Clinical trial NCT04460183
Conditions: COVID-19
Sponsor: Thirty Respiratory Limited
Start date: 2020-07-29; Completion date: 2021-05-21
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The effect of RESP301 as an add on treatment to SOC will be evaluated for its efficacy in reducing rate of progression to a more severe level of COVID-19 and for safety, by comparison with SOC alone in hospitalized COVID-19 patients.

Detailed description:
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using a sequential adaptive design to evaluate the efficacy and safety of RESP301 plus SOC versus SOC alone in hospitalized patients with COVID-19 (World Health Organization \[WHO\] ordinal scale level 3 or 4).

Approximately 300 participants will be enrolled and randomized 2:1 to the Investigational arm or the Control arm. The study will be divided into the following periods: Screening period: (up to 2 days), Intervention (up to 10 days), follow-up (Day 14 and Day 28).

Arms: arm 1: Participants will receive inhaled RESP301 administered using a nebulizer three times a day for up to 10 days in addition to the standard of care. arm 2: Participants will receive institutional SOC for the treatment of COVID-19
Interventions: intervention 1: RESP301, a Nitric Oxide generating solution intervention 2: Standard of Care
Intervention descriptions: intervention 1: Product application requires inhalation using a standard handheld nebulizer. intervention 2: Participants will receive institutional SOC for the treatment of COVID-19.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
NOCoV2 - An 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 requiring 
supplemental oxygen 
 
 
 
ClinicalTrials.gov Identifier: NCT04460183 
 
 
 
 
Original Protocol: 01 May 2020 (Version 1.0) 
Amendment 1: 05 Jun 2020 (Version 2.0) 
Amendment 2: 10 Jun 2020 (Version 3.0) 
Amendment 3: 16 Sep 2020 (Version 4.0) 


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30 Respiratory 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
Final 
7 of 83 
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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: NOCoV2 - An 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 requiring 
supplemental oxygen 
Sponsor Protocol No.: RESP301-002 
Study Phase: Phase 2/Phase 3 
Sponsor: 30 Respiratory 
Rationale: 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design. Participants will be consented and randomized 2:1 to the 
Investigational arm or the Control arm. Participants randomized to the Investigational arm will 
receive inhaled RESP301 (6 mL) administered using a nebulizer 3 times a day (TID) for up to 
10 days in addition to the standard of care (SOC) while participants in the Control arm will 
receive SOC alone. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 4 in the 
modified World Health Organization 
(WHO) ordinal scale into levels >4 
• Proportion of participants who progress to 
level >4 of modified WHO ordinal scale 
due to COVID-19 by Day 14 
Key Secondary 
• To assess the effect of RESP301 as 
measured by room air SpO2 
• Change in room air SpO2 from baseline 
over time 
• To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
• Change in NEWS 2 symptom score from 
baseline over time 


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30 Respiratory 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
Final 
9 of 83 
01 May 2020 
 
Overall Design: 
• Open-label, randomized, multicenter, parallel group, concurrent, controlled study using a 
sequential adaptive design in hospitalized patients with COVID-19 requiring 
supplemental oxygen. 
• Participants will be stratified by country and presence of risk factors for severe outcomes 
of COVID-19, based on comorbidities and age as detailed in Section 6.3. 
• The study treatment will be permanently discontinued prior to 10 days if the participant: 
o Improves to level 1 or 2 of the modified WHO ordinal scale; 
o Progresses to a level > 4 of the modified WHO ordinal scale; 
o Experiences adverse drug reaction or suspected adverse drug reaction. 
• An Independent Data Monitoring Committee (IDMC) will be responsible for closely 
reviewing the safety and efficacy data from interim analyses and for providing their 
recommendations on continuation of the study. The IDMC will meet after 10, 20, 60 and 
150 participants have completed the study (see Sections 9.5 and 9.6). 
Disclosure Statement: This is a parallel group treatment study with two arms that are 
open-label. 
Number of Participants: 
Approximately 300 participants will be randomly assigned to study intervention (200 to the 
Investigational arm and 100 to the Control arm). 
Intervention Groups and Duration: 
The total study duration for a participant from screening to last follow up will be up to 30 days. 
The study will be divided into the following periods: 
• 
Screening period: up to 2 days (48 hours) prior to the day of treatment initiation; 
Days −2, −1 and 1 
• 
Intervention period: up to 10 days; Day 1 to Day 10 
• 
Efficacy follow-up: Day 14 and Day 28 
• 
Safety follow-up:  28 days after treatment initiation; with the participant being 
contacted by phone call, if not still hospitalized, on Day 28 (±1 day) 




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1.3 Schedule of Activities (SoA) 
Table 1-1 
Schedule of Activities (SoA) 
Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 1 day) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 1 day) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Informed consent 
X 
 
 
 
 
 
 
 
Confirmation of COVID-19 infection 
by nasopharyngeal RT-PCR 3 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Recheck clinical status 
before 1st dose of study 
intervention 
Demographics 
X 
 
 
 
 
 
 
 
Physical examination including 
height and weight 
X 
 
 
X 
X 
 
X 2 
Full physical exam and 
height only at screening 
Medical history (includes substance 
usage) 
X 
 
 
 
 
 
 
History of substance 
usage or abuse to be 
recorded but is not 
exclusionary 
Medication history 
X 
 
 
 
 
 
 
In the prior 3 months 
TB screening 
X 
 
 
 
 
 
 
Serum TB test as per 
local site 
Laboratory assessments (including 
liver chemistries) 4 
X 
X 
X 4 
X 
X 
 
X 2 
 
12-lead ECG  
X 
X 
X 
X 
X 
 
X 
After resting supine for 
approximately 5 minutes.  
QRS, QT, QTcF, PR, 
RR, rate 
Vital signs 5 
X 
X 
X 5 
X 
X 
 
X 
Within 15 minutes prior 
to study intervention 
administration 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 1 day) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 1 day) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Randomization 
 
X 
 
 
 
 
 
 
Study intervention, TID 6 
 
X 
X 
X 
 
 
 
Where possible study 
intervention should be 
administered at 
approximately the same 
times each day 
At least 4 hours between 
2 consecutive inhalations 
AE/SAE review 
 
X 
X 
X 
X 
X 
X 
 
Device deficiencies check 
 
X 
X 
X 
 
 
 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
 
Oxygen / respiratory assessment 7 
X 
X 
X 
X 
 
 
 
 
SpO2 on room air (after at least 
1 minute) prior to study intervention 
administration and immediately at the 
end of nebulization 6 
 
X 
X 
X 
 
 
 
See Section 8.1.2 
Modified WHO ordinal scale 
X 
X 
X 
X 
 
X 
X 
See Section 8.1.1 
NEWS 2 assessment 7 
 
X 
X 
X 
 
 
 
Prior to study 
intervention in the 
morning. See 
Section 8.1.3 


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Clinical Study Protocol 
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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 1 day) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 1 day) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Abbreviations: AE=adverse event; aPTT= activated partial thromboplastin time; CBC=complete blood count; Chem 7=blood chemistry panel (sodium, potassium, chloride, 
bicarbonate/CO2, blood urea nitrogen, creatinine, glucose); CV=cardiovascular; ECG=electrocardiogram; LFTs=liver function tests; mHb=methemoglobin; 
PT/INR=prothrombin time/international normalized ratio; RT-PCR=reverse transcription-polymerase chain reaction; SAE=serious adverse event; TB=tuberculosis; 
TID=three times daily. 
1. Screening and randomization can be the same day, providing all eligibility criteria are met. 
2. Safety laboratory tests and ECG at follow-up to be collected for participants in hospital at EoS only. For participants who are already discharged at follow-up, there 
will be a phone call to check AEs/SAEs, concomitant medications, and modified WHO ordinal scale. 
3. COVID-19 infection must be confirmed and documented in chart with a positive result on a validated test. 
4. Safety: CBC, chem 7; Screening: CBC, chem 7, mHb, LFTs, coagulation (PT/INR, aPTT). Laboratory tests to be repeated as per SOC during treatment period. 
5. Vital signs: temperature, heart rate, blood pressure, respiratory rate. Vital signs to be repeated as per SOC during treatment period. 
6. Study intervention comprises the following procedures which are to be done in order and as quickly as possible: 
a. 
Recording of oxygen flow level including mode (nasal cannula, mask) 
b. Recording of SpO2 and heart rate 
c. 
Discontinuation of supplemental oxygen administration * 
d. Close participant oversight by trained health care professional until SpO2 is stable on ambient air after one minute at least * 
e. 
Recording of SpO2 * pre-nebulization on ambient air 
f. 
Preparation of the admixture of RESP301* 
g. Administration of the nebulization via Philips InnoSpire Go nebulizer while monitoring SpO2 and heart rate (alarms set to 89% and 120 beats / min, or as 
indicated by the Investigator, for stopping study intervention administration and resuming supplemental oxygen) * 
h. Discontinuation of nebulization after 5 minutes or no product left in the device, whichever comes first * 
i. 
Recording of SpO2 * post nebulization on ambient air 
j. 
Resuming supplemental oxygen * 
k. Participant oversight until SpO2 is stable * 
l. 
Recording of SpO2 * 
* for participants on active treatment arm only 
7. Immediately before participant is discontinued from oxygen for study intervention administration and assessment of SpO2 at room air 


