.9 
Protocol Approval and Amendment .................................................................................................... 74 


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11.10 
Liability and Insurance ......................................................................................................................... 74 
11.11 
Access to Source Data ........................................................................................................................... 74 
12 
REFERENCES ........................................................................................................... 75 
APPENDIX 1: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ............................. 79 
Definition of AE ................................................................................................................................................... 79 
Definition of SAE ................................................................................................................................................. 80 
Recording and Follow-up of AE and SAE ......................................................................................................... 81 
Reporting of SAE ................................................................................................................................................. 83 
INVESTIGATOR AGREEMENT PAGE ........................................................................... 86 
 
 
 
List of Figures 
 
 
 
 
 
 
 
 
 
LIST OF TABLES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 Study Synopsis 
Title 
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)  
Short title 
COmmunity patients at Risk of Viral Infections including SARS-
CoV-2 (CORVIS) 
Protocol number 
RESP301-005 
IRAS ID 
290709 
EudraCT number 
2020-004951-34 
Phase 
Phase 2 
Sponsor 
Thirty Respiratory Limited 
Chief Investigator 
Professor Anthony De Soyza, Newcastle Hospitals, UK 
Rationale 
Nitric Oxide (NO) is a potent antimicrobial produced naturally in 
the human body and is a key component of our defence against 
microbial infection in the lung. Gaseous NO is an approved product 
for treatment of pulmonary hypertension in neonates and has 
already been delivered as a potential pulmonary vasodilator in 
COPD. RESP301 readily produces NO and has distinct advantages 
over gaseous NO by delivering a more targeted and localised 
delivery. RESP301 is a formulation consisting of 3 agents already 
used in clinical practice: mannitol, sodium nitrite and citric acid. 
RESP301 is administered as nebulised fine particle droplets via a 
handheld nebuliser. In vitro, RESP301 has been shown to be highly 
effective against a range of respiratory viruses, including SARS-
CoV-2 and influenza strains, and multiple types of bacteria. 
RESP301 is currently being used as treatment for hospitalised 
COVID-19 patients in an ongoing randomised controlled trial. 
Community patients with pre-existing respiratory disease are at 
higher risk of adverse outcomes such as hospitalisation and/or 
death due to exacerbations caused by SARS-CoV-2 or other 
respiratory infections. This study will first determine the maximum 
tolerated dose of RESP301 in patients with COPD or 
bronchiectasis, and will then assess the feasibility of recruiting and 
retaining these patients and treating them with RESP301 in the 
community at onset of viral infection symptoms. Additionally, we 
will collect safety, tolerability and disease symptom data. 
Objectives 
Primary objectives: 


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• To determine the maximum tolerable dose (MTD) and 
recommended therapeutic dose (RTD) of single agent 
RESP301 in patients with mild to moderate COPD or 
bronchiectasis 
• To assess the feasibility of administering RESP301 safely at 
the MTD with the co-administration of a short acting 
bronchodilator 
• To assess the feasibility of recruiting and retaining patients 
with COPD or bronchiectasis who have viral infection 
symptoms and treating these patients with RESP301 in a 
community setting. 
Secondary objectives: 
The following secondary objectives will be considered for the 
cohort as a whole, and in addition for a sub-cohort of those who 
have confirmed SARS-CoV-2 infection: 
• To assess the safety and tolerability of single doses of 
RESP301 in patients with COPD or bronchiectasis, who are at 
high risk of SARS-CoV-2 and other acute respiratory 
pathogens. 
• To assess the safety and tolerability of RESP301 and a pre-
dose short acting bronchodilator (two inhalations of Ventolin 
)  in patients with COPD or bronchiectasis. 
• To collect preliminary data on the efficacy of RESP301 in 
treating exacerbations in patients with COPD or 
bronchiectasis. 
Intervention/treatment 
RESP301 is delivered by vibrating mesh nebuliser at least 4 hours 
apart. Each dose of RESP301 is an admixture of 
sodium 
nitrite, 
 mannitol and 
 citric acid, buffered at pH 
  
 
Part 1(a): Dose Finding Phase 
The MTD of RESP301 will be determined in order to obtain the 
RTD for the Expansion Phase. 
 
Part 1(b): Concomitant Medication Expansion Phase 
Up to 8 patients with COPD  or bronchiectasis will be enrolled 
into a cohort to receive a short acting inhaled broncholdilator 
through a spacer device 10 minutes before receiving a single test 
dose of RESP301 at the MTD  
 


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Part 2: Expansion Phase  
A test dose of RESP301 at RTD will be administered during the 
baseline visit under clinical supervision in a minimum of 50 
patients. Patients who tolerate the test dose will progress to the 
Dormant Period to which a further 100 participants will also be 
recruited with or without a test dose (depending on review of 
safety data after the first 50 patients). Participants in the 
Dormant Period will inform the clinical team if symptoms develop 
indicative of a possible respiratory infection (exacerbation) and 
will then progress to the Treatment Period, in which eligible 
participants receive RESP301 by courier or at a subsequent clinic 
visit for treatment by self-administration at home. During the 
Treatment Period, RESP301 is taken at the RTD three times a day 
at least 4 hours apart for 7 days alongside normal Standard of 
Care (SOC) (treatment period may extend into Day 8 depending 
on time of commencing on Day 1). During the Treatment Period 
participants may use rescue medication as required. 
 
 
Comparator 
Not applicable 
Study design 
This is a single arm, non-randomised, open-label study.  
Part 1(a): Dose Finding Phase 
Up to 48 eligible participants will be administered single ascending 
doses of RESP301 under clinical supervision to determine the MTD, 
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 
Safety data will be reviewed by the PIs and Sponsor after each dose 
before proceeding to the next higher dose. 
Safety data will include: 
• Treatment-related Adverses Events including troublesome 
cough, chest pain or tightness, bronchospasm or dyspnoea 
the patients finds intolerable 
• Changes in FEV1  
• Changes in methaemoglobin level 


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Provided that individual stopping criteria are not met in ≥ three 
participants, and there are no serious adverse events that are at 
least possibly related to RESP301, the next dose cohort can be 
enrolled. 
Subjects can 
be 
enrolled into 
more 
than 
one 
dose cohort provided they did not meet individual stopping 
criteria from any  given prior dose. 
A Safety Advisory Committee will review the data from the 8 
participants in Part 1(a) and determine a Maximum Tolerated 
Dose(MTD) and Recommended Therapeutic Dose (RTD). 
 
Part 1(b): Concomitant Medication Expansion Phase 
Up to 8 eligible participants will be administered a single dose of 
RESP301 at the MTD under clinical supervision to assess the effect 
(if any) of a short acting bronchodilator upon symptomatic or 
asymptomatic 
bronchial 
hyper-reactivity 
associated 
with 
nebulised RESP301.  Administration will be according to the 
following schedule: 
• 8 participants to receive RESP301 at the determined MTD after 
pre-dosing with a short acting inhaled bronchodilator (2 
inhalations of Ventolin - 
 per inhalation) through a 
spacer device  10 minutes before administration of RESP301.  
 
Once the Maximum Tolerated Dose (MTD) has been determined 
in Part 1(a), a cohort of 8 patients who are not experiencing an 
exacerbation will be recruited and RESP301 administered at the 
MTD but will in addition receive a single dose of a short acting 
bronchodilator (2 inhalations of Ventolin - 
 per inhalation) 
through a spacer device 10 minutes preceding administration of 
RESP301. The following parameters will be measured: 
• Assess response to RESP301 (incl. recording any AEs, FEV1 
pre- and post dose and monitoring up to 1 hour post dose).  
Part 1 (b) will be conducted after an MTD and RTD have been 
determined in Part 1(a) but will not delay initiation of Part 2. A 
Safety Advisory Committee will review the data from the 8 
participants in Part 1(b). Participants from cohorts 1(a) and 1(b)  
may also enter the Dormant and Treatment Phase of the study, as 
long as they meet eligibility criteria.  
 


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Part 2: Expansion Phase 
Once the Recommended Therapeutic Dose has been determined 
in Part 1 (a), a minimum of 150 patients will be enrolled in to the 
Expansion Phase, which is split into 3 periods. For participants 
taking part in the Dose Finding Phase (Part 1), eligibility criteria will 
be reassessed prior to entering Part 2 of the trial. 
1) Baseline visit 
In a minimum of 50 participants the following will be performed: 
• Administration of a test dose of RESP301, at the RTD 
• Assesses response to RESP301 (incl. recording any AEs, 
FEV1 pre- and post dose and monitoring methaemoglobin 
levels pre-, during and post- administration, using fingertip 
sensor; methaemoglobin level should be <=2% before, 
<=5% during, and <=3% at 30-60 mins post dose (i.e. if still 
>3% at 30 mins, check again at 60mins post dose). 
During the visit participants who satisfactorily tolerate the test 
dose will then be enrolled into the “dormant period” of the study 
for 12 months.  
An independent Data Monitoring Committee will review the data 
from the 50 participants that received the RTD. Based on the data 
from these participants, it will be decided whether test doses 
should be administered to further participants before enrolling 
them into the Dormant Period. 
2) Dormant Period 
Dormant period patients are requested at the baseline visit, and 
monthly follow-up calls, to inform the study team if they develop 
exacerbation symptoms indicative of a respiratory infection. There 
will be no other study procedures or data collection during the 
“dormant study phase” unless the participant experiences 
exacerbation symptoms. 
3) Treatment Period 
A patient who experiences exacerbation symptoms for at least 24 
hours should contact the study team as soon as practicable to 
allow a study interaction to be undertaken remotely (via video link, 
if possible), within 72 hours of onset of at least one of the 
following: fever (>38.0°C), systemic malaise, increased cough or 
wheeze, increased  sputum volume or increased purulence. During 
the remote visit the patient’s symptoms will be discussed and if 


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the patient is willing to continue in the study, they will have a rapid 
delivery of a study pack containing study IMP and nebuliser and 
other equipment for the trial. 
Note that if COVID-19 is suspected, the patient will be advised to 
follow the prevailing NHS guidance on testing for COVID-19 taking 
into account any specific recommendations for patients with 
COPD or bronchiectasis.  Where serial SARS-CoV-2 swabs are 
undertaken, data will be collected for analysis. 
During the treatment period, lasting 7 days, at home/ community 
setting, patients will be asked to: 
• Administer RESP301 three times daily at the RTD 
• Take daily temperature measurements 
• Complete a daily diary to record treatment doses  
• Attend a daily call with study coordinator to check 
compliance, assist with issues with product, and report any 
AEs and changes to medications or medical history, 
including COVID-19 test results, if available 
Each participant will receive a maximum of one course of 
treatment of RESP301 during the study. Remote follow up visit will 
be carried out approximately 14 and 28 days following end of 
treatment to record any AEs and changes to medications or 
medical history, including COVID-19 test results, if available. 
Additionally, participants whose symptoms had not returned to 
baseline by the end of treatment period, will be followed up with 
a phone call 2 weeks post end of treatment.  
Endpoints 
Primary endpoint: 
• Proportion of patients tolerating RESP301 at each dose 
level in Part 1 (according to pre-defined criteria) 
• Feasibility of self-administering RESP301 treatment with 
nebuliser in terms of: 
o percentage of patients who, having experienced 
and correctly reported an exacerbation, 
commence self-administeration of the treatment 
on the day the treatment is delivered 
o compliance with RESP301 administration schedule 
over the treatment period: for those participants 
commencing treatment, the percentage of  total 
doses taken 
Secondary endpoints: 


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To be evaluated on the full cohort, and separately in the sub-
cohort of those who test positive for SARS-CoV-2: 
• Safety and tolerability of RESP301 in terms of: 
o % of participants able to tolerate the test dose in 
Parts 1(a), 1 (b) and 2 
o Total counts and cumulative incidence of: 
§ Adverse Events (AEs) 
§ Serious Adverse Events (SAEs) 
§ Suspected Unexpected Serious Adverse 
Reactions (SUSARs) 
§ Severe AEs 
§ Treatment-related AEs/SAEs 
• Feasibility in terms of percentage of patients who, having 
experienced and correctly reported an exacerbation, 
receive the treatment within 48 hours of reporting their 
exacerbation 
• Efficacy of RESP301 in terms of: 
o % of participants recovered by Day 7 and Day 14 
post starting treatment 
o time to recovery (days until patient feels all their 
symptoms are back to their usual baseline (all VAS 
= 0))  
o preventing exacerbation-related hospitalisation 
and/or death 
o change in CCQ score 
Duration of participation 
in the study 
The overall study duration for each participant will be at most 
approximately 60 weeks, including one or more visits at a study 
centre in Parts 1/2, monthly follow-up calls, and, for those who 
experience an exacerbation, one week of treatment and 
additional monitoring calls at the beginning, during and following 
the treatment period. 
Study population 
Participants will be adult patients with spirometry-confirmed 
COPD or computerised tomography (CT) proven bronchiectasis, 
recruited from secondary and primary care sites in the UK.  
Sample size 
Part 1(a):  
We aim to recruit up to 48 participants. All participants who 
complete Part 1a, will also be eligible to enter Part 2 of the trial. 
Part 1(b):  
We aim to recruit 8 participants who are not experiencing an 
exacerbation. These participants will receive a short acting 


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inhaled bronchodilator 10 minutes before receiving a single dose 
of RESP301 at the MTD. Participants from Part 1b may also enter 
Part 2 of the study if they fullfill eligibity criteria.  
 