 
 
 
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2 Introduction 
2.1 Background 
Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by a novel coronavirus 
(SARS-CoV-2). COVID-19 was first described in Wuhan, China, in December 2019 and is now 
a global pandemic (Matos et al, 2020). Most of those affected have milder illness (80%), 15% 
will be severely ill (require oxygen) and 5% will require intensive care unit care (Novel 
Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020). Of those who are 
critically ill, most require early intubation and mechanical ventilation. Other complications 
include septic shock and multi-organ failure, including acute kidney injury and cardiac injury 
(Yang et al, 2020). Older age and comorbid diseases, such as chronic obstructive pulmonary 
disease (COPD), hypertension, and diabetes, increase risk of death (Huang et al, 2020; Zhou et 
al, 2020). The virus is highly contagious and spread via respiratory droplets, direct contact and, if 
aerosolized, airborne routes. The most common symptoms include fever, fatigue, dry cough, and 
shortness of breath.  
A critical early component of innate host defense 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 nitric oxide (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 nebulizer, 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. 


 
 
 
 
 
 
 
 
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RESP301 is a NO-generating liquid designed to release NO in situ in the upper airways and deep 
in the alveolar spaces. RESP301 is delivered via a handheld nebulizer and has specific 
advantages (see below) over inhaled NO gas in treating patients with COVID-19 during the 
current pandemic. It has 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 nebulizer; 
• 
The formulation is nebulized 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 Sponsor has conducted a number of supportive in vitro studies to assess the activity of NO-
generating solutions against major respiratory viruses responsible for infections in humans. 
These studies include the following: 
• 
Preliminary in vitro study to demonstrate the effects of RESP301 on SARS-CoV-2 
replication (Study RP026a) 
• 
In vitro study of RESP301 against influenza A (H1N1) and human rhinovirus including 
in vitro RESP301 cytotoxicity study (Study RP010) 
• 
Determination of the anti-viral efficacy of six NO-releasing formulations against two 
strains of virus (influenza A virus [H1N1] and human rhinovirus 16) (Study 30 
Respiratory 009) 
• 
Evaluation of inhaled nitrite immune effects and antimicrobial activity against 
intracellular drug sensitive and drug resistant Mycobacterium tuberculosis and 
M. abscessus infections (Study RP014) 
• 
RESP301 in combination with antibiotic treatment (Study RP002) 
• 
Anti-microbial activity of acidified nitrite solution against M. abscessus (Study TR001) 
Preliminary data suggest that incubation with RESP301 for 48 hours inhibits replication of 
SARS-CoV-2 (Log10 TCID 50/mL – 2.1- fold reduction), and reduces the viral load to levels 
below the limit of detection of the assay, at concentrations which were not associated with 
cytotoxicity (Study RP026a).  
Studies of inhaled nebulized sodium nitrite (AIR001) in healthy subjects and in patients showed 
that inhaled acidified nitrite produces dose proportional plasma pharmacokinetics without 


 
 
 
 
 
 
 
 
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accumulation following repeated administration, with low systemic blood levels of nitrite and 
methemoglobin (<3%) (Rix et al, 2015). Inhaled nitrite (AIR001) at doses up to 90 mg three 
times daily (TID) displayed a good safety profile and is well tolerated (Parsley et al, 2013; 
Simon et al, 2016), thus supporting the investigation of RESP301 in the clinical setting. 
RESP301 is an admix solution of two precursor solutions mixed together at point of care for 
immediate inhaled administration via a nebulizer device (a hand-held CE marked Philips 
InnoSpire Go vibrating mesh nebulizer, Food and Drug Administration [FDA]-approved and 
European CE marked). The silent mesh nebulizer is used for the treatment of children and adults 
with pulmonary diseases. The InnoSpire nebulizer generates aerosols by vibrating to draw liquid 
medication through approximately 1000 funnel-shaped apertures (Ari and Fink, 2020) and has 
been shown to be an effective mesh nebulizer in a small scale experiment intended to test new 
in-process controls minimizing variability in aerosol performance (Hatley et al, 2016). The 
device is small, portable, easy to use, and cleaning and maintenance is simple due to the 
simplicity of the device (Ari and Fink, 2020). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of RESP301 is 
provided in the Investigator’s Brochure. 
2.2 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. 
2.2.1 
Risk Assessment 
Table 2-1 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention RESP301 
Participants need to be 
discontinued from 
supplemental oxygen for up 
to 4 minutes to receive 
nebulized study treatment 
Study treatment is to be 
administered via a hand-held 
mesh nebulizer (Philips 
InnoSpire Go) which is 
designed for oral inhalation. 
In addition, as NO 
spontaneously reacts with O2 
Participants unable to be 
safely discontinued from 
supplemental oxygen will be 
excluded (Exclusion 
criterion 2) 


 
 
 
 
 
 
 
 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
to produce NO2 (a bronchial 
irritant), it is potentially 
unsafe to use both treatments 
concomitantly 
Treatment administration is to 
be performed as quickly as 
possible (Section 1.3) 
Oxygen saturation (SpO2) 
and heart rate will be 
monitored throughout the 
study intervention 
administration (Section 1.3) 
Stopping rules to resume 
supplemental O2 in case of 
decrease in SpO2 or clinical 
signs of intolerance 
(Section 7.1) 
Risk of methemoglobinemia 
Very low levels are produced 
but as methemoglobinemia 
has been reported with 
continuous NO gas 
administration, the risk 
cannot be firmly ruled out 
Participants with a history of 
methemoglobinemia will be 
excluded (Exclusion 
criterion 4) and 
methemoglobin (mHb) is 
included in safety laboratory 
tests (Section 1.3) 
Risk of clinical bronchial 
hyper-responsiveness related 
to nebulization 
Excipients in the nebulized 
RESP301 include mannitol 
which is a known bronchial 
irritant and may potentially 
cause or exacerbate cough or 
bronchospasm 
Participants with a known 
history of moderate or severe 
bronchial hyperreactivity 
(such as in asthma) or 
presence of signs of 
significant bronchospasm on 
examination will be excluded 
from study participation 
(Exclusion criterion 5) 


 
 
 
 
 
 
 
 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Procedures 
Nebulization 
The delivered dose of 
RESP301, estimated to be 
~40% of the masses listed in 
Table 6-2, can be affected by 
patient technique and 
inspiratory capacity leading 
to inter- and intra-patient 
variation in actual doses of 
these ingredients, given the 
acute nature and high disease 
burden in this proposed 
clinical setting 
Training will be provided to 
study staff to minimize 
variation in dose 
Other 
Risk of spreading SARS-
CoV-2 
SARS-CoV-2 is known to be 
transmissable via respiratory 
droplets and any interventions 
that may potentially increase 
cough or aerosolization of 
respiratory secretions of an 
infected patient may increase 
risk of spread of disease  
Proper personal protective 
equipment including 
appropriate mask, face shield, 
gown and gloves should be 
used at all times. When 
possible, the site staff should 
not remain in the room during 
study intervention 
administration (providing that 
continuous O2 monitoring can 
be conducted remotely and 
study intervention can be 
administered correctly) 
2.2.2 
Benefit Assessment 
To date, no treatment of COVID-19 has demonstrated clinical efficacy. Patients and their 
physicians are critically in need for treatments that decrease the risk of severe levels of disease, 


 
 
 
 
 
 
 
 
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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. 
Nitric Oxide is already marketed (e.g., INOmax®, NOXIVENT™, etc) in the United States (US) 
and other countries as a gas for continuous use in preterm and near-term (>34 weeks gestation) 
neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence 
of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents. 
It is well tolerated, although under continuous use, a small number of cases of 
methemoglobinemia have been reported (NOXIVENT™ FDA Prescribing Information). 
Nitric oxide has been shown in vitro to inhibit the replication cycle of severe acute respiratory 
syndrome coronavirus (Akerström S et al, 2005). In addition, NO is a naturally occurring and 
potent antimicrobial agent in the human body, which is active against viruses, bacteria, fungus, 
and yeasts (Fang, 1997). In particular, NO inhibits replication in vitro in a number of respiratory 
viruses including influenza A and B (Rimmelzwaan et al, 1999, Regev-Shoshani et al, 2013), 
human rhinovirus (Sanders et al, 1998), and respiratory syncytial virus (Ali-Ahmad D et al, 
2003). 
The ability of RESP301 to have a marked antibacterial action is highly relevant in the context of 
treating patients with SARS-CoV-2 infection since superimposed bacterial infection is a critical 
factor and a major cause of morbidity and mortality. RESP301 would restore and replenish the 
NO deficiency in patients who have succumbed to SARS-CoV-2 infection. RESP301 also has 
key advantages over inhaled NO gas, as discussed in Section 2.1. 
The product will be delivered via a Philips InnoSpire Go nebulizer which is approved for use 
both in the United States of America (510k Clearance) and in Europe (CE mark). The InnoSpire 
Go is a hand-held, single patient use, vibrating mesh nebulizer system designed to aerosolize 
liquid medications for respiratory disease. The device operates continuously once initiated and 
automatically switches off once the medication has been delivered. The device may be used in 
pediatric and adult populations, as permitted by the prescribed medication, and is suitable for use 
in home environments or hospital/clinic settings. It appears to be easily cleaned and delivers a 
fine mist (particle size < 10 µM) (FDA InnoSpire Go Indications for Use). 
As testing inefficient product would distract sites from participating in other research efforts, two 
interim analysis for futility purpose have been planned. 


 
 
 
 
 
 
 
 
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2.2.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with RESP301 are justified by the anticipated 
benefits that may be afforded to participants with COVID-19. 
3 Objectives and Endpoints 
Table 3-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 4 in the 
modified World Health Organization 
(WHO) ordinal scale into levels >4 
• Proportion of participants who progress to 
level >4 of modified WHO ordinal scale 
due to COVID-19 by Day 14 
Key Secondary 
• To assess the effect of RESP301 as 
measured by room air SpO2 
• Change in room air SpO2 from baseline 
over time 
• To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
• Change in NEWS 2 symptom score from 
baseline over time 
• To assess the treatment response on 
clinical status 
• Change from baseline on the modified 
WHO ordinal scale at each visit up to 
Day 28 
• Time to improvement to a lower level 
(<4) of modified WHO ordinal scale 
• Time to progression to a higher level (>4) 
of modified WHO ordinal scale 
Additional Secondary 
• To assess the treatment response on 
clinical status 
• Time to hospital discharge 
• Incidence of mortality by Day 28 
Safety 
• To assess the overall safety profile of 
RESP301 in COVID-19 participants 
• Clinical safety laboratory measurements 
• Physical examinations 
• Vital signs 


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• 
Safety follow-up: 28 days after treatment initiation; with the participant being contacted 
by phone call, if not still hospitalized, on Day 28 (±1 day) 
After screening, eligible participants will be randomized to either RESP301+SOC or SOC alone 
on Day 1, and the study treatment will be initiated as applicable (Table 1-1). Screening and 
randomization may happen on the same day (Day 1).  
An individual administration of study intervention will be stopped, and supplemental oxygen 
resumed, if threshold limits of SpO2 89% or heart rate 120 beats/min (or as indicated by the 
Investigator) are exceeded (see Section 4.2 and Section 8.1.2). However, the participant may 
continue with subsequent doses if the investigator judges that the benefit risk remain positive. In 
this case, the instruction to continue should be duly recorded in the participant’s hospital file and 
the subsequent nebulization should be closely monitored. Inhalation of study intervention should 
be completed within 20 minutes. 
The study treatment will be permanently discontinued prior to 10 days if the participant: 
• Improves to level 1 or 2 of the modified WHO ordinal scale; 
• Progresses to a level > 4 of the modified WHO ordinal scale; 
• Experiences adverse drug reaction or suspected adverse drug reaction. 
In the above cases, participants will be considered as ongoing in the study until the final Safety 
follow-up phone call (Day 28). Participants will be withdrawn from the study prior to Day 10 
(Early withdrawal) only if they withdraw consent.  
The total study duration for a participant from screening to last follow up will be up to 30 days. 
Participants will be stratified by country and presence of risk factor(s) for severe outcomes of 
COVID-19, based on comorbidities and age, as detailed in Section 6.3. 
Two interim analyses are planned (see Section 9.5 for details). 
An Independent Data Monitoring Committee (IDMC) will be responsible for closely reviewing 
the safety and efficacy data from the interim analyses and for providing their recommendations 
on continuation of the study. The IDMC will meet after 10, 20, 60 and 150 participants have 
completed the study (see Sections 9.5 and 9.6). 
4.2 Scientific Rationale for Study Design 
NO is a naturally occurring and potent antimicrobial agent in the human body which has been 
shown in vitro to inhibit replication in vitro of severe acute respiratory syndrome coronavirus 


 
 
 
 
 
 
 
 
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(Akerström S et al, 2005), including SARS-CoV2, and other respiratory viruses. NO as an 
inhaled gas is already marketed in the US and other countries (see Section 2.2.2) but has 
disadvantages over NO produced locally in the oropharynx or lung airways (lengthy treatment 
requiring NO canisters, the inhaled NO is expelled in exhalation, the NO gas oxidizes in air to 
form toxic NO2 which is a potential lung irritant and a contaminant in the patient’s environment, 
and the half-life of NO in air is short).  
RESP301 has potential advantages over inhaled NO gas: 
• 
RESP301 demonstrates powerful evidence in vitro as a broad-spectrum anti-microbial; 
• 
Treatment is quick, easy and portable using a standard handheld nebulizer; 
• 
The formulation is nebulized 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. 
In this study, the effect of RESP301 as an add on treatment to SOC will be evaluated for its 
efficacy in reducing rate of progression to a more severe level of COVID-19 and for safety by 
comparison with SOC alone in hospitalized COVID-19 patients. A sequential adaptive design 
was chosen in order to assess futility and sample size after interim analyses (see Section 9.5). 
The study design was developed in accordance with the latest WHO and regional regulatory 
agencies guidelines.  
Several risks factors for severe or fatal outcomes have been reported (Bialek et al, 2020; Huang 
et al, 2020; Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020; 
Rong-Hui et al, 2020; Zhou et al, 2020). To minimize bias, the results will be stratified according 
to the known risk factors as described in Section 6.3. 
In this study, measures will be in place to trigger discontinuation of study intervention at a SpO2 
limit pre-agreed at the site (see Section 8.1.2). There is no critical level of oxygen saturation 
below which tissue hypoxia occurs due to the large number of variables that contribute to 
hypoxia at the tissue and cellular level (temperature, pH, tissue blood flow). As a result, there is 
no consensus about what constitutes normal and abnormal oximetry (ATS/ACCP, 2003). To 
support and guide the team in charge of study intervention administration, a default value of 
SpO2=89% and heart rate (120 beats/min) has been proposed as a suitable limit of tolerance. 
However, for the reason stated above, this limit can be overruled by the Investigator in either 
direction. 