Part 2:  
We aim to recruit 150 patients from secondary care and primary 
care sites in the UK (includes eligible participants from Part 1 of 
the study). A minimum of 50 consented participants will receive 
an initial test dose of RESP301. We estimate that over 12 months, 
a minimum of 30 of the enrolled participants will exacerbate. 
These participants will commence self-administered RESP301 
treatment. Non-exacerbating participants will receive no further 
study interventions. 
Inclusion criteria 
1. Female of non-childbearing potential or male ≥35 years of 
age, at the time of signing the informed consent 
2. Able and willing to provide informed consent 
3. Spirometry-confirmed diagnosis of COPD (FEV1/FVC<0.7 post-
bronchodilator at screen 1, or from historical data) or 
computerised tomography (CT) proven bronchiectasis 
4. Part 1 only: FEV1 ≥50% predicted at screen 1 (i.e. FEV1 prior 
to any in-clinic administered short acting bronchodilator) 
Exclusion criteria 
1. Unable to safely use a nebuliser as required by the study 
according to Investigator’s opinion 
2. Severe COPD or bronchiectasis defined as FEV1 % predicted 
<20% or requiring non-invasive ventilation 
3. History of methaemoglobinaemia 
4. Baseline methaemoglobin concentration (using fingertip 
sensor) > 2% 
5. Uncontrolled or severe asthma or history of severe 
bronchospasm 
6. Presence of tracheostomy/inability to provide spirometry or 
contraindication for performing spirometry 
7. Allergy to any of the components of the study intervention 
8. Participation in other clinical investigations utilising 
investigational treatment within the last 30 days / 5 half-lives 
whichever is longer 
9. Deemed unlikely to be able to adhere to protocol in view of 
investigator 
10. Any subject who in the opinion of the investigator would not 
be best served by participating in this clinical trial 


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11. Any unstable, uncontrolled or severe medical condition which 
in the opinion of the investigator would make the patient 
unsuitable for the trial 
12. Participant lives at home with no other adults in the 
household (Part 2 only) 
13. On long-term non-invasive ventilation and/or at higher risk of 
bronchospasm 
14. Prescribed Nitric Oxide donating agent 
15. Female of childbearing potential 
16. Clinical diagnosis of COPD but Screening Visit spirometry at 
study centre excludes COPD (i.e. FEV1/FVC post 
bronchodilator ratio is not <0.7) 
Study centres 
The study will be conducted at two sites, Newcastle Hospitals, 
the NIHR National Patient Recruitment Centre, Newcastle, and 
the Medicines Evaluation Unit (MEU) Ltd.  
Statistical planning 
The primary objective is to determine the MTD of RESP301 and to 
assess the feasibility of recruiting and retaining patients with 
COPD or bronchiectasis who have viral infection symptoms and 
treating these patients with RESP301 in a community setting. No 
formal statistical planning has been carried out. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 Abbreviations 
AE 
CCQ 
adverse event 
Clinical COPD Questionnaire 
CFR 
Code of Federal Regulations  
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
CRO 
contract research organisation 
CT 
computerised tomography 
DMC 
Data Monitoring Committee 
DRE 
disease-related events 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
mHb 
Methaemoglobin 
NHS 
National Health Service 
NO 
Nitric oxide 
NO2 
Nitrogen dioxide 
NOx 
Oxide of nitrogen 
PEoT 
Post End of Treatment 
PP 
Per protocol 
RTD 
Recommended therapeutic dose 
SAC 
Safety Advisory Committee 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Standard deviation 
SoA 
Schedule of activities 
SOC 
Standard of care 
SP 
Safety population 
SpO2 
Oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
TID 
VAS 
Three times daily 
Visual Analogue Scale 
 
 
 
 
 
 


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3 Introduction 
3.1 Background 
Chronic obstructive pulmonary disease (COPD) and bronchiectasis are chronic lung conditions 
mainly affecting middle-aged or older adults. A Global Burden of Disease report in 2020 
estimates COPD as being the 6th largest cause of wordwide disease burden (and the 3rd largest 
for those 75 years and older)(GBD 2019 Diseases and Injuries Collaborators, 2020). 
Bronchiectasis is less common but around 1,000 people die each year from the disease in 
England and Wales (Roberts and Hubbard, 2010).  
COPD is characterised by chronic obstruction of lung airflow that interferes with normal 
breathing and is not fully reversible. COPD patients are prone to worsening of symptoms and 
lung function due to infection; these episodes are known as exacerbations.  The frequency of 
exacerbations tends to increase in line with the severity of the undelying COPD.  Furthermore, 
exacerbations contribute to the progression of the condition, being associated with a rapid 
decline in lung function and increased mortality. 
One in eight emergency admissions in the UK is due to a COPD exacerbation, making it the 
second most common cause; 31% of patients were re-admitted to hospital within 30 days 
(British Thoracic Society, 2012; Devon LPC and Mediapharm, 2014). Exacerbations of COPD 
patients are most often caused by respiratory viruses, which tend to lead to more severe 
symptoms and hospitalisation; other triggers are bacterial infections, air pollutants and ambient 
temperature.   
The occurrence of COPD exacerbations is linked to the stage of the disease, as seen in the 
ECLIPSE study in which the exacerbation rates were 0.85 per person for patients with 
moderate disease (GOLD stage 2) and 2.00 for those with very severe disease (GOLD stage 4; 
Hurst et al, 2010). Other factors for exacerbations were seasonal effects or inhalation of 
harmful substances, and epidemic peaks in exacerbations of COPD were noted in the autumn 
and winter months (Johnston & Sears, 2006). As with COPD, infections can also cause severe 
symptoms in patients with bronchiectasis who are particularly vulnerable to recurrent acute 
chest infections (Chalmers et al, 2018).  
Of particular concern at the present time is the appearance of a new and potent coronavirus 
which has caused the global COVID-19 pandemic. The appearance of this deadly virus is of 
major concern for those patients with underlying lung conditions. Viral-detected exacerbations 
showed a larger decline in lung function and longer recovery time than non-viral exacerbations 
(Seemungal et al, 2001; Bafadhel et al, 2011). A critical factor is the tendency of viral 
infections to provoke secondary bacterial infections. Viral and sequential bacterial infections 
may be associated with severe respiratory symptoms (van der Molen et al, 2003 


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van der Molen T, Willemse BW, Schokker S, ten Hacken NH, Postma DS, Juniper EF. 
Development, validity and responsiveness of the clinical COPD questionnaire. Health Qual 
Life Outcomes. 2003; 28:1–13. 
Wilkinson et al, 2006; Harper et al, 2009; Mallia et al, 2012). 
A critical early component of innate host defence in the airway is the ability of respiratory 
epithelial cells to produce high levels of NO (Kao et al, 2001). NO functions as a signaling 
molecule in initiation of the inflammatory response to viruses, and also has direct antiviral 
effects (Folkerts et al, 1998). The airway epithelium has highly efficient nitric oxide (NO) 
synthetic machinery which is amplified in viral infection. Healthy human airway epithelium 
has abundant expression of the endothelial enzyme NOS II due to continuous transcriptional 
activation of the gene in vivo. Loss of NO synthesis in lung diseases predisposes individuals 
to increased virus/microbe infection (Xu et al, 2006). 
The physiological roles of NO and the enzymatic pathways for its synthesis via NO synthase 
have been clearly established for many years (Tucker et al, 2007). In particular, NO has been 
demonstrated to have potent anti-microbial properties against a wide range of pathogens. An 
alternative non-enzymatic synthetic pathway for NO synthesis has been developed, which 
generates NO and related higher oxides of nitrogen (NOx) via the chemical reactions of 
acidified nitrite (Hardwick et al, 2001, Tucker et al, 1999). A solution of co-mixed NO/NOx 
and ascorbic acid (RespiNOS), delivered by nebuliser, was found to be safe and well tolerated 
in healthy volunteers (Tucker et al, 2007). Spectral investigations further confirmed that there 
were no potentially harmful moieties present in the solution. The study concluded that 
RespiNOS had potential for use as a broad-spectrum anti-microbial agent in patients with 
chronic bronchial sepsis such as bronchiectasis, COPD, and cystic fibrosis. 
Thirty Respiratory Limited has developed a NO-generating liquid designed to release NO in 
situ in the upper airways and deep in the alveolar spaces (RESP301). RESP301 is an admixture 
solution of two precursor solutions mixed together at point of care for immediate inhaled 
administration via a CE-marked handheld nebuliser and has specific advantages 
 
over inhaled NO gas in treating a range of respiratory viruses, including SARS-CoV-2 in 
laboratory testing. RESP301 has also demonstrated potent activity against various influenza 
virus strains, rhinovirus and coronavirus. It has also shown high in vitro activity against 
respiratory pathogens, both viral and bacterial. 
Key advantages of RESP301 over inhaled NO gas are: 
• 
RESP301 demonstrates powerful evidence in vitro as a broad-spectrum 
anti-microbial; 
• 
Treatment is quick, easy and portable using a standard handheld nebuliser; 


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• 
The formulation is nebulised and forms a fine particle mist that settles on the lung 
surface, at the point of infection, and is therefore a more targeted approach; 
• 
NO production continues in-situ post treatment; 
• 
Because of the design of the formulation, production of NO2 is negligible by virtue 
of the NO2 being rapidly converted to a NO donor species. 
The novel concept for RESP301 is that it will restore the levels of NO in the lungs with a dual 
action of both killing virus and bacteria and boosting the host response against these pathogenic 
microbes.  
RESP301 delivers NO in a specifically focused way and with a unique mode of action. It is an 
important evolutionary step in delivering NO that is more physiological and overcomes the 
technical difficulties and efficacy limitations of current NO gas therapy. 
 
 
 
 
 
 
 
 
 RESP301 has at least 3 distinct mechanisms of action in fighting 
virus infection 
 two of which are common to many viruses and one is very specific 
to coronaviruses, such as SARS-CoV-2:  
• 
First it has a direct kill effect on the virus in the extracellular space. Nitric oxide-mediated 
nitrosylation of viral and host macromolecules appears to block viral replication and this 
has been demonstrated for several viruses (Saura et al, 1999; Basu et al, 1999). Enzymes, 
such as proteases (reverse transcriptases, and ribonucleotide reductase) which are vital 
for the life-cycle of the virus, are targets for nitric oxide nitrosylation (Benz et al, 2002; 
Chalmers et al, 2018 
• 
Chalmers JD, Chang AB, Chotirmall SH, Dhar R, McShane PJ. Bronchiectasis. Nat Rev 
Dis Primers. 2018; 4:45. 
• 
Colasanti et al, 1999). 
• 
Second, in coronaviruses, like SARS-CoV-2, it specifically prevents membrane fusion 
of the S-protein (the spike protein that gives the virus its characteristic crown-like 
appearance) to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell.  
• 
A third mechanism of action attacks the virus indirectly. Since viruses are non-living 
entities and do not have their own metabolism, they hijack the host cell’s metabolic 
processes, and derive their energy and specific cellular substrates from the host cell. 




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The proposed clinical trial will be an open-label, multicentre, feasibility study of an inhaled 
nitric oxide generating solution (RESP 301) in participants with COPD or bronchiectasis who 
are at risk of Respiratory Viral Infections, including SARS-CoV-2. 
 
Patients in the community with pre-existing respiratory disease are at a higher risk of adverse 
outcomes such as hospitalisation and/or death due to exacerbations caused by SARS-CoV-2 or 
other respiratory infections. This study will assess the safety, tolerability and feasibility of 
recruiting and retaining these patients and treating them with RESP 301 in the community at 
onset of viral symptoms.  
 
  
 
 
 


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3.2 Benefit/Risk assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of RESP301 may be found in the Investigator’s Brochure. 
3.2.1 Risk assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Potential Risk of Clinical 
Significance 
Summary of 
Data/Rationale for Risk 
Mitigation Strategy 
patient may increase risk of 
spread of disease 
minimise the risk of spread 
of disease. 
 
3.2.2 Benefit assessment 
Patients with an underlying respiratory illness (e.g. COPD, bronchiectasis) are at higher risk of 
adverse outcomes due to exacerbations caused by SARS-CoV-2 or other respiratory infections. 
To date, no treatment of COVID-19 has demonstrated clinical efficacy. Patients and their 
physicians are critically in need of treatments that decrease the risk of severe levels of disease, 
particularly the rate of intubation or other ventilatory support as they significantly lead to fatal 
outcomes. Considering the current pandemic, even a limited improvement in the rate of 
progression to severe stage of the disease would provide sizable benefits for patients and 
society. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.2.3 Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimise risk to participants in this study, the 
potential risks identified in association with RESP301 are justified by the anticipated benefits 
that may be afforded to participants at high risk of adverse outcomes due to exacerbations 
caused by SARS-CoV-2 or other respiratory infections. 
4 Objectives and endpoints 
Table 4-1 
Objectives and Endpoints 
 


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Objectives 
Endpoints 
Primary 
• To determine the maximum tolerable 
dose (MTD) and recommended 
therapeutic dose (RTD) of RESP301 in 
patients with mild to moderate COPD or 
bronchiectasis 
• To assess the feasibility of recruiting 
and retaining patients with COPD or 
bronchiectasis who have viral infection 
symptoms and treating these patients 
with RESP301 in a community setting. 
• Proportion of patients tolerating 
RESP301 at each dose level in Part 1 
(according to pre-defined criteria) 
• Feasibility of self-administering 
RESP301 treatment with nebuliser  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
Secondary 
The following secondary objectives will be 
considered for the cohort as a whole, and in 
addition for a sub-cohort of those who have 
confirmed SARS-CoV-2 infection: 
1) To assess the safety and tolerability of 
RESP301 in patients with COPD or 
bronchiectasis, who are at high risk of 
SARS-CoV-2 and other acute 
respiratory pathogens. 
 
 
 
To be evaluated on the full cohort, and 
separately in the sub-cohort of those who 
test positive for SARS-CoV-2: 
 
1) Safety and tolerability of RESP301  
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2) To collect preliminary data on the 
efficacy of RESP301 in treating 
exacerbations in patients with COPD or 
bronchiectasis. 
o 
 
 
 
 
 
 
 
 
 
 
 
 
•  Total counts and cumulative incidence 
of: 
• Adverse Events (AEs) 
• Serious Adverse Events (SAEs) 
• Suspected Unexpected Serious 
Adverse Reaction (SUSARs) 
• Severe AEs 
• Treatment-related AEs/SAEs 
 
Feasibility in terms of percentage of patients 
who, having experienced and correctly 
reported an exacerbation, receive the 
treatment within 
 of reporting their 
exacerbation 
 
2) Efficacy of RESP301 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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5 Study design 
5.1 Overall design 
This is an open-label, single arm, multicentre study to investigate the feasibility, safety and 
tolerability of RESP301 in patients with pre-existing respiratory disease who are at higher risk 
of adverse outcomes such as hospitalisation and/or death due to exacerbations caused by 
SARS-CoV-2 or other respiratory infections. The study is conducted in a clinical setting in Part 
1 
 Part 2 of the study will assess the 
feasibility of recruiting and retaining these patients in a community setting 
 
 
 
Part 1(a): Dose Finding Phase 
In Part 1(a), 
 subjects with COPD will be enrolled in separate cohorts to receive a 
single dose of 
 or 
of RESP301. Each cohort will comprise 
 
subjects. This part of the study will consist of one visit in which subjects receive a single dose 
of RESP301 in the clinic on Day 1, with a follow up safety phone call being conducted on the 
morning of Day 2 to check for any adverse events. Enrollment to these cohorts will be 
sequential and subsequent cohorts will only be enrolled after safety review of the previous 
cohort. The safety reviews will be conducted by the safety advisory committee (SAC), 
comprising the site Principal Investigators (or delegates) and the Sponsor’s Executive Medical 
Officer as a minimum. 
 
o 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 


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Subjects can receive more than one dose level as long as they did not meet individual stopping 
criteria from any given prior dose. 
Part 1(b): Concomitant Medication Expansion Phase 
In part 1(b) up to 
patients with COPD or bronchiectasis will be enrolled into a cohort to 
receive a short-acting inhaled broncholdilator (2 inhalations of Ventolin - 
 per 
inhalation) through a spacer device 10 minutes before receiving a single dose of RESP301 at 
the MTD determined in part 1(a). Subjects will continue Standard of Care medication prior to 
receiving RESP301 apart from their usual short acting bronchodilators which will be withheld 
for 
 before dosing with RESP301. Pre-dose short acting bronchodilator will then be 
administered in clinic. 
Subjects from Part 1a may also enter Part 1b (if deemed eligibile). 
This part of the study will operate under the same oversight, monitoring and follow up criteria 
as Part 1(a) 
Part 2: Expansion Phase 
Baseline Visit 
Once the RTD has been established in Part 1, 
 
 
• 
 
 
 
 
 
 
During the visit participants who satisfactorily tolerate the test dose will be enrolled into the 
“dormant period”.  
All patients including those receiving the test dose will undergo the following procedures  
• Informed consent 
• Inclusion and exclusion criteria 
• Any medical assessments (e.g. heart or lung examination) which in the PI’s opinion are 
required to assess whether the patient is suitable for the trial 
• Demographic information 
• Medical history and concurrent medications 
• Height and weight 
• Vital signs 
• Pulmonary function tests (FEV1, FVC and % predicted), if required 


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Subjects that participate in Part 1 and do not meet any of the individual stopping criteria can 
enrol in Part 2. Eligibility criteria will be reassessed prior to entering Part 2 of the trial. 
Participants who have not satisfied inclusion/exclusion criteria will be excluded from 
continuing in the study.  
 
An independent Data Monitoring Committee will review the data from the 
 participants that 
received RTD. Based on the data from these participants, it will be decided whether test doses 
should be administered to further participants for the remaining duration of the study. 
 
Dormant period 
 
A minimum of 
 patients will be enrolled into the dormant period and it is expected that 
approximately 
 patients will go on to receive treatment in the treatment period of the trial. 
The duration of the dormant period is from Day 1 of Part 2 of the trial, until the first 
exacerbation or end of study at week 52. During this period, monthly calls will be conducted. 
 
Treatment period 
 
A patient entered into the dormant period who experiences exacerbation symptoms for at least 
 will be eligible to enter the Treatment period. Patients will be instructed to contact 
the study team as soon as practicable to allow a study interaction to be undertaken remotely 
(via video link, if possible), within 
 of onset of at least one of the following:  
• Fever (>38.0°C),  
• Systemic malaise,  
• Increased cough or wheeze,  
• Increased  sputum volume or increased purulence.  
During the remote visit the patient’s symptoms will be discussed and if the patient is willing to 
continue in the study,
 
 
 
Note that if COVID-19 is suspected, the patient will be advised to follow the prevailing NHS 
guidance on testing for COVID-19 taking into account any specific recommendations for 
patients with COPD or bronchiectasis.  Where serial SARS-CoV-2 swabs are undertaken, data 
will be collected for analysis. 
During the treatment period, 
, at home/ community setting, patients will be asked 
to: 
• Administer RESP301 
 at the dose determined in Part 1 of the study 
(RTD). 
• Take daily temperature measurements 
• Complete a daily diary to record treatment doses  




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5.4 End of Study Definition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of the study is defined as the last participant’s last follow up call. 
6 Study Population and Recruitment 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 


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The study population will consist of male and female patients with 
 
Participants must be able to provide written consent and meet all the inclusion criteria and none 
of the exclusion criteria. 
 
 
 
 
 Participants can also be recruited through advertising 
on social media, newsletters, websites etc. using materials approved by the Research Ethics 
Committee. 
6.1 Study Rationale 
This is a single arm, non-randomised, multicentre, open-label study to determine 
 
 
 
 
.  
Considering 
the current public 
health emergency resulting from the COVID-19 pandemic, a Phase 2 study of RESP301 is 
considered reasonable in order to generate efficacy data in patients at risk of adverse outcomes 
such as hospitalisation and/or death due to exacerbations caused by SARS-CoV-2 or other 
respiratory infections. 
 
 
 


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6.2 Inclusion Criteria 
 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is a female of non-childbearing potential or male 
 at the 
time of signing the informed consent. 
Informed Consent 
2. Participant is capable of giving signed informed consent as described in Section 11.2 
 
 
Type of Participant and Disease Characteristics 
3. Spirometry-confirmed diagnosis of COPD (
 
a) or CT proven bronchiectasis 
4. 
 
 
6.3 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Unable to safely use a nebuliser as required by the study according to Investigator’s opinion 
2. Severe COPD or bronchiectasis defined 
  
3. History of methaemoglobinaemia 
4. 
 
5. Uncontrolled or severe asthma or history of severe bronchospasm 
6. Presence of tracheostomy/inability to provide spirometry or contraindication for 
performing spirometry 
7. Any unstable, uncontrolled or severe medical condition which in the opinion of the 
investigator would make the patient unsuitable for the trial 
8. On long-term non-invasive ventilation and/or at higher risk of bronchospasm 
9. 
 
 


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Prior/Concurrent Clinical Study Experience 
10. Participation in other clinical investigations utilising investigational treatment within the 
last 30 days / 5 half-lives whichever is longer, excluding participation in Part 1 of this study 
Other exclusions 
11. Allergy to any of the components of the study intervention 
12. Deemed unlikely to be able to adhere to protocol in view of investigator 
13. Any subject who in the opinion of the investigator would not be best served by participating 
in this clinical trial 
14. Participant lives at home with no other adults in the household (Part 2 only) 
15. 
 
 
16. Female of childbearing potential 
 
 
6.4 Lifestyle Considerations 
No restrictions are required. 
6.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
do not subsequently meet all of the inclusion criteria or meet one or more of the exclusion 
criteria 
 
 
 
 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. 
6.6 Screening and Enrollment Log and Participant Identification 
Numbers 
The participant’s enrollment will be recorded in the Screening and Enrollment Log. 
Upon enrollment, each participant will receive a unique participant identification number. 
Participant numbers must not be re-used for different participants. 
 


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7 Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
7.1 Study Intervention Administered 
Table 7-1 
Study Intervention(s) Administered 
 
Study Treatment 
 
Intervention Name: 
RESP301 
Type: 
Drug 
Dosage Formulation: 
Admixture for inhalation 
Unit Dose 
Strength(s): 
 
 
 
Dosage Level(s): 
 
 
Route of 
Administration: 
Inhalation 
IMP and NIMP: 
IMP 
Sourcing: 
RESP301 provided centrally by the Sponsor. 
Dosing Instructions: 
 
 
 
 
 
 
 
Packaging and 
Labeling: 
 
 
  
 
7.1.1 Medical Devices 
1. Medical device 
 provided for 
use in this study will be an FDA-approved and CE-marked 
 nebuliser.  
2. Instructions for medical device use will be provided in the participant instruction 
manual which will be provided at the first study visit and with the device. 