 
 
 
 
 
 
 
 
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Newly released guidelines for ongoing clinical trials during the COVID-19 pandemic have 
emphasized the need to reduce the burden on sites and clinical trial personnel/investigators 
whether they be administrative, site visit, or other burdens (ACRO, 2020; EMA, 2020; HRS, 
2020). Thus, without blinding and a placebo, along with minimal procedures, the additional 
burden on clinical staff has been reduced as much as possible. 
4.3 Justification for Dose 
Studies with nebulized sodium nitrite (AIR001) in healthy subjects and in patients have shown 
that inhaled nitrite produces dose proportional plasma pharmacokinetic without accumulation 
following repeated administration, with low systemic blood levels of nitrite and methemoglobin 
(<3%). Inhaled nitrite at doses up to 90 mg TID displayed a good safety profile and is well 
tolerated (Rix et al, 2015; Parsley et al, 2013; Simon et al, 2016).  
In this study, 6.0 mL RESP301 (delivered dose 62 mg) will be administered via a Philips 
InnoSpire Go hand-held vibrating mesh nebulizer, TID with at least 4 hours between each dose. 
Each 6.0mL dose for nebulization contains the masses described in Table 6-2. 
4.4 End of Study Definition 
A participant is considered to have completed the study if he/she has completed the Treatment 
Period and the Follow-up Period (through the Day 28 EoS Follow-up). 
5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of participants with COVID-19. Participants must be able to 
provide written consent and meet all the inclusion criteria and none of the exclusion criteria. 
5.1 Study Rationale 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design to evaluate the efficacy and safety of RESP301 plus SOC versus 
SOC alone in hospitalized patients with COVID-19 requiring supplemental oxygen (WHO 
level 4). 
Each constituent (see Section 6.2) of RESP301 is used as SOC for various conditions. Product 
application is straightforward, requiring a few minutes of inhalation using a standard nebulizer. 


 
 
 
 
 
 
 
 
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RESP301 is likely to be beneficial in treating patients with COVID-19 who are not receiving 
ventilation but are using supplementary oxygen in order to maintain a safe level of SpO2. 
Considering the well-established and global use of NO and the device, and the current public 
health emergency resulting from the COVID-19 pandemic, a Phase2/3 study of RESP301 is 
considered reasonable in order to generate efficacy data in patients infected with COVID-19. 
5.2 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is ≥18 years of age, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participant has laboratory-confirmed SARS-CoV-2 infection as determined by reverse 
transcriptase polymerase chain reaction (RT-PCR) or other approved clinical testing prior 
to randomization. 
3. Participant is hospitalized in relation to COVID-19, requiring supplemental oxygen to 
maintain SpO2 at a safe level (WHO level 4). 
Sex 
4. Participant is male or female. 
Informed Consent 
5. Participant is capable of giving signed informed consent as described in Appendix 1 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.3 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Rapidly deteriorating or likely to require escalation to high flow oxygen, invasive or 
non-invasive ventilatory support within 24 hours according to Investigator’s opinion. 
2. Unable to safely receive a nebulized treatment while on room air for approximately 
4 minutes according to Investigator’s opinion. 


 
 
 
 
 
 
 
 
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3. Unable to receive or considered ineligible for invasive or non-invasive ventilatory 
support. 
4. History of methemoglobinemia. 
5. Uncontrolled asthma or history of severe bronchospasm. 
6. Severe (requiring baseline oxygen therapy > 12 h/day prehospitalization) chronic 
respiratory disease (e.g., known COPD, pulmonary arterial hypertension, idiopathic 
pulmonary fibrosis, interstitial lung disease). 
7. Suspected or confirmed untreated, active tuberculosis. 
8. Severely immune-compromised participants in Investigator’s opinion. 
9. Recent (within 3 months) active coronary artery disease or decompensated heart failure 
(New York Heart Association class 3-4). 
10. Presence of tracheostomy. 
Prior/Concomitant Therapy 
11. Chronic (≥4 weeks) use of corticosteroids >10 mg/day of prednisone or equivalent within 
4 weeks of randomization. 
Prior/Concurrent Clinical Study Experience 
12. Participation in other clinical investigations utilizing investigational treatment or within 
30 days / 5 half-lives whichever is longer. 
Diagnostic Assessments 
13. Clinically significant abnormalities in clinical chemistry or hematology at screening, 
defined as: 
• 
Platelet count <50,000 mm3 
• 
Alanine aminotransferase or aspartate aminotransferase >5 × upper limit of normal 
(ULN). 
• 
Estimated glomerular filtration rate <30 mL/min/1.73 m2 (modification of diet in renal 
disease formula) or requiring hemofiltration or dialysis. 
Other Exclusions 
14. Anticipated transfer to another hospital which is not a study site during the treatment 
period. 
15. Allergy to any of the components of the study intervention. 


 
 
 
 
 
 
 
 
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5.4 Lifestyle Considerations 
No restrictions are required. 
5.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography and reason for screen 
failure (e.g., eligibility requirements failed). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
5.5.1 
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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6 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. 
6.1 Study Intervention(s) Administered 
Table 6-1 
Study Intervention(s) Administered 
Study Treatment 
RESP301 + SOC 
Intervention Name: 
RESP301 
Type: 
Drug 
Dosage Formulation: 
Admixture for inhalation 
Unit Dose 
Strength(s): 
Delivered dose (62 mg) sodium nitrite (NaNO2) 
(6 mL of NO-generating admixture containing 150 mM NaNO2, 50 mM mannitol and 
100 mM citric acid) 
Dosage Level(s): 
One 6 mL-inhalation TID with at least 4 hours between 2 consecutive inhalations. 
Route of 
Administration: 
Inhalation 
IMP and NIMP: 
IMP 
Sourcing: 
RESP301 provided centrally by the Sponsor. 
Dosing Instructions: 
A CE marked Philips InnoSpire Go hand-held vibrating mesh nebulizer will be used to 
administer the RESP301, under the direction of the study physician. 
Treatment is to commence within 5 minutes of RESP301 preparation and each 
inhalation takes approximately 3-5 minutes. 
Before initiating each RESP301 inhalation, supplemental oxygen will be interrupted 
for a few minutes until SpO2 levels are stable. Depending on the extent of SpO2 
decrease, the RESP301 inhalation may be initiated or supplemental oxygen may be 
resumed at the discretion of the investigator. 
Packaging and 
Labeling: 
Study intervention will be provided as two separate ampoules of NaNO2/mannitol 
(3 mL) and citric acid buffered to pH 5.4 (3 mL) which will be labeled as required per 
country requirement.  
 
6.1.1 
Medical Devices 
1. Medical devices (not manufactured by or for 30 Respiratory) provided for use in this 
study are FDA approved and CE marked Philips InnoSpire Go hand-held vibrating mesh 
nebulizer.  
2. Instructions for medical device use are provided in the User Manual. 


 
 
 
 
 
 
 
 
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3. All medical device deficiencies, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout the 
study (see Section 8.3.7). 
6.1.2 
Device Training 
Training will be provided to ensure all study staff are familiar with the device, including mixing 
the solutions, adding the admixture to the device and cleaning the device. 
6.2 Preparation, Handling, Storage, and Accountability 
6.2.1 
Preparation of Study Intervention Product 
RESP301 is prepared at bedside by mixing two sterile 3 mL solutions (one of NaNO2/mannitol 
and one of citric acid buffered to pH 5.4). The solution is to be nebulized immediately or within 
5 minutes post mixing as per the instructions given in the SoA (Table 1-1). The first 
administration of study intervention should be provided under medical supervision. 
The unmixed RESP301 drug product consists of a solution of concentrated sodium nitrite with 
mannitol excipient (3 mL). The citric acid solution (3 mL) is then added to the sodium 
nitrite/mannitol pre-mixture ampoule and inverted 10 times to mix no more than 5 minutes prior 
to application into the nebulizer (see Table 6-2 for details of composition). This combined mildly 
acidified nitrite solution (6 mL) is then inhaled through the mouth using a Philips InnoSpire Go 
hand-held mesh nebulizer under the direction of a physician. The purpose of the acidified nitrite 
aerosol is to deliver NO2 to the participant; each dose of 41.4 mg of nitrite (as the anion) could 
theoretically deliver 27.0 mg of NO2, assuming a 100% conversation rate. The amount of NO2 is 
not measured directly but inferred from the amount of nitrite available for conversion. 