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7.1.2 Device Training  
Training will be provided to ensure all study staff are familiar with the device, 
 
 cleaning the device. 
7.2 Preparation, Handling, Storage, and Accountability 
7.2.1 
Preparation of Study Intervention Product 
RESP301 is prepared by mixing 
 
 in the nebuliser. The solution is to be nebulised within 5 minutes post 
mixing as per the instructions given in the SoA 
  
RESP301 is mixed in the nebuliser chamber before use following the steps below 
 
 
 
 
 
 
 
 
 
 
 
 purpose of the aerosol is to deliver NO to the participant.
 
 
 
 
 
 
 


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7.2.2 
Storage and Accountability of Study Intervention at site 
The Investigator or designee must document whether appropriate temperature conditions 
have been maintained during storage for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
 
 
 
 
 
Only participants enrolled in the study may receive study intervention and only authorised site 
staff may supply or administer the test dose at site. All RESP301 kept at site(s) must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorised site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (e.g., 
receipt, reconciliation, and final disposition records) for RESP301 stored at site. 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Investigator Manual. 
 


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7.2.3 Storage of Study Intervention at home 
 
All RESP301 delivered to the study participants must be stored securely at 
 
 
7.3 Measures to Minimise Bias: Randomisation and Blinding 
This is an open-label, non-randomised single arm study. Potential bias will be reduced by 
keeping the eligibility criteria as broad as possible, and by enrolling participants through both 
primary and secondary care sites. All participants included in the study are at high risk of 
adverse outcomes due to exacerbations caused by SARS-CoV-2 or other respiratory infections 
 
 
 
7.4 Study Intervention Compliance 
Participants will receive the first study intervention dose directly from the Investigator or 
designee, under clinical supervision. 
 
  
 
 
 
 
7.5 Concomitant Therapy 
During the study, participants will receive SOC for the treatment of respiratory infection and 
underlying conditions. 
 
 
 
 
 The Medical Monitor should be 
contacted if there are any questions regarding concomitant or prior therapy. 
 
 
 
 
 


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• 
 
 
 
 
 
7.5.1 
Rescue Medication 
Not applicable.
 
 
 
 
7.6 Intervention After the End of the Study 
After the end of the study, participants may continue their SOC (if any). 
 
 
7.7 Stopping Criteria for Dose Finding Phase (Part 1a &1b) 
7.7.1 Dose Finding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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7.7.4 Study Stopping Criteria 
 
The Sponsor and the Investigator reserves the right to discontinue this study or the participation 
of any subject at any time for any reason. Certain circumstances may require the premature 
termination of the study, if the Investigator or the Sponsor feel that the type, number, 
relatedness, and/or severity of AEs justify discontinuation of the trial. 
 
  
 
 
 
 
 
 
 
 
 
7.8 Discontinuation of Study Intervention and Participant 
Discontinuation  
7.8.1 Permanent Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is definitively discontinued, the participant will remain 
in the study to be evaluated for safety on 
 
 
 
 
 


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7.8.2 Temporary Discontinuation of Study Intervention 
 
Brief temporary discontinuation of study intervention is permitted during the test dose 
administration and treatment period, 
 
  
 
 
 
 
7.8.3 Participant Discontinuation/Withdrawal from the Study 
 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioural, or 
administrative reasons. The participant will be definitively discontinued from both the study 
intervention and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 
 
 
 
7.8.4 Loss of Participants to Follow-Up 
A participant will be considered lost to follow-up if he or she is unable to be contacted by the 
study site. 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
7.9 RESP301 Safety 
 
NOCOV2 Study 
NOCOV2, is a first-in-human, phase 2/3 open-label, adaptive randomized, controlled 
multicenter study to evaluate the efficacy and safety of RESP301 plus standard of care (SOC) 
compared to SOC alone in hospitalized participants with COVID-19 WHO grade 3&4 in the 
UK (NCT04460183)  
At the time of writing the safety data have not been audited and are incomplete,
 
 
 
 
 
 
 
 
 
   
CORVIS 
 
At the time of writing 4 patients have been screened, which included each receiving a test dose 
of RESP301. 
 
 
 
  
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At the time of writing the safety data have not been audited and are incomplete, as the trial is 
currently temporarily suspended to allow for a substantial amendment to be submitted. 
 
8 Study Assessments and Procedures 
 
 
 


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Table 8-1 
Schedule of Activities (SoA) 
 
Part 1 (a & b) 
Part 2 
 
Procedure 
Screen 1 
Screen 
2/Dosing Visit 
(Day 1) a 
Follow-up 
Phone Call 
(Day 2) 
Screen 
1 
Screen 2 
/ 
Baseline 
Visitb 
Dormant 
period 
(monthly 
call) 
Pre-
treatment 
call 
(within 24 
- 72 hrs of 
exacerbati
on onset) 
Treatment 
Period 
(daily 
monitoring 
call for 8 
days) 
Post-
treatment 
Follow-up 
call (Day 
14 (± 3) 
PEoT  
Post-
treatment 
Follow-up 
call 
(Day 28 (± 
3) PEoT) 
Early 
withdrawal 
(Days 0, 14 
and 28 (± 3) 
post 
withdrawal) 
Notes 
Informed consent 
X 
 
 
X 
X 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
X 
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
X 
 
 
 
 
 
 
 
 
Medication history and 
concomitant 
medications 
X 
 
 
X 
 
 
 
 
 
 
 
 
Height, weight, BMI 
X 
 
 
X 
 
 
 
 
 
 
 
 
Physical examinations 
(X) 
(X) 
 
(X) 
(X) 
 
 
 
 
 
 
Any 
examinatio
ns which in 
the PI’s 
opinion are 
required in 
order to 
assess  
suitability 


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Pulmonary function 
tests 
(X)c 
X 
 
(X) 
X 
 
 
 
 
 
 
In Part 1 
and Part 2 
Screen 1, 
post 
bronchodila
tor if not 
recorded in 
medical 
record. Pre 
bronchodila
tor should 
be assessed 
at a screen 
visit (prior 
to test dose) 
In Part 2, 
first 50 
participants 
only: FEV1 
% predicted 
measured 
pre and 
post test 
dose.  
 
Vital signs 
X 
X 
 
X 
X 
 
 
 
 
 
 
Body 
temperature
, pulse, 
respiration 
rate, blood 
pressure 


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Part 1 (a & b) 
Part 2 
 
Procedure 
Screen 1 
Screen 
2/Dosing Visit 
(Day 1) a 
Follow-up 
Phone Call 
(Day 2) 
Screen 
1 
Screen 2 
/ 
Baseline 
Visitb 
Dormant 
period 
(monthly 
call) 
Pre-
treatment 
call 
(within 24 
- 72 hrs of 
exacerbati
on onset) 
Treatment 
Period 
(daily 
monitoring 
call for 8 
days) 
Post-
treatment 
Follow-up 
call (Day 
14 (± 3) 
PEoT  
Post-
treatment 
Follow-up 
call 
(Day 28 (± 
3) PEoT) 
Early 
withdrawal 
(Days 0, 14 
and 28 (± 3) 
post 
withdrawal) 
Notes 
Methaemoglobin level  
X 
X 
 
X 
X 
 
 
 
 
 
 
Pre-, during 
and post- 
test dose  
Short acting 
bronchodilator before 
single dose 
administration of 
RESP301 
 
X (Part 1(b) 
only) 
 
 
 
 
 
 
 
 
 
2 puffs of 
100cg 
Ventolin 
through a 
spacer 10 
mins before 
test dose 
Test dose 
administration of 
RESP301 and assessing 
response 
 
X 
 
 
X 
 
 
 
 
 
 
In Part 2, 
for the first 
50 
participants 
at 
minimum. 
CCQ 
 
 
 
 
X 
 
 
X (days 1 
and 7) 
X 
 
 
 


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Part 1 (a & b) 
Part 2 
 
Procedure 
Screen 1 
Screen 
2/Dosing Visit 
(Day 1) a 
Follow-up 
Phone Call 
(Day 2) 
Screen 
1 
Screen 2 
/ 
Baseline 
Visitb 
Dormant 
period 
(monthly 
call) 
Pre-
treatment 
call 
 
 
Treatment 
Period 
 
 
 
 
Post-
treatment 
Follow-up 
 
 
Post-
treatment 
Follow-up 
 
 
Early 
withdrawal 
 
 
 
Notes 
Instructions to 
participants 
 
 
 
 
X 
 
X 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Review of symptoms 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Study intervention, TID 
 
 
 
 
 
 
 
X 
 
 
 
 






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Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Table 8-1). 
8.1 Screening Visits (Part 1 and Part 2) 
 
 
 
8.1.1 Informed Consent 
Informed consent must be documented according to Section 11.2. 
8.1.2 Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or designee to ensure 
that the participant qualifies for the study. 
8.1.3 Demographics 
Age, gender and ethnicity should be recorded in the eCRF. 
8.1.4 Medical history and medications 
A medical history will be obtained by the Investigator or qualified designee. 
 
 
 
 
 
 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 3 months prior to screening.  


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Smoking status and history should also be recorded in the eCRF. 
8.1.5 Examinations and tests 
Physical examinations 
Height and weight should be measured and recorded in the eCRF, along with BMI. 
 
 
 
  For all participants in 
Part 1 and for the minimum of first 50 participants in Part 2, spirometry will be perfomed to 
 For all participants 
thereafter, these will be measured only if the Data Monitoring Committee recommends that 
post test dose assessments should be continued.  
 
 
 
  
No other physical examinations are required for the study. However, the Principal Investigators 
should use their clinical judgement to assess the patients’ suitability for the trial, and as part of 
this assessment, may decide to perform some physical examinations. Any abnormal physical 
examination findings should be recorded in the eCRF and medical records. 
Vital signs 
Vital signs to be collected include 
 
 signs should be taken while the patient is supine. 
 
 
  
 
  
Methaemoglobin level 
As part of eligibility screening, methaemoglobin level will be measured using a non-invasive 
fingertip monitor 
 


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8.1.6 RESP301 tolerability 
In Part 1 of the study, RESP301 tolerability will be assessed in all participants at each dose 
cohort against the individual stopping criteria (Section 7.7.2). In Part 2 of the study, a minimum 
of 50 consented participants who passed the eligibility criteria will receive a test dose of 
RESP301 to assess tolerability. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In Part 1, participants who do not meet any of the Individual Stopping Criteria (Section 7.7.2), 
and are suitable in the Investigator’s opinion to proceed, can proceed to the next cohort (subject 
to SAC review). 
In Part 2, participants who satisfactorily tolerate the test dose based on the above assessments, 
and are suitable in the Investigator’s opinion to proceed, will be enrolled into the dormant 
period of the study. 
Participants who completed the Screening visit and test dose but were not suitable to continue 
to the dormant period, should be followed up with a phone call 7
 
. 


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8.1.7 The Clinical COPD Questionnaire (CCQ) (Part 2 only) 
The Clinical COPD Questionnaire (CCQ) is a validated, self-administered 10-item 
questionnaire which measures health status and can be used to assess health-related quality of 
life (van der Molen et al, 2003). It has three domains: symptoms (4 items), functional status (4 
items) and mental state (2 items), graded on a 7-point Likert scale from 0 to 6 (0 = no 
impairment). The final score is the sum of all items divided by 10; separate scores for all three 
domains can be calculated. Higher scores indicate a worse health status. 
8.1.8 Instructions to participants (Part 2 only) 
Participants who satisfactorily tolerate the test dose in Part 2, or are not required to take the 
test dose (subject to DMC recommendations), will be trained in preparation, administration 
and transport of the drug product, and the care and cleaning of the nebuliser. 
 
  
 
  
 
 
 
 
 
 
8.1.9 AE/SAE 
Any Adverse Events observed during the visit should be recorded in the eCRF. 
 
 
 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up until the AE has resolved, has stabilised or is otherwise explained, is no longer of clinical 
concern, or the patient is lost to follow-up 
 
8.2 Dormant period 
During the dormant period, the participants will receive monthly follow-up calls to remind 
them to contact the study team if they start experiencing exacerbation symptoms. 


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8.3 Pre-treatment appointment 
A participant who experiences symptoms for at least 
 should contact the study team 
as soon as practicable to allow a remote study appointment to be undertaken within 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any changes to medical history or medications reported by the patient should be recorded in 
the eCRF. 
8.4 Treatment period 
During the treatment period at home/community setting, patients will be asked to: 
• 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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Each participant will only receive a maximum of one course of treatment of RESP301 during 
the study. 
 
 
 
 
 
Participants should return the completed diaries and CCQ questionnaires to the study team 
 
8.5 Post-treatment Follow-up calls 
For all participants enrolled into the treatment period, follow-up calls will be conducted
 
 to discuss any AEs, changes to medications or 
medical history (including COVID-19 test results, if available). 
Symptoms, AEs, and changes to medications or medical history (including COVID-19 test 
results, if available) will be recorded in eCRF. 
The 
 follow-up call will be the end of study for participants enrolled into the treatment 
period, unless there are any unresolved AEs which should be followed up until resolved,  
stabilised or otherwise explained, no longer of clinical concern, or the patient is lost to follow-
up 
 
8.6 Early Withdrawal 
At the time of discontinuing from the study, if possible, an early discontinuation assessment 
should be conducted, as shown in the SoA (Table 8-1). 
 
 
• 
 
 
 
 
 
 
 
 
 
 


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9 Pharmacovigilance 
Further details are provided in Appendix 1: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting. 
9.1 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 1: Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up until the AE has resolved, has stabilised or is otherwise explained, is no longer of clinical 
concern, or the patient is lost to follow-up 
 
9.2 Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from signing of informed consent until the last follow-up 
visit at the time points specified in the SoA (Table 8-1). 
 
 
 
 
 
 
 
9.3 Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 1: Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
 
 
 
9.4 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 


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stabilisation, until the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section
 
Further information on follow-up procedures is given in Appendix 1: Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
9.5 Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours) by the Investigator to the Sponsor of an SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the local IRB/IEC, if appropriate according to local 
requirements.. 
9.6 Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs (Not Applicable) 
 
9.7 Adverse Events of Special Interest (Not Applicable) 
No AEs of special interest are defined for this study. 
9.8 Medical Device Deficiencies (Not Applicable) 
The medical device to be used in this study is a 
 nebuliser that is FDA-approved 
and CE-marked and is to be used per the manufacturer’s recommendations. Therefore, data on 
device deficiencies will not be collected in this study. 


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10 Statistical Considerations 
10.1 Statistical Hypothesis 
Since this is an open label non-randomised study where the primary objective is to assess 
feasibility, no formal statistical analysis will be performed.  
10.2 Sample Size Determination 
The primary objective of this study is to determine
 
 and no formal sample size calculation was performed.  
In Part 1, we aim to recruit 
 participants 
 
In Part 2, we aim to recruit 150 patients from secondary care and primary care sites in the UK 
into the dormant period. 
 
 
 
  
 
 
10.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 


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Table 10-1 
Populations for Analysis 
Population (Analysis 
Set) 
Description 
Intent-To-Treat (ITT) 
Population 
The ITT Population will include all participants enrolled into 
the treatment period. Participants who withdraw from 
treatment early will be followed for the assessment of the Day 
7 primary endpoint. All efficacy analyses will be performed 
using the ITT Population. 
Per Protocol (PP) 
Population 
The PP Population will include all participants in the ITT 
Population with no major protocol deviations that may 
significantly impact data integrity or patient safety. The PP 
Population will be used for supportive analyses of the efficacy 
measurements. 
Safety Population (SP) 
The SP will include all participants who inhale any amount of 
study intervention. 
 
The ITT Population will be the primary analysis set for all efficacy analyses and the PP 
Population will be used to demonstrate robustness of results for the efficacy endpoint. 
10.4 Statistical Analyses 
Below is a description of planned statistical analyses. Further details are presented in the 
Statistical Analysis Plan (SAP). 
10.4.1 General Considerations 
Data will be presented using appropriate summary statistics and patient data listings. In general, 
missing values will not be replaced unless otherwise stated. Baseline will be considered the 
latest assessment before first dose of study treatment. 
A flow diagram of participant progress will be provided, including the number assessed for 
eligibility and reasons for exclusion, number enrolled, and participants with early withdrawal 
from the study, together with the primary reasons for discontinuations. Any recorded protocol 
deviations will be listed. 
10.4.2 Primary Endpoint 
 
In Part 1, the primary endpoint is the proportion of patients tolerating RESP301 at each dose 
level in (according to pre-defined criteria). 
 


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In Part 2, the primary endpoint is the feasibility of self-administering RESP301 treatment with 
nebuliser 
 
• 
 
 
  
 
 
 
 
 
 
10.4.3 Secondary Endpoint(s) 
The secondary endpoints, which will be analysed on the full cohort and separately in the sub-
cohort of those who test positive for SARS-CoV-2, are safety and tolerability and efficacy of 
RESP301. The endpoints are further defined below. 
1) Safety and tolerability of RESP301 
 
• 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
All safety analyses will be performed on the Safety Population, ITT and PP,. Adverse Events 
will be coded using the MedDRA coding dictionary. 


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The number and percentage of participants with any AE, any related AE, any SAE, any related 
SAE, any severe AE, and related severe AE as well as the total number of events for each 
category will be summarised. The number of deaths due to an AE, hospitalisation due to an 
AE, and study discontinuation due to an AE will be summarised. 
The number and percentage of participants with an AE, as well as the total number of AEs, 
will be summarised by SOC and preferred term. This tabulation will be repeated for related 
AEs, SAEs, related SAEs, severe AEs, and related severe AEs. 
All AEs will be provided in patient listings. Patient listings of AEs causing discontinuation of 
study medication, AEs leading to death, SAEs, related AEs, and severe AEs will be produced. 
2) Efficacy of RESP301 
 
•
 
 
  
 
 
  
  
 
 
 
10.4.4 Other Analyses 
Other analyses may be added to the SAP as applicable. 
10.5 Interim Analyses 
No formal statistical interim analysis is planned. 
10.6 Data Monitoring Committee (DMC) 
An IDMC will be responsible for closely reviewing the safety data and for providing their 
recommendations on continuation of the study. The detailed procedures and schedule of the 
meetings will be described in the DMC Charter. 
11 Regulatory, Ethical, and Study Oversight Considerations 
11.1 Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 


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o Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines. 
o Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IEC/IRB approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC. 
• Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures. 
• Overall conduct of the study at the site and adherence to requirements of 21 Code 
of Federal Regulations (CFR), ICH GCP guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
11.2 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be required 
to sign a statement of informed consent that meets the local regulations, ICH guidelines, and 
the IRB/IEC or study centre. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol. If the ICF is revised, it must be reviewed and approved by the appropriate 
IEC/IRB and signed by all participants subsequently enrolled in the study as well as those 


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currently enrolled in the study if they are affected by the revisions. A measured approach 
should be taken to determine which participants need to be reconsented. 
11.3 Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
11.4 Committees Structure 
An IDMC will be responsible for closely reviewing the safety data and for providing their 
recommendations on continuation of the study (see Sections 10.5 and 10.6). 
11.5 Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategies (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 


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• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organisations [CROs]). 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorised site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 2 years after the last approval of a 
marketing application or 15 years from completion of the study, whichever is longer 
according to the relevant local laws and/or regulations. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may 
be transferred to another location or party without written notification to the Sponsor. 
• All data generated by the site personnel will be captured electronically at each study 
center using eCRFs. Once the eCRF clinical data have been submitted to the eCRF, 
corrections to the data fields will be captured in an audit trail. The reason for change, 
the name of the person who performed the change, together with the time and date will 
be logged to provide an audit trail. 
• If additional corrections are needed, the responsible monitor or data manager will raise 
a query in the electronic data capture (EDC) application. The appropriate staff at the 
study site will answer queries sent to the Investigator. The name of the staff member 
responding to the query, and time and date stamp will be captured to provide an audit 
trail.  
• The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site 
personnel will receive training on the EDC system/eCRF. 
11.6  Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 


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11.7 Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the first participant signing the informed consent 
form and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure (on site visit or remote closure) has been 
performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
11.8 Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
at least one month before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicentre studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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11.9 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. 
The Sponsor must ensure that all ethical and legal requirements have been met before the first 
participant is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate).  
Administrative changes (not affecting the participant benefit/risk ratio) may be made without 
the need for a formal amendment. All amendments will be distributed to all protocol recipients, 
with appropriate instructions. 
11.10 Liability and Insurance 
The study Sponsor holds a Clinical Trials Insurance for legal liabilities arising in relation to 
this trial. NHS bodies are legally liable for the negligent acts and omissions of their employees. 
If a patient is harmed whilst taking part in a clinical study as a result of negligence on the part 
of a member of the study team this liability cover would apply. 
11.11 Access to Source Data 
Access to source data is described in the Clinical Trial Agreement for each site. 
 
 
 
 
 
 
 
 
 
 
 


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ACRO, 2020 
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inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J. Virol. 
2005; 79:1966–9. 
Ali-Ahmad D et al, 2003 
Ali-Ahmad D, Bonville CA, Rosenberg HF & Domachowske JB. Replication of respiratory 
syncytial virus is inhibited in target cells generating nitric oxide in situ. Frontiers in 
Biosciences. 2003; 8:a48-53. 
Bafadhel et al, 2011 
Bafadhel M, Mckenna S, Terry S, Mistry V, Reid C, Haldar P, et al. Acute exacerbations of 
chronic obstructive pulmonary disease: identification of biologic clusters and their 
biomarkers. Am J Respir Crit Care Med. 2011; 184:662–71. 
Basu et al, 1999 
Basu A, Sehajpal PK, Ogiste JS, Lander HM: Targeting cysteine residues of human 
immunodeficiency virus type 1 protease by reactive free radical species. Antioxidants & 
Redox Signaling. 1999; 1:105-12. 
Benz et al, 2002 
Benz D, Cadet P, Mantione K, Zhu W, Stefano GB. Tonal nitric oxide and health: 
antibacterial and antiviral actions and implications for HIV. Med Sci Monit. 2002; 8:27-31. 
Brannan et al, 2005 
Brannan D, Anderson SD, Perry CP, Freed-Martens F, Lassig AR, Charlton B and the Aridol 
Study Group. The safety and efficacy of inhaled dry powder mannitol as a bronchial 
provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic 
(4.5%) saline. Respiratory Research 2005; 6:144. 
British Thoracic Society, 2012 
British Thoracic Society 2012 COPD Care Bundles Project, London, United Kingdom 
Chalmers et al, 2018 
Chalmers JD, Chang AB, Chotirmall SH, Dhar R, McShane PJ. Bronchiectasis. Nat Rev Dis 
Primers. 2018; 4:45. 
Colasanti et al, 1999 
Colasanti M, Persichini T, Venturini G, Ascenzi P. S-nitrosylation of viral proteins: 
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Cox et al, 2020 
Cox MJ, Loman N, Bogaert D, O’Grady J. Co-infections: potentially lethal and unexplored in 
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Devon LPC and Mediapharm, 2014 
Devon Local Pharmaceutical Committee (LPC) and Mediapharm. Chronnic Obstructive 
Pulmonary Disease (COPD) Consultation Toolkit. http://psnc.org.uk/devon-lpc/wp-
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October 2020] 
EMA, 2020 
European Medicines Agency (EMA). Guidance on the Management of Clinical Trials during 
the COVID-19 (Coronavirus) pandemic, v.2 (27 March 2020). 
Fang, 1997 
Fang FC. Mechanisms of nitric oxide-related antimicrobial activity. J. Clin. Invest. 1997; 
9:2818-25 
Folkerts et al, 1998 
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hyperresponsiveness and asthma. Am J Respiratory Critical Care Medicine. 1998; 157:1708-
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GBD 2019 Diseases and Injuries Collaborators, 2020 
GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 
204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of 
Disease Study 2019. Lancet. 2020; 396:1024-22. 
Hardwick et al, 2001 
Hardwick JB, Tucker AT, Wilks M, Johnston A, Benjamin NA. Novel method for the 
delivery of nitric oxide therapy to the skin of human subjects using a semi-permeable 
membrane. Clin Sci (Lond). 2001; 100:395-400. 
Harper et al, 2009 
Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG, et al. Seasonal 
influenza in adults and children–diagnosis, treatment, chemoprophylaxis, and institutional 
outbreak management: clinical practice guidelines of the Infectious Diseases Society of 
America. Clin Infect Dis. 2009; 48:1003–32. 
HRA, 2020 
Health Research Authority (HRA) (NHS), UK. Guidance about COVID-19 for sponsors, 
sites and researchers, v2.2, 26 March 2020. 
Huang et al, 2020 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected 
with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:497-506. 