 
 
 
 
 
 
 
 
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Table 6-2 
Composition of Drug Product, Diluent and Admixure 
 
Material 
Function 
Quantity per vial 
Drug Product 
Sodium Nitrite 
Drug Substance 
62.10 mg 
 
Mannitol 
Excipient  
54.66 mg  
 
Sterile water for injection 
Diluent 
 
 
Total Volume 
 
3.0 mL 
Diluent 
Citric Acid  
Diluent 
115.28 mg 
 
Sterile water for injection 
Diluent 
 
 
Total Volume 
 
3.0 mL 
Acidified Drug 
Product Mixture 
Sodium Nitrite 
Drug Substance 
62.10 mg 
 
Mannitol 
Excipient  
54.66 mg  
 
Citric Acid  
Diluent 
115.28 mg 
 
Sterile water for injection 
Diluent 
 
 
Total Volume 
 
6.0 mL 
 
6.2.2 
Storage and Accountability of Study Intervention 
The investigator or designee must maintain a log to confirm appropriate temperature conditions 
have been maintained during transit 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 authorized site 
staff may supply or administer study intervention. All study interventions 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 authorized 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). 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Investigator Manual. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; however, the specific intervention to be taken by a participant will be 
assigned using an interactive voice response system (IVRS)/interactive web response system 


 
 
 
 
 
 
 
 
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(IWRS). The site will contact the IVRS/IWRS prior to the start of study intervention 
administration for each participant. The site will record the intervention assignment on the 
applicable case report form (CRF), if required.  
Potential bias will be reduced using a central stratified randomization to assign participants into 
one of the study treatment arms, RESP301+SOC or SOC (control), with a randomization ratio of 
2:1. Participants will be stratified by country and presence of risk factors for severe outcomes of 
COVID-19, based on comorbidities and age as follows: 
1. Age >65 years 
2. Ongoing or currently treated diabetes mellitus 
3. Ongoing or currently treated hypertension 
4. Ongoing or currently treated cardiovascular disease 
5. Ongoing or currently treated chronic lung disease 
6. Cancer history of less than 3 years, basal cell skin carcinoma excluded 
7. Ongoing or currently treated chronic kidney disease 
Participants will be stratified as no risk factor (none of the above criteria), one risk factor (one 
single of the above) or high-risk factor (2 or more of the above). 
6.4 Study Intervention Compliance 
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each inhalation will be recorded in the source 
documents and recorded in the CRF. The study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the study 
intervention. 
6.5 Concomitant Therapy 
During the study, participants will receive institutional SOC for the treatment of COVID-19. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 


 
 
 
 
 
 
 
 
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• 
Dosage information including dose and frequency and route 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6 Intervention After the End of the Study 
After the end of the study, participants may resume or continue their SOC (if any). Study 
intervention for COVID-19 will not continue beyond this study. 
7 Discontinuation of Study Intervention and Participant Discontinuation 
7.1 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 the Day 14 and Day 28 safety follow-ups. See the SoA 
(Table 1-1) for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
Study intervention will be permanently discontinued prior to 10 days if the participant: 
• Improves to level 1 or 2 of the modified WHO ordinal scale; 
• Progresses to a level > 4 of the modified WHO ordinal scale; 
• Experiences adverse drug reaction or suspected adverse drug reaction. 
Additionally, study intervention should be discontinued in the following circumstances: 
1. Clinical intolerance to nebulization. 
An individual administration of study treatment will be stopped, and supplemental 
oxygen resumed, if threshold limits of SpO2 89% or heart rate 120 beats/min (or as 
indicated by the Investigator) are exceeded (see Sections 4.2 and 8.1.2). 
2. Discontinuation of study intervention for abnormal liver tests should be considered if the 
Investigator believes that it is in best interest of the participant. 
3. If a clinically significant change in ECG is identified, the Investigator should exercise 
their clinical judgement to decide whether continuing study intervention administration is 
in the best interest of safety of the participant. 


 
 
 
 
 
 
 
 
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4. AE/SAE if the Investigator believes that it is in best interest of the participant, including 
the following: 
5. Development of significant broncho spasm or worsening of cough: 
• Progressive COVID-19 requiring initiation of non-invasive or invasive ventilation or high 
flow oxygen 
• Development of mHb level above 3% 
• Inability to safely continue receiving study intervention due to compromised respiratory 
status while off supplemental oxygen and receiving nebulized therapy (manifest by drop 
in SpO2, increased respiratory rate or clinical other findings) 
6. Progression of disease. 
Refer to the SoA (Table 1-1) for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Brief temporary discontinuation of study intervention is permitted during the study, providing 
inhalation of study intervention is completed within 20 minutes. The participant may continue 
with subsequent doses if the investigator judges that the benefit risk remain positive. 
7.2 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, behavioral, 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. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
At the time of discontinuing from the study, if possible, an early discontinuation assessment 
should be conducted, as shown in the SoA (Table 1-1). 


 
 
 
 
 
 
 
 
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7.3 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. The following actions must be taken if a participant cannot be contacted at Day 14 or 
Day 28: 
• 
The site must attempt to contact the participant and counsel the participant on the 
importance of maintaining the assigned schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• 
In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant (where possible, 
three telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record/CRF. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
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 utilized 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 1-1). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 20 mL. 


 
 
 
 
 
 
 
 
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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Informed Consent 
Informed consent must be documented according to Appendix 1, Section 10.1.3.  
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or designee to ensure 
that the participant qualifies for the study. 
Participant Identification Card 
All participants will be given a participant identification card identifying them as participants in 
a research study. The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency. The Investigator or qualified designee will 
provide the participant with a participant identification card immediately after the participant 
provides written informed consent. At the time of intervention allocation/randomization, site 
personnel will add the intervention/randomization number to the participant identification card. 
Medical History 
A medical history will be obtained by the Investigator or qualified designee. The medical history 
will collect all active conditions and any condition diagnosed that the Investigator considers to be 
clinically relevant. Details regarding the disease for which the participant has enrolled in this 
study will be recorded separately and not listed as medical history. 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 3 months prior to screening. This should include a 
history of hypertension medication, in particular angiotensin-converting enzyme inhibitors and 
angiotensin receptor blockers. 
The Investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the last assessment. Concomitant medications will be recorded on an 
ongoing basis during the study (or longer if related to an SAE). 


 
 
 
 
 
 
 
 
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8.1 Efficacy Assessments 
8.1.1 
Modified WHO Ordinal Scale 
A modified WHO ordinal scale will be used for consistency with the recent study of 
lopinavir-ritonavir in adults hospitalized with severe COVID-19 (Cao et al, 2020), to record the 
participant’s status at the time of assessment. The modified WHO ordinal scale includes the 
following levels: 
1. Not hospitalized, no limitations on activities; 
2. Not hospitalized, limitation on activities; 
3. Hospitalized, not requiring supplemental oxygen; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 
6. Hospitalized, on invasive mechanical ventilation or extra corporeal membrane 
oxygenation (ECMO); 
7. Death. 
8.1.2 
Pulse Oximetry 
Pulse oximetry measurements will be performed to evaluate SpO2 as outlined in the SoA 
(Table 1-1) and in accordance with the site standard operating procedures, on a medical-grade 
medical device. Measurements will be taken with a probe on fingertip or earlobe and recorded as 
percent oxygenated hemoglobin. Supplemental oxygen used at the time of assessment and 
method of oxygen delivery will be collected and documented along with the SpO2. 
Prior to administration of study intervention, supplemental oxygen will be held for at least a 
minute and SpO2 checked in order to ensure participant may safely receive the study 
intervention. For safety reasons, since due to the current pandemic it cannot be guaranteed that 
study intervention will be consistently administered under direct medical supervision, the study 
Investigators should provide study personnel who are able to monitor the participant and their 
SpO2 and ensure that should it decline to a threshold, this would trigger immediate 
discontinuation. By default, unless overruled by the study Investigator, this SpO2 threshold is set 
to 89%. This threshold should be entered into the saturation monitoring device to trigger an 
alarm during nebulization. 
FiO2 will be measured per site standard practice and recorded in the eCRF. The device used to 
administer oxygen should also be recorded. 


 
 
 
 
 
 
 
 
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8.1.3 
National Early Warning Score (NEWS) 2 
The NEWS 2 will be measured prior to study intervention in the morning according to the SoA 
in Table 1-1. 
The NEWS is based on a simple aggregate scoring system in which a score is allocated to 
physiological measurements, already recorded in routine practice, when patients present to, or 
are being monitored in hospital (RCP, 2012). Six simple physiological parameters form the basis 
of the scoring system: 
1. Respiration rate 
2. Oxygen saturation 
3. Systolic blood pressure 
4. Pulse rate 
5. Level of consciousness or new confusion* 
6. Temperature 
*The patient has new-onset confusion, disorientation and/or agitation, where previously their 
mental state was normal – this may be subtle. The patient may respond to questions coherently, 
but there is some confusion, disorientation and/or agitation. This would score 3 or 4 on the 
Glasgow Coma Scale (rather than the normal 5 for verbal response), and scores 3 on the NEWS 
system. 
A score is allocated to each parameter as they are measured, with the magnitude of the score 
reflecting how extremely the parameter varies from the norm (zero for ‘normal’; maximum 
score 3). The score is then aggregated. The score is increased by 2 points for people requiring 
supplemental oxygen to maintain their recommended oxygen saturation. This is a pragmatic 
approach, with a key emphasis on system-wide standardization and the use of physiological 
parameters that are already routinely measured in National Health Service (NHS) hospitals and 
in prehospital care, recorded on a standardized clinical chart – the NEWS 2 chart (Refer to 
Appendix 2: The NEWS 2 Scoring System). 
Reproduced from: Royal College of Physicians. National Early Warning Score (NEWS) 2: 
Standardising the assessment of acute-illness severity in the NHS. Updated report of a working 
party. London: RCP, 2017 (RCP, 2017). 


 
 
 
 
 
 
 
 
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8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1-1). 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
head/ear/eyes/nose/throat, cardiovascular, respiratory, gastrointestinal, lymphatic, skin and 
neurological systems. Height (screening only) and weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
8.2.2 
Vital Signs 
Vital signs to be collected as outlined in the SoA (Table 1-1) and include body temperature, heart 
rate, blood pressure, and respiratory rate. 
Body temperature will be assessed per the local practice (temporal or otic are preferred sites), 
and site will be recorded. Pulse rate, respiratory rate, and blood pressure will also be assessed per 
site SOC. Where possible the same methods should be used throughout the study for an 
individual participant. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). During study 
intervention administration, an alarm threshold should be set for heart rate at 120 beats/min (or 
as indicated by the Investigator), as outlined in the SoA (Table 1-1). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of one pulse and 
one blood pressure measurement (after the participant has been sitting for 5 minutes). 
8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (Table 1-1) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals for 
local reading.  
8.2.4 
Clinical Safety Laboratory Assessments 
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA 
(Table 1-1) for the timing and frequency. 


 
 
 
 
 
 
 
 
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The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically abnormal during participation in the study 
or within 4 days after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator 
or Medical Monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, where possible, and the 
Sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the laboratory manual and the SoA (Table 1-1). 
• 
If laboratory values from laboratory assessments not specified in the protocol and 
performed at the institution’s local laboratory result in the need for a change in 
participant management or are considered clinically relevant by the Investigator (e.g., 
are considered to be an SAE or an AE or require dose modification), then the results 
must be recorded in the CRF. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 4. 
Table 8-1 summarizes the categories of AEs. 
Table 8-1 
Categories of Adverse Event 
 
Non-device related 
Device- or procedure-related 
Non-Serious 
AE (includes all categories) 
ADE 
Serious 
SAE (includes all categories that are serious) 
SADE 
Anticipated 
Unanticipated 
ASADE 
USADE 
Abbreviations: ADE=adverse device effect; AE=adverse event; ASADE=anticipated serious adverse device effect; 
SADE=serious adverse device effect; SAE=serious adverse event; USADE=unanticipated serious adverse device 
effect 
 


 
 
 
 
 
 
 
 
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The definitions of AEs and SAEs (including adverse device effects [ADEs], serious ADEs 
[SADEs], and unanticipated SADEs [USADEs]), can be found in Appendix 5. Device 
deficiencies are covered in Section 8.3.8. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized 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 AE that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue the study intervention (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from randomization until the last follow-up visit at the time 
points specified in the SoA (Table 1-1). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the CRF 
not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 4. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obliged to actively seek AEs or SAEs after the conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 
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 4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 


 
 
 
 
 
 
 
 
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8.3.3 
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, stabilization, 
until the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Appendix 4) 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. 
For all studies except those utilizing medical devices, 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 IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy (Not Applicable) 
Women of childbearing potential and pregnant women are allowed in the study. 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
The following disease-related events (DREs) are common in participants with COVID-19 and 
can be serious/life-threatening: 
• 
Fever 
• 
Cough 
• 
Dyspnea* 


 
 
 
 
 
 
 
 
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• 
Asthenia 
* A cough or dyspnea episode related to study intervention administration does not meet the 
definition of a DRE and should be reported as an AE. 
Because these events are typically associated with the disease under study, they will not be 
reported as AEs. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an SAE (instead of a DRE): 
• 
The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant. 
OR 
• 
The Investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.3.7 
Adverse Events of Special Interest (Not Applicable) 
No AEs of special interest are defined for this study. 
8.3.8 
Medical Device Deficiencies 
The definition of a medical device deficiency and instructions for documenting medical device 
deficiencies are provided in Appendix 5. 
Medical devices are being provided for use in this study as the study intervention is supplied 
with a Philips InnoSpire Go hand-held vibrating mesh nebulizer. To fulfill regulatory reporting 
obligations worldwide, the Investigator is responsible for the detection and documentation of 
events meeting the definitions of device deficiency that occur during the study with such devices. 
NOTE: Device deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3 and Appendix 4 of the protocol. 
8.3.8.1 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used. 


 
 
 
 
 
 
 
 
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• If the Investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such deficiency is considered reasonably related to a 
medical device provided for the study, the Investigator will promptly notify the Sponsor. 
The method of documenting medical device deficiency is provided in Appendix 5. 
8.3.8.2 
Follow-up of Medical Device Deficiencies 
• Follow-up applies to all participants, including those who discontinue study intervention. 
• The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the Investigator. 
8.3.8.3 
Prompt Reporting of Medical Device Deficiencies to Sponsor 
• Medical device deficiencies will be reported to the Sponsor within 24 hours after the 
Investigator determines that the event meets the protocol definition of a medical device 
deficiency. 
• The method of reporting medical device deficiencies is provided in Appendix 5. 
• The Sponsor will be the contact for the receipt of device deficiency reports. 
8.3.8.4 
Regulatory Reporting Requirements for Medical Device Deficiencies 
• The Investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the Sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies. 
• The Investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of deficiencies to the IRB/IEC. 
8.4 Treatment of Overdose (Not Applicable) 
There is no risk of overdose. 
8.5 Pharmacokinetics (Not Applicable) 
Pharmacokinetic parameters are not evaluated in this study. 