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Hurst et al, 2010 
Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H, Tal-Singer R, et al. Susceptibility 
to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010; 363:1128–38. 
Johnston & Sears, 2006 
Johnston NW & Sears MR. Asthma exacerbations. 1: epidemiology. Thorax. 2006; 61:722–8. 
Kao et al, 2001 
Kao YJ, Piedra PA, Larsen GL, & Colasurdo GN. Induction and regulation of nitric oxide 
synthase in airway epithelial cells by respiratory syncytial virus. Am J Respir Crit Care Med. 
2001; 163:532-9. 
Mallia et al, 2012 
Mallia P, Footitt J, Sotero R, Jepson A, Contoli M, Trujillo-Torralbo MB, et al. Rhinovirus 
infection induces degradation of antimicrobial peptides and secondary bacterial infection in 
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012; 186:1117–24. 
Parsley et al, 2013 
Parsley EL, Masamune H, Hoye WL, Rubin LJ & Gladwin MT. P66: Nebulized inhaled 
nitrite (AIR001) for pulmonary arterial hypertension: Studies to determine safety, 
pharmacokinetics, and maximum tolerated dose, lack of pharmacodynamic interaction with 
sildenafil and optimal nebuliser device. Nitroc Oxide. 2013; 31(Suppl 1):S41-42. 
Regev-Shoshani et al, 2013 
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nitric oxide reduces influenza infectivity in vitro. Nitric oxide. 2013; 31:48-53. 
Rimmelzwaan et al, 1999 
Rimmelzwaan GF, Baars MM, de Lijster P, Fouchier RA & Osterhaus AD. Inhibition of 
influenza virus replication by nitric oxide. J. Virol. 1999; 73:8880–3. 
Rix et al, 2015 
Rix PJ, Vick A, Attkins NJ, Barker GE, Bott AW, Alcorn Jr. H, et al. Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of Nebulized Sodium Nitrite (AIR001) 
Following Repeat-Dose Inhalation in Healthy Subjects. Clin Pharmacokinet. 2015; 54:261–
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Roberts and Hubbard, 2010  
Roberts HJ, Hubbard R. Trends in bronchiectasis mortality in England and Wales. Respir 
Med. 2010; 104:981-5. 
Sanders et al, 1998 
Sanders SP, Siekierski ES, Porter JD, Richards SM & Proud D. Nitric oxide inhibits 
rhinovirus-induced cytokine production and viral replication in a human respiratory epithelial 
cell line. J. Virol. 1998; 72:934-42. 
Saura et al, 1999 
Saura M, Zaragoza C, McMillan A, Quick RA, Hohenadl C, Lowenstein JM, et al. An 
antiviral mechanism of nitric oxide: inhibition of a viral protease. Immunity. 1999; 10:21-8. 


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Seemungal et al, 2001 
Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, et al. 
Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable 
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001; 164:1618–23. 
Simon et al, 2016 
Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, et al. Acute 
hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with 
heart failure with preserved ejection fraction. JCI Insight. 2016; 1:e89620. 
Tucker et al, 2007 
Tucker AT, Barnes NC, Johnston A, Elston WJ, Watson D, Wilks M et al. Formulation and 
validation of a novel solution of nitric oxide for delivery to the respiratory tract. Br. J. Clin. 
Pharmacol. 2007:781-781 (abstract). 
Tucker et al, 1999 
Tucker AT, Pearson RM, Cooke ED, Benjamin N. Effect of nitric-oxide-generating system 
on microcirculatory blood flow in skin of patients with severe Raynaud's syndrome: a 
randomised trial. Lancet. 1999; 354:1670-5.van der Molen et al, 2003 
van der Molen T, Willemse BW, Schokker S, ten Hacken NH, Postma DS, Juniper EF. 
Development, validity and responsiveness of the clinical COPD questionnaire. Health Qual 
Life Outcomes. 2003; 28:1–13. 
Wilkinson et al, 2006 
Wilkinson TM, Hurst JR, Perera WR, Wilks M, Donaldson GC & Wedzicha JA. Effect of 
interactions between lower airway bacterial and rhinoviral infection in exacerbations of 
COPD. Chest. 2006; 129:317–24. 
Xu et al, 2006 
Xu W, Zheng S, Dweik RA, & Erzurum SP. Role of epithelial nitric oxide in airway viral 
infection. Free Radical Biology and Medicine. 2006; 41:19-28 
Zhou et al, 2020 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality 
of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 
2020; 395:1054–62. 
 
 
 
 












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- 
Any AE that could be related to the protocol procedures and which could modify 
the conduct of the trial. 
The Investigator must report any SAEs to the Sponsor within 24 hours of becoming 
aware of the event by emailing an SAE form to the Sponsor’s PV department. 
The Sponsor’s PV department will confirm receipt within one business day. The site 
should re-send any report where acknowledgement of receipt is not provided. 
Each episode of an SAE must be recorded on a separate SAE form. If new or amended 
information on a previously reported SAE becomes available, the Investigator should 
report this to the PV department on a new SAE form. 
Where an SAE has not been reported to the Sponsor within the specified timelines, a 
reason for lateness must be included with the SAE form. 
All SAEs will be recorded from signing of informed consent until the end of the study. 
Serious adverse events occurring after the end of the study and coming to the attention of 
the Investigator must be reported only if they are considered (in the opinion of the 
Investigator) causally related to study intervention. 
• The primary mechanism for reporting an SAE will be using a paper SAE reporting 
form  
• The Investigator and the Sponsor (or Sponsor’s designated agent) will review each 
SAE report and the Sponsor will evaluate the seriousness and the causal relationship 
of the event to study intervention. In addition, the Sponsor (or Sponsor’s designated 
agent) will evaluate the expectedness according to the reference document (Reference 
Safety Information section in the Investigator Brochure). Based on the Investigator 
and Sponsor’s assessment of the event, a decision will be made concerning the need 
for further action. 
 
 
 
 
 
 
 
 
 




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Investigator Agreement Page 
 
Declaration of the Principal Investigator 
Title: 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) 
This study protocol was subjected to critical review and has been approved by the Sponsor. 
The information it contains is consistent with the current risk/benefit evaluation of the 
investigational product as well as with the moral, ethical, and scientific principles governing 
clinical research as set out in the Declaration of Helsinki and the guidelines on Good Clinical 
Practice. 
 
Principal Investigator 
 
_____________________________________ 
_____________________ 
Signature  
 
 
 
 
 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
 
 
 
 
 

SAP_001.pdf: 
                                             
                                                     Page 1 of 20 
                                                                                                                               RESP301-005 
v.1.0 03-Apr-2024 
                                                    
 
 
Statistical Analysis Plan  
Version: 1.0 
Version Date: 3rd of April 2024 
 
For the 
 
CORVIS-Study: 
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) 
 
 
 
Protocol No.:  RESP301-005 
Study Phase: Phase 2 
ClinicalTrials.gov ID: NCT04858451 
Regulatory Agency Identifier Number(s): CTA 53004/0002/001-0006 
EudraCT No: 2020-004951-34 
Protocol Version No.:  5.0 
 
Date of Protocol:  18 November 2021 
 
 
 
 
Sponsor contact details 
Thirty Respiratory Limited  
  
  
  
  
 
 
 
 
 
 
 
CONFIDENTIAL PROPERTY OF Thirty Respiratory Ltd   
The information contained in this record is proprietary and confidential.  It must not be copied in whole 
or in part in any form or communicated for the use of any party without the expressed written consent 
by Thirty Holdings. 


                                             
                                                     Page 2 of 20 
                                                                                                                               RESP301-005 
v.1.0 03-Apr-2024 
 
SIGNATURE PAGE 
 
 
 
 
 
Prepared by:  
 
 
 
 
 
 
 
 
 
Approved by:  
  
 
 
 
 
 
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
Approved by:  
 
 
 
 
 
       
                            
 
 
 
 
 
 
 
 


                                             
                                                     Page 3 of 20 
                                                                                                                               RESP301-005 
v.1.0 03-Apr-2024 
 
TABLE OF CONTENTS 
 
GLOSSARY OF ABBREVIATION ........................................................................... 4 
1. INTRODUCTION.................................................................................................... 6 
2. STUDY OVERVIEW .............................................................................................. 6 
2.1 Study Objectives and Hypotheses ...................................................... 6 
2.2 Study Design .................................................................................... 7 
2.3 Data and Analysis Quality Control .................................................... 12 
3. EFFICACY AND SAFETY VARIABLES .......................................................... 12 
3.1 Efficacy .......................................................................................... 12 
3.2 Safety variables .............................................................................. 13 
4. SAMPLE SIZE JUSTIFICATION ...................................................................... 13 
5. MEHODS OF ANALYSIS AND PRESENTATION .......................................... 13 
5.1 General Principles ........................................................................... 13 
5.2 Definition of Analysis Populations ..................................................... 14 
5.3 Disposition of Subjects .................................................................... 15 
5.4 Demographic and Baseline Characteristics ........................................ 15 
5.5 Medical History ............................................................................... 15 
5.6 Physical Examination ....................................................................... 15 
5.7 Protocol Deviations ......................................................................... 16 
5.8 Prior and Concomitant Medications .................................................. 16 
5.9 Extent of Exposure .......................................................................... 16 
5.10 Analysis of Efficacy Variables ......................................................... 16 
5.11 Analysis of Safety Variables ........................................................... 16 
5.12 Interim Analysis and Data Monitoring ............................................. 17 
5.13 Revised/Additional Versions ........................................................... 17 
6. REFERENCES ....................................................................................................... 17 
END-OF-TEXT TABLES AND FIGURES ............................................................. 18 
15.1 Demographic and Baseline Characteristics ...................................... 18 
15.2 Efficacy Results ............................................................................. 19 
15.3 Safety Results ............................................................................... 19 
SUBJECT DATA LISTINGS ................................................................................... 19 
 
 
 


                                             
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                                                                                                                               RESP301-005 
v.1.0 03-Apr-2024 
 
GLOSSARY OF ABBREVIATION 
AE 
Adverse Event 
ATC 
Anatomical Therapeutically Chemical 
BMI 
Body Mass Index 
CCQ 
Clinical COPD Questionnaire 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
eCRF 
electronic Case Report Form 
CRO 
Contract Research Organization 
CT 
Computerized Tomography 
DMC 
Data Monitoring Committee 
DRE 
Disease Related Event 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
MedDRA         Medical Dictionary for Regulatory Activities 
mHb 
Methaemoglobin 
NHS 
National Health Service 
NO 
Nitric oxide 
NO2 
Nitrogen dioxide 
NOx 
Oxide of nitrogen 
PEoT 
Post End of Treatment 
PR 
Pulse Rate 
PT 
Preferred Term 
PP 
Per Protocol 
QC 
Quality Control 
RTD 
Recommended Therapeutic Dose 
SAC 
Safety Advisory Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis system 
SD 
Standard Deviation 


                                             
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                                                                                                                               RESP301-005 
v.1.0 03-Apr-2024 
SEM 
Standard Error of the Mean 
SoA 
Schedule of activities 
SOC 
Standard of Care or System Organ Class 
SP 
Safety population 
SpO2 
Oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SOP 
Standard Operative Procedure 
TEAE 
Treatment-emergent adverse event 
TID 
Three Times Daily 
TMF 
Trial Master file 
VAS 
Visual Analogue Scale 
WHO-DD 
World Health Organization Drug Dictionary  
 


                                             
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                                                                                                                               RESP301-005 
v.1.0 03-Apr-2024 
1. INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a more 
technical and detailed description of the statistical methods mentioned in the 
protocol of study RESP301-005:  
CORVIS-Study: 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). 
 
This analysis plan is developed based on ICH E3 and E9 guidelines and in 
reference to the following documents: 
• the last version of the protocol (18th of November 2021, vers. 5.0) 
• the annotated eCRF (13th of September 2021, vers. 1.0) 
• the trial monitoring plan for Clinical Trials Sponsored by Thirty 
Respiratory Limited, Version 4.0, 17th of February 2022 
 
Any significant changes from the methodology defined in the current 
protocol/eCRF or protocol amendments agreed after the approval of this SAP 
may require changes to this SAP, see section 5.13 for details. 
 
2. STUDY OVERVIEW 
 
2.1 Study Objectives and Hypotheses 
This study is divided in two parts, a dose finding part (part 1) followed by an 
expansion phase (part 2): 
In part 1, the maximum tolerable dose (MTD) and the recommended 
therapeutic dose (RTD) of a single agent RESP301 in patients with mild to 
moderate COPD or bronchiectasis will be determined. In an additional cohort, 
the safety and tolerability of administering RESP301 at the MTD with the co-
administration of a short acting bronchodilator will be investigated. 
In part 2, the effects on recruiting and retaining patients with COPD or 
bronchiectasis who have viral infection symptoms and treating these patients 
with RESP301 in a community setting will be investigated. 
 
The secondary objectives of this study are: 
• To assess the safety and tolerability of single doses of RESP301 in 
patients with COPD or bronchiectasis, who are at high risk of SARS-
CoV-2 and other acute respiratory pathogens.  
• To assess the safety and tolerability of single doses of RESP301 in 
combination with a short acting bronchodilator. 
• To collect preliminary data on the efficacy of RESP301. 
 


                                             
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                                                                                                                               RESP301-005 
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2.2 Study Design 
This is a phase II, single-group, non-randomized, two-center, open-label 
study conducted in two parts.  
In part 1 (Dose Finding Phase), eligible patients will be administered a single  
dose of RESP301 under clinical supervision. The first eight patients (group 1) 
will receive a dose of 1 ml, the next eight patients (group 2) 2 ml, the next 
eight patients (group 3) 3 ml, etc. until a maximum dose of 6 ml. After the 
completion of each dose level (treatment group) the safety data will be 
reviewed by the PIs and Sponsor before proceeding to the next higher dose. 
After the completion of all groups a safety advisory committee (SAC) will 
review the data from all participants and determine a Maximum Tolerated 
Dose(MTD) and a Recommended Therapeutic Dose (RTD). 
Thereafter eight eligible patients will be administered a single dose of 
RESP301 at the MTD in combination with a short acting bronchodilator also 
under clinical supervision. 
 
In part 2 (Expansion Phase), a minimum of 150 patients will be enrolled into 
the Expansion Phase and treated at the Recommended Therapeutic Dose 
(RTD) determined in Part 1. The expansion phase is split into three periods, a 
baseline visit, a dormant period (max. 12 months) and a treatment period (7 
days). The first 50 patients at baseline will receive a RTD test dose on site to 
further investigate the safety and tolerability of RESP301.  
An Independent Data Monitoring Committee (IDMC) will review this data and  
decide whether further RTD test doses should be administered to further 
patients before enrolling them into the Dormant Period or whether patients 
could be enrolled into the dormant period without a RTD test dose at 
baseline. 
    
Female of non-childbearing potential or male ≥35 years of age, at the time of 
signing the informed consent with spirometry-confirmed COPD or 
computerized tomography (CT) proven bronchiectasis are included in the 
study. Further details of the inclusion/exclusion criteria are defined in sections 
6.2 and 6.3 of the protocol.  
Eligible patients in part 1 may be enrolled in more than one of the seven 
treatment groups and patients from part 1 will also be eligible to enter Part 2 
of the trial.  
The overall study duration for each patient will be at approximately 60 weeks, 
including one or more visits at a study center in parts 1/2, monthly follow-up 
calls, and, for those who experience an exacerbation (part 2), one week of 
treatment and additional monitoring calls at the beginning, during and 
following the treatment period.  
 
The eight treatment groups, the number of subjects per group and the 
corresponding treatment labels used for the statistical evaluation are 
summarized in table 1.  
 


                                             
                                                     Page 8 of 20 
                                                                                                                               RESP301-005 
v.1.0 03-Apr-2024 
 
Table 1: Treatment Groups  
Part  
Treatment group* 
Label  
Short label** 
 
 
 
1 
1 (N=8) 
RESP301 1 ml       
1ml 
2 (N=8) 
 RESP301 2 ml      
2ml 
3 (N=8) 
RESP301 3 ml       
3ml 
4 (N=8) 
RESP301 4 ml       
4ml 
5 (N=8) 
 RESP301 5 ml      
5ml 
6 (N=8) 
RESP301 6 ml       
6ml 
7 (N=8) 
RESP+Vent 6 ml     
R+V  
2 
8 (N=150) 
RESP301 RTD       
RTD 
*  During a meeting on the 11th of January 2022 it was decided that the RTD dose is 4 ml and the 
    MTD dose 6 ml. 
** Short labels may be used due to paper space requirements. 
    
RESP301 is prepared by mixing two sterile solutions (one of NaNO2/mannitol 
and one of citric acid buffered to pH 
) in the nebulizer. The solution is to 
be nebulized within 5 minutes post mixing as per the instructions given in the 
SoA. The inhalation of the medication should start within 5 minutes of mixing 
the solutions and the inhalation process should be complete within 20 
minutes of starting inhalation.  
 
An overview of the study procedures is provided in table 2 below for part 1 of 
the study and in table 3 for part 2, see protocol page 51, table 8-1: 
 
 


                                             
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Table 2: Schedule of Study Assessments (Part 1) 
Procedure 
Screen 1 
Screen 2/Dosing Visit 
(Day 1)3 
Follow-up Phone call 
(Day 2) 
Informed Consent 
X 
 
 
Inclusion and Exclusion 
Criteria 
X 
X 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Medication history and 
concomitant medications 
X 
X 
X 
Height, Weight and BMI 
X 
 
 
Physical Examination1 
X 
X 
 
Pulmonary function test 
X 
X 
 
Vital signs 
X 
X 
 
Methaemoglobin level 
X 
X 
 
Short acting bronchodilator2 
 
X1 
 
RESP301 administration 
 
X 
 
Follow-up  
 
 
X 
AE/SAE review 
X 
X 
X 
1)  Only done if deemed necessary by the investigator 
2) Only done in the combination group, i.e., RESP301 + short acting bronchodilator (group 7) 
3) Screen 1 and Screen 2 may be combined if the patient has historic evidence of a FEV1/FVC   
   ratio<0.7.  
 
 


                                             
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Table 3: Schedule of Study Assessments (Part 2) 
Procedure 
Screen 1 
Screen 2/ 
Baseline 
Visit1  
Dormant 
Period 
(monthly 
calls) 
Pre-Treatment call 
(within 24-72 hrs 
of exacerbation 
onset) 
Treatment 
Period (daily 
monitoring 
calls for 8 
days) 
Post 
Treatment 
Follow-up 
call (Day 
14±3 PEoT) 
Post 
Treatment 
Follow-up 
call (Day 
28±3 PEoT) 
Early 
withdrawal 
(Days 0, 14 
or 28 ± 3) 
Informed Consent 
X 
X 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
X 
X 
X 
X 
X 
Medication history and 
concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
Height, Weight and BMI 
X 
 
 
 
 
 
 
 
Physical Examination2 
X 
X 
 
 
 
 
 
 
Pulmonary function test3 
X 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
 
 
 
Methemoglobin level 
X 
X 
 
 
 
 
 
 
RESP301 administration4 
 
X 
 
 
X 
 
 
 
CCQ 
 
X 
X 
 
X5 
X 
 
 
Instructions of nebulizer 
 
X 
 
X 
X 
 
 
 
Follow-up6 
 
 
X 
 
 
 
 
 
Review of symptoms 
 
 
 
X 
X 
X 
 
 
AE/SAE review 
X 
X 
 
 
X 
X 
X 
X 
VAS7 
 
 
 
 
X 
X 
 
 


                                             
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Body temperature7 
 
 
 
X 
X 
X 
 
 
Treatment compliance 
 
 
 
 
X 
 
 
 
1) Patients who received a RTD test dose only and did not proceed to the dormant period, will receive a follow-up call on day 7±3 to discuss and record AEs. 
2) Only done if deemed necessary by the investigator 
3) Only done in patients who received a RTD test dose at the Baseline visit 
4) At baseline a single RTD dose for patients who were assigned to test dose and at the treatment period TID for 1- 7 days in patient with an exacerbation 
5) Done at Day 1 and Day 7 
6) Patients reminded to contact the study team if they experience exacerbation symptoms   
7) Daily during the treatment period, and if not recovered by end of treatment, continued until recovery or Day 14 post end of treatment 
 
 


                                             
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2.3 Data and Analysis Quality Control 
The trial monitoring plan for Clinical Trials Sponsored by Thirty Respiratory 
Limited for this study will detail the quality assurance and quality control 
systems to be implemented to assure the quality of the data. Similarly, the 
quality control of the statistical analysis will follow the SOPs of institution 
performing the statistical analysis. 
 
3. EFFICACY AND SAFETY VARIABLES 
 
3.1 Efficacy 
The primary objective in part 1 (Dose Finding Phase) is to determine the 
maximum tolerable dose (MTD) and the recommended therapeutic dose 
(RTD) of the single agent RESP301. For these decisions individual and cohort 
stopping criteria were defined, see section 7.7.2 and 7.7.3 of the protocol. In 
a Safety Advisory Committee (SAC) meeting prior to part 2 of this study these 
doses will be determined. Hence no single primary and/or secondary endpoint 
for part 1 was defined.     
 
In part 2 (Expansion Phase), the primary endpoints are: 
• Percentage of patients entering the dormant period who, having  
  experienced and correctly reported an exacerbation, commence self-   
  administration of the treatment at home on the day the treatment is 
  delivered. 
• Percentage of patients who, having experienced and correctly 
  reported an exacerbation, receive the treatment within 48 hours of  
  reporting their exacerbation. 
• Compliance with RESP301 administration schedule over the   
  treatment period: for those participants commencing treatment, the    
  percentage of total doses taken. 
 
 
The secondary endpoints, which will be analyzed by treatment dose and 
separately in the sub-group of patients who had a positive test result for 
SARS-CoV-2 are defined as: 
• % of participants able to tolerate the test dose in Part 1(a), Part 1(b) and 
Part 2, i.e. able to complete the test dose without any of the following: 
o Troublesome cough, chest pain or tightness, bronchospasm or   
    
dyspnea that is deemed unacceptable by the patient. 
o methemoglobin >5% during or >3% post dose (30 or 60 mins) 
o 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 period in the Investigator’s opinion 
o for the first 50 patients who will undergo pre and post-test dose  
spirometry, >20% reduction in FEV1 from pre-test dose to post  


                                             
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test at 60 min dose with symptoms listed above (patients with 
>20% reduction in FEV1 without symptoms would be offered 
the option to continue in the study).  
 
3.2 Safety variables 
The safety end-points for this study are: 
• Adverse Events (AEs) 
• Serious Adverse Events (SAEs) 
• Suspected Unexpected Serious Adverse Reactions (SUSARs) 
• Severe AEs 
• Treatment-related AEs/SAEs Adverse events (AEs) and serious adverse 
events (SAEs) 
 
4. SAMPLE SIZE JUSTIFICATION 
The primary objective of this study is to determine the MTD and RTD of 
RESP301 and to assess feasibility. No formal sample size calculation was 
performed. In Part 1, we aim to recruit up to 56 participants (8 per dose 
group) to receive one dose of RESP301 (alone or in combination). 
In Part 2, we aim to recruit around 150 patients from secondary care and 
primary care sites in the UK into the dormant period. The first 50 consented 
participants will receive an initial test dose of RESP301 before progressing to 
the dormant period. If, based on the first 50 participants, the DMC 
determines that it is safe to do so, the remaining consenting participants will 
not be required to receive a test dose before progressing to the dormant 
period. It is estimated that over 12 months, 30 of the 150 enrolled 
participants will exacerbate. These participants will commence self-
administered RESP301 treatment. Non-exacerbating participants will receive 
no further study interventions.  
 