 
 
 
 
 
 
 
 
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8.6 Pharmacodynamics (Not Applicable) 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 Genetics (Not Applicable) 
Pharmacogenomics are not evaluated in this study. 
8.8 Biomarkers (Not Applicable) 
Biomarkers are not evaluated in this study. 
8.9 Medical Resource Utilization and Health Economics (Not Applicable) 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9 Statistical Considerations 
9.1 Statistical Hypothesis 
RESP301 reduces the rate of progression to level 5 and above in the modified WHO ordinal 
scale in COVID-19 (see Section 8.1.1). 
This represents a composite endpoint of (i) death (level 7), (ii) hospitalized, on invasive 
mechanical ventilation or ECMO (level 6), or (iii) hospitalized, on non-invasive ventilation or 
high-flow oxygen devices (level 5). 
9.2 Sample Size Determination 
A total of 300 hospitalized participants with confirmed COVID-19 will be randomized 2:1 to 
receive RESP301+SOC (200 participants) or SOC alone (100 participants). 
The comparison between the treatment arms for the primary endpoint will have approximately 
80% power and alpha level 0.025 (one-sided) to demonstrate significant reductions (15% versus 
30%) of the primary endpoint between RESP001+SOC and the Control arm (SOC), a 50% 
relative reduction for the proportion of participants who progress to level >4 (see definition of 
the primary endpoint). 
Two interim analyses are planned (see Section 9.5 for details): 


 
 
 
 
 
 
 
 
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1. The first IDMC interim analysis will take place after the first 60 participants have 
completed Day 7 of the study to evaluate whether the study can be stopped for futility 
based on change from baseline in room air SpO2. 
2. The second interim analysis will take place after 150 participants have completed Day 14 
post-randomization based on event rate for the primary endpoint. The purpose of the 
second interim analysis will be futility as well as a potential sample size re-estimation in 
case the actual results differ from the original assumptions. 
In addition to the review of efficacy data, safety will be assessed at each of the interim analysis 
by the IDMC. Further details are provided in Appendix 6. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Table 9-1 
Populations for Analysis 
Population (Analysis Set) 
Description 
Intent-To-Treat (ITT) 
Population 
The ITT Population will include all randomized participants. The 
ITT participants will be analyzed according to randomized 
treatment, irrespective of the actual treatment received. 
Participants who withdraw from treatment early will be followed 
for the assessment of the Day 14 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 randomized participants who inhale any 
amount of study intervention or are randomized to the control 
arm. The SP will be analyzed according to the actual treatment 
received. This set will be used for the safety analyses. 
 
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 primary efficacy endpoint. 
9.4 Statistical Analyses 
Below is a description of planned statistical analyses. Further details are presented in the 
Statistical Analysis Plan (SAP). 


 
 
 
 
 
 
 
 
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9.4.1 
General Considerations 
All statistical analyses will be conducted using SAS, Version 9.4 or later. Baseline characteristics 
will be summarized by treatment arm. For continuous measures the mean and standard deviation 
(SD) will be summarized. Categorical variables will be described by the proportion in each 
category. In addition, 95% confidence intervals (CIs) will be computed as indicated. 
All the categorical variables including the primary endpoint will be summarized by treatment 
with the numbers and percentages of the participants. Treatment difference will be tested using a 
Cochran–Mantel–Haenszel test stratified by 1) country and 2) participant’s clinical status at 
Baseline. For the categorical endpoints, relative risk and its 95% CI will be presented. 
All of the continuous variables, including the changes from Baseline, will be summarized by 
treatment with the means, SD, medians and the ranges. The mixed model with repeated 
measurements /analysis of covariance model with treatment, country, participant’s clinical status 
at Baseline and visit as the model term, and Baseline value as the covariate will be used to test 
for the significance of the treatment difference. Least square means, standard errors, 95% CIs 
and p-values will be presented. 
Time to event endpoints will be analyzed using the Cox Proportional Hazard model with 
treatment, participant’s clinical status at Baseline and country as the model term. The hazard 
ratio of RESP301+SOC versus SOC will be presented along with 95% CI and p-value from the 
model. The Kaplan-Meier curves of the time to events will be presented by treatment for each 
applicable endpoint. 
Handling of missing data 
If participants are discharged from the hospital prior to Day 14 due to improvement of the 
clinical status and their status on Day 14 cannot be obtained, their status on Day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. Depending on the 
reasons for missing data on the primary endpoint up to Day 14, additional sensitivity analyses 
will be performed. Further details on handling on missing data will be provided in the SAP. 
9.4.2 
Primary Endpoint 
The primary endpoint is the proportion of participants who progress to level >4 of the modified 
WHO ordinal scale due to COVID-19 by Day 14. 


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The number and percentage of patients 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 summarized. The number of deaths due to an AE, hospitalization due to an AE, and study 
discontinuation due to an AE will be summarized. 
The number and percentage of patients with an AE, as well as the total number of AEs, will be 
summarized 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. 
9.4.5.2 
Clinical Laboratory Evaluation 
Baseline is defined as the last non-missing value obtained at the screening visit and prior to the 
first exposure to study drug. Actual values and changes from Baseline clinical laboratory tests 
will be summarized by study day. If more than one laboratory result is reported per study visit 
per parameter, the last non-missing result will be selected for change from Baseline analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the Investigator. The number of patients with a non-missing result, 
the number and percentage of patients with a clinically significant result less than the lower limit 
of normal, non-clinically significant result more than the ULN, and clinically significant result 
more than the ULN will be summarized by study visit. If more than one laboratory result is 
reported per study day per parameter, the result yielding the most severe classification will be 
selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study day per parameters, the result yielding the 
most severe classification will be selected for analysis. 
Patients with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the Investigator for a patient across study visit. 
9.4.5.3 
Vital Signs 
Baseline is defined as the last non‑missing value obtained in screening and prior to the first 
exposure to study drug. Actual values and changes from Baseline in vital signs will be 


 
 
 
 
 
 
 
 
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summarized by study day and study time point. All vital sign data will be presented in patient 
listings. 
Vital sign values will be classified according to the clinical significance as determined by the 
Investigator. The number of patients with a non-missing result, the number and percentage of 
patients with a non-clinically significant result, and clinically significant result will be 
summarized by study visit and study time point. If more than one vital sign result is reported per 
study day and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis. 
Patients with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the Investigator to be clinically 
significant for a patient across study time points. 
9.4.5.4 
Physical Examination 
Abnormal physical examination findings will be listed. 
9.4.6 
Other Analyses 
Other analyses may be added to the SAP as applicable. 
9.5 Interim Analyses 
Two interim analyses will be performed.  
1. The first analysis will be conducted when about 60 participants (40 participants in the 
RESP301+SOC arm and 20 participants in the SOC arm) have completed the Day 7 
assessment. The purpose of this analysis is to evaluate efficacy of RESP301 with the 
application of a futility criterion based on the results on SpO2 change from baseline on 
Day 7. The following futility criterion will be used for this first interim analysis: 
If the difference in the percentage of participants with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints 
will be considered as well.  
As no other modification of the study at the time of the first interim analysis is considered, 
no adjustment of the alpha level is required. 


 
 
 
 
 
 
 
 
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2. The second interim analysis will be conducted after 150 participants (100 participants in 
the RESP301+SOC arm and 50 participants in the SOC arm) have completed the Day 14 
assessment. The purpose of this analysis is the assessment of futility or a sample size 
re-estimation (increase only) in case the actual results differ from the original 
assumptions for the power calculations of the study, related to the percentage of 
participants meeting the primary endpoint in the control arm and/or the relative treatment 
benefit achieved in the RESP301+SOC arm compared to the SOC arm. 
To account for the multiple testing due to the second interim analysis an adjustment for 
the type I error alpha will be applied using the Haybittle-Peto approach which would 
spend one sided alpha=0.0005 at the second interim analysis and leave one-sided nominal 
alpha of 0.0249 for the final analysis. The futility criterion for the second interim analysis 
will be based on the conditional power (CP) for the final results based on the assumption 
that the remainder of the study will follow the same trend as observed in the interim 
analysis. If CP at the time of the second interim analysis is less than 20% consideration 
will be given to stop the study for futility. At the same time sample size re-estimation will 
be performed to achieve 80% power at the end of the study. The methodology for the 
adjustment and the procedure to maintain the type I error level will be described in greater 
detail in the SAP. 
Detailed information, including the boundaries futility and characteristics for the sample size 
re-estimation at the time of the interim analyses will be provided in the SAP and Data 
Monitoring Committee (DMC) Charter. Further details are also provided in Appendix 6. 
9.6 Data Monitoring Committee (DMC) 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study. The IDMC will 
meet to review after 10 and 20 participants have completed as well as at the time of the interim 
analyses (ie, after 60 and 150 participants have completed; see Section 9.5). 
The detailed procedures and criteria of the interim analyses will be described in the DMC 
Charter. 