5. METHODS OF ANALYSIS AND PRESENTATION 
 
5.1 General Principles 
The statistical analysis will be performed using the validated software package 
SAS version 9.4 or higher (SAS Institute Inc., Cary, NC 27513, USA). 
All recorded and derived variables will be presented by treatment group and 
visits (if appropriate) using descriptive summary tables (continuous data: 
sample size, mean, standard deviation (SD), minimum, median, maximum; 
categorical data: sample size, absolute and relative frequency).  
The mean and median will be presented to one more decimal place than the 
raw data. The SD will be presented to two more decimal places than the raw 
data. The percentages will be presented to 1 decimal place. In all the 
summaries, the treatment groups will be displayed in the following order: part 
1 (RESP301 1 ml, 2 ml, …6 ml, RESP+Vent 6 ml) and then part 2. 


                                             
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For all parameters, baseline is defined as the last available pre-treatment 
value (i.e. the last non-missing value available before study drug 
administration. In general, missing data will be treated as missing and no 
attempts will be made to impute values for missing data.  
 
No formal interim efficacy analyses are planned in this study; however, 
several safety interim analyses by the Safety Advisory Committee (SAC) will 
be performed as detailed in the protocol, see section 7.7 for part 1 and an 
Independent Data Monitoring Committee (IDMC) will review the safety data 
on an ongoing basis as described in the DMC charter, see section 10.6 of the 
protocol.    
 
Subjects who did not receive any study medication (screening failures) will be 
listed separately and not presented in any table or figure, except in the 
patient’s disposition table. 
 
The versions of the following international dictionaries (MedDRA version 26.1 
and WHO DD, version 2024) will be used for medical coding: 
Adverse events:   Medical Dictionary for Regulatory Activities (MedDRA). 
Medical Histories: Medical Dictionary for Regulatory Activities (MedDRA). 
Medications: World Health Organization (WHO) Drug Dictionary including 
                  Anatomical Therapeutic and Chemical (ATC) classification. 
If a medication in the drug dictionary (DD) table is associated with more than 
one ATC code, the first ATC code will be assigned to that medication. 
 
 
5.2 Definition of Analysis Populations 
The following analysis sets will be identified prior to database lock, see 
section 10.3 of the protocol. Please note, that the FAS definition is slightly 
different from the ITT population in the protocol. 
 
Screening  
All patients who were screened (i.e. given informed 
consent) 
 
 
Safety Set (SS) 
All patients who inhaled at least one dose of (complete 
or partial) study medication. Subjects will be analyzed as 
treated. 
 
 
Full Analysis Set (FAS) All patients in the safety set (SS) who have at least one 
post treatment assessment. 
 
 
Per-Protocol Set (PPS) All patients in the FAS without a major protocol deviation 
that may significantly impact data integrity or patient 
safety. 
The FAS set will be the primary analysis set for all efficacy analyses and the 
PPS set will be used to demonstrate robustness of results for the efficacy 


                                             
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endpoints. Alll other analyses will be based on the patients from the safety 
set. 
All protocol violations/deviations will be reviewed and classified as either 
‘minor’ (unlikely to appreciably affect trial outcomes) or ‘major’ (likely to affect 
outcomes) and this classification will be utilised to define the study 
populations for analysis purposes. 
The assessment of major violations will be performed before the study 
database is locked and will be documented in the corresponding meeting/TC 
minutes. At a minimum the investigator, a sponsor representative and the 
CRA/monitor will participate in this review and will sign the meeting minutes. 
 
5.3 Disposition of Subjects 
A summary of the subject disposition will be created including number of 
patients screened, number of screen failures, if any, number of patients 
treated, number of patients who completed the study in each treatment 
group. In addition, a summary of the number and percentage of patients in 
the safety set who were available at each visit will be presented by treatment 
group and overall. 
 
5.4 Demographic and Baseline Characteristics 
Demographic characteristics (age, gender and ethnicity) and body 
measurements (height, weight and BMI) and vital signs (body temperature, 
systolic blood pressure, diastolic blood pressure, heart rate and respiratory 
rate) collected at baseline will be summarized by treatment group and overall, 
for the safety set.  
Body mass index (BMI in kg/m**2) will be calculated as weight (in kg) 
divided by height (in m) **2. 
Any additional baseline characteristics, like smoking status, COPD and 
bronchiectasis history will also be presented descriptively be treatment group 
and overall. 
 
5.5 Medical History 
Medical history and concurrent diseases will be coded using MedDRA. The 
number and percentage of patients with past medical conditions grouped by 
MedDRA SOC will be displayed on the preferred term level (PT) by treatment 
group for the safety set. A similar summary will be produced for concurrent 
medical conditions at baseline (before start of first administration of study 
medication). 
 
5.6 Physical Examination 
The number and percentage of patients with abnormal physical examination 
at baseline will be displayed for each body system as indicated in the eCRF in 
the safety set.  
All the details collected in the eCRF of the physical examination at baseline 
will be presented in a separate listing for all subjects in the safety set. 


                                             
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5.7 Protocol Deviations 
Any protocol deviations (minor and major) will be identified by the clinical 
team prior to locking the database. The number and percentage of patients 
with each deviation and each treatment group will be summarized for the 
safety set. 
 
5.8 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using WHO-DD and will be 
assigned to the first corresponding ATC code. All the medications will be listed 
for the safety set. 
The number and percentage of subjects with concomitant medications 
ongoing at baseline (i.e. ongoing the day before administration of first dose of 
study medication) classified by ATC levels 2 and 3 will be displayed by 
treatment group in the safety set. A similar summary will be produced for 
concomitant medication started after baseline (i.e. those medications started 
on or after the day of first dose and on or before the date of last dose). Any 
medications starting after last dose will be listed only. 
 
5.9 Extent of Exposure 
Overall compliance regarding the administration of the study medication 
during the study part 2 will be calculated for the dormant phase based on the 
number of dispensed medications minus the number of medications returned 
as a percentage of the number of medications that should have been 
administrated. A summary with descriptive statistics will be produced by 
treatment group in the safety set. For part 1 and the test dose phase in part 2 
the number and percentage of correct administrations will be presented. 
The exposure to study medication will be calculated in days as: 
Last dose date of study medication – First dose date + 1. 
 
5.10 Analysis of Efficacy Variables 
All primary and secondary efficacy parameters, see section 3, will be 
summarized descriptively and no formal statistical analyses will be performed.  
The analyses will be performed by treatment group and overall, for both the 
FAS and PPS set using appropriate descriptive statistics. 
The results of the spirometry will also be presented over time, i.e. baseline, 
30-, 60- and 90-minutes post baseline. 
 
Explorative /Sub-group analysis 
Summary statistics of the primary and secondary endpoints may also be 
presented for specific sub-groups, if the number of patients in these sub-
groups are high enough to allow a meaningful interpretation of the results.      
 
5.11 Analysis of Safety Variables 
These analyses will be conducted for the safety set (SS) only and no formal 
statistical testing will be performed in the safety endpoints. 


                                             
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Adverse Events 
For the safety analysis only adverse events with an onset after the first 
administration of the study medication (TEAEs) will be displayed in summary 
tables. AEs starting before the first administration will be listed only.  
Adverse event summaries will be presented by treatment group and overall. 
An overall summary of AEs will be produced including the number of TEAEs; 
the number and % of subjects reporting at least 1 TEAE, serious TEAE (where 
SAE is reported as ‘Yes’), TEAE leading to withdrawal from the study and the 
number and % of subjects reporting TEAEs by severity and relationship to 
study drug. A subject with multiple occurrences of the same AE is counted 
only once at the maximum level of severity or the highest association to 
study drug. 
Adverse events will be coded using MedDRA and will be presented on the 
MedDRA preferred term (PT) level. 
The tables will list for each adverse event, the number of events and the 
number and percentage of patients in each treatment group in whom the 
event occurred. Adverse events will be grouped by system organ class. 
All serious adverse events (SAEs) will be listed separately.  
 
VAS Scores  
For each parameter will be summarized by treatment group using descriptive 
statistics at each time point.  
 
5.12 Interim Analysis and Data Monitoring 
There are no planned interim efficacy analyses. However, an Independent 
Data Monitoring Committee (IDMC) will review the safety data on an ongoing 
basis. 
 
5.13 Revised/Additional Versions 
Not applicable, this is the first version. 
 
6. REFERENCES 
1) Study protocol: CORVIS-Study: 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), Version: 5.0, 18th of 
November 2021. 
2) Annotated eCRF for the CORVIS-Study, Part 1 13th of September 2021,  
Part 2 9th of March 2022. 
3) TRIAL MONITORING PLAN for Clinical Trials Sponsored by Thirty  
Respiratory Limited, Version 4.0, 17th of February 2022. 
4) ICH Guideline E3, Structure and content of clinical study reports,  




                                             
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Table 3.1 
Medical history (MedDRA system organ classes) – Safety set 
Table 3.2 
Concurrent diseases (MedDRA system organ classes) – Safety set 
Table 3.3 
Concomitant medications ongoing at baseline – Safety set 
Table 3.4 
Concomitant medications started after baseline – Safety set 
Table 4.1 
Summary of physical examination – Safety set 
Table 5.1 
Compliance with study medication – Safety set 
 
15.2 Efficacy Results 
Table 1.1 
Summary of primary endpoints, part 2 – FAS/PPS set 
Table 1.2 
Summary of secondary endpoints – FAS/PPS set 
Table 1.3 
Summary statistics of spirometry over time – FAS/PPS set 
Table 1.4 
Summary of VAS scales – FAS/PPS set 
Table 1.5 
Summary statistics of explorative/sub-group analyses, if any – FAS/PPS set 
 
15.3 Safety Results 
Table 1.1 
Overview of all adverse events – Safety set 
Table 1.2 
Patients with adverse events at MedDRA system organ class level – Safety 
set 
Table 1.3 
Patients with adverse events, preferred term grouped by MedDRA system 
organ class – Safety set 
 
 
Appendix 16.2 Subject Data Listings 
Appendix 16.2.1 Subject Disposition 
Listing 1 
End of study assessment – Safety set 
Listing 2 
Screening failures – All screened subjects 
Listing 3 
Subjects treated – Safety set 
Listing 4 
Protocol deviations - Safety set 
 
Appendix 16.2.2 Informed Consent, Protocol Deviations, 
and Inclusion and Exclusion Criteria 
Listing 1 
Informed consent – Safety set 
Listing 2 
Inclusion criteria – Safety set 
Listing 3 
Exclusion criteria – Safety set 
 
Appendix 16.2.3 Subjects Excluded from Analyses 
Listing 1 
Reasons for non-eligibility for the Full Analysis Set – Safety set 
Listing 2 
Reasons for non-eligibility for the Per Protocol Set – Full analysis set 
 
Appendix 16.2.4 Demographics, Medical History, and 
Prior/Concomitant Medications 
Listing 1 
Demographics – Safety set 
Listing 2 
Medical history – Safety set 
Listing 3 
Concurrent conditions – Safety set 


                                             
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Listing 4 
Prior and concomitant medication – Safety set 
 
Appendix 16.2.5 Study Drug Administration 
Listing 1 
Treatment received – Safety set 
Listing 2.1 
Compliance – Safety set 
 
Appendix 16.2.6 Efficacy Data 
Listing 1 
Primary endpoint, part 2 – Safety set 
Listing 2 
Secondary endpoints – Safety set 
Listing 3 
Spirometry – Safety set 
Listing 4 
VAS scales – Safety set 
 
Appendix 16.2.7 Adverse Events 
Listing 1 
Adverse events – Safety set 
Listing 2 
Serious adverse events – Safety set 
 
Appendix 16.2.9 Vital Signs, ECGs, and Physical 
Examination 
Listing 1 
Vital signs – Safety set 
Listing 2 
Physical examination findings – Safety set 
Listing 3 
Pregnancy test – Safety set 
Listing 4 
Additional notes (Safety set)