 
 
 
 
 
 
 
 
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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 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. 
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. 
10.1.2 Financial Disclosure 
Information on financial disclosure can be found in the study monitoring plan. 
10.1.3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. 


 
 
 
 
 
 
 
 
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Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
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 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
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 currently enrolled in 
the study. 
10.1.4 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 authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 Committees Structure 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study (see Sections 9.5 
and 9.6). 


 
 
 
 
 
 
 
 
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10.1.6 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. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized 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. 


 
 
 
 
 
 
 
 
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• All data generated by the site personnel will be captured electronically at each study 
center using eCRFs. Data from external sources (such as laboratory data) will be 
imported into the database. Once the eCRF clinical data have been submitted to the 
central server at the independent data center, 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. Once all 
source data verification is complete and all queries are closed, the monitor will freeze the 
eCRF page. 
• 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. 
10.1.7 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. 
10.1.8 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 visit 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. 


 
 
 
 
 
 
 
 
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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 contract research 
organization(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 
10.1.9 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 
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 multicenter 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. 
10.1.10 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). In the US: Following approval, the protocol 


 
 
 
 
 
 
 
 
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amendment(s) will be submitted to the Investigational New Drug application under which the 
study is being conducted. 
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. 
10.1.11 Liability and Insurance 
10.1.11.1 Access to Source Data 
Access to source data is described in the Monitoring Plan. 


 
 
 
 
 
 
 
 
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10.2 Appendix 2: The NEWS 2 Scoring System 
Chart 1: The NEWS 2 scoring system 
 
Abbreviations: CVPU: C=new onset confusion, disorientation or agitation, V=responds to voice, P=responds to 
pain, U=unresponsive; SpO2=oxygen saturation. 
Source: Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of 
acute-illness severity in the NHS. Updated report of a working party. London: RCP, 2017. 
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2 
 










 
 
 
 
 
 
 
 
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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
(Applies only during the safety follow up period for patients who may have been 
discharged during the treatment period, ie, between Day 1 and Day 10) 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are considered 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective intervention of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive intervention 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 










 
 
 
 
 
 
 
 
 
 
 
 
 
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After receipt of the initial report, the safety center will review the information and, if necessary, 
contact the Investigator, to obtain further information for assessment of the event. Parexel will be 
responsible for all information processing and reporting according to local legal requirements. 
Where necessary, Investigators will inform regulatory authorities in their own countries. 
 






 
 
 
 
 
 
 
 
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10.6 Appendix 6: Statistical Design Considerations 
10.6.1 Some General Design Considerations 
1. Binary primary endpoint: progression to critical stage/death up to Day 14 
• to be analyzed by a Cochran-Mantel-Haenszel (CMH) stratified for the factors used in 
the stratified randomization 
• subjects who withdraw from study treatment will be followed up until their primary 
endpoint outcome is known (i.e., up to Day 14 or progression to critical stage/death, 
whatever is first) 
• it is, therefore, not clear what current protocol synopsis text could mean: If subjects 
are discharged from the hospital prior to day 14 due to improvement of the clinical 
status and their status on day 14 cannot be obtained, their status on day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. and what 
the implications on statistical study characteristics could be. Further discussion is 
needed.  
2. Timing of the two planned interim analyses with stopping options is stated as 
There are 2 interim analyses planned, the first interim analysis after the first 60 patients have 
completed day 7 of the observation period … and a second interim analysis after 150 
patients have completed day 14 of the observation period. 
With the current text for the timing of the first interim analysis, it is not clear how many 
subjects will have been randomized at least 14 days prior to the interim data cut-off date and 
can therefore provide data for the binary primary endpoint (“progression to critical 
stage/death up to Day 14”).  
For such a binary endpoint, Parexel does not recommend including any subject randomized 
less than 14 days prior to the interim data cut-off date (note this would be different to a study 
with a time-to-event endpoint) as 
• for such subjects not yet progressed, the outcome up to Day 14 is unknown and 
should not be imputed as “not progressed up to Day 14” 
• for such subjects progressed prior to Day 14, the outcome is known but their 
inclusion would bias the estimation of progression probability up to Day 14 in a 
upwards direction.  


 
 
 
 
 
 
 
 
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In order to set up the adaptive group-sequential study design, the following assumptions have 
been used: 
• first interim analysis: a total of ≈ 39 subjects randomized at least 14 days prior to data 
cut-off date 
• second interim analysis: a total of ≈ 50% of the initially planned number of subjects 
randomized at least 14 days prior to data cut-off date. 
3. Non-binding DMC guidance for stopping the study for futility at the first interim analysis 
is stated as: 
If the difference in the percentage of patients with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, a benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints will 
be considered as well. 
As the main futility stopping criterion is based on improvement in SpO2 (and not on the 
primary efficacy endpoint), this first interim analysis will be “ignored” in these statistical 
considerations for an adaptive group-sequential design. We may revisit the first interim 
analysis at a later point in time when more information is available.  
4. Non-binding DMC guidance for stopping the study for futility at the second interim 
analysis stated as:  
The futility criterion for the second interim analysis will be based on the conditional power 
(CP) for the final results based on the assumption that the remainder of the trial will follow 
the same trend as observed in the interim analysis. If CP at the time of the second interim 
analysis is less than 20% consideration will be given to stop the study for futility. 
5. Current DMC guidance for stopping the study for superior efficacy at the second interim 
analysis is stated as: 
To account for the multiple testing due to the second interim analysis an adjustment for the 
type-I-error probability will be applied using the Haybittle-Peto approach with one sided 
alpha=0.0005 at the second interim analysis and leave one-sided nominal alpha of 0.0249 
for the final analysis. 
6. For initial sample size calculation, the following additional assumptions / features from 
the protocol have been used 
• progression probability up to Day 14 for Standard of Care (SOC): 30% 


 
 
 
 
 
 
 
 
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• progression probability up to Day 14 for RESP301+SOC: 15%  
• desired power assuming the alternative hypothesis stated above: 80% 
• 2:1 randomization 
7. Method for adaptation of the sample size based on the second interim analysis data is 
stated as 
A sample size re-estimation will be performed to achieve 80% conditional power at the end 
of the study. The methodology for the adjustment and the procedure to maintain the type-I-
error level will be described in greater detail in an appendix to the protocol.  The maximum 
increase of the sample size will be limited to a total number of 600 randomized subjects.  
Parexel has put a suggestions with some fictitious interim data for illustration in 
Section 10.6.3; that section also illustrates by simulations the Cui/Hung/Wang (CWH) 
approach using a weighted (weights fixed at the design-stage) test for the final analysis 
versus the Chen/DeMets/Lan (CDL) approach without such weights at the final analysis. 
 
 


 
 
 
 
 
 
 
 
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10.6.2 General Design Characteristics 
Parexel proposes to base non-binding futility stopping criteria on conditional power criteria. 
Conditional power (CP) is the conditional probability for achieving statistically significant 
superiority of RESP301+SOC over SOC at the final analysis, given the interim results and 
calculated by assuming the interim estimates to be the true distribution parameters for the 
remaining part of the study (an alternative would be predictive power (PP), a Bayesian version of 
CP where prior distributions and observed interim results are combined to obtain the probability 
for achieving statistically significant superiority of gimsilumab over placebo at the final 
analysis).  
Randomization 2:1 
Group-Sequential Design 
1st Interim Analysis (IA) 
N ≈ 39 for D14 
2nd IA 
≈ 50% for D14 
Futility criterion 1st IA 
Based on SpO2 
Futility criterion 2nd IA 
Superior efficacy criterion 2nd IA 
CP < 4% 
p < 0.0005 
Total sample size required for 80% power 
300 
Futility stopping probability at 2nd IA under 
“No effect” 
1st IA: NA 
2nd IA: 70% 
Futility stopping probability at 2nd IA under 
“Planned effect 30% vs 15%” 
1st IA: NA 
2nd IA: 6% 
Superiority stopping probability at 2nd IA 
under “Planned effect 30% vs 15%” 
10% 
Superiority stopping probability at 2nd IA 
under “30% vs 10%” 
28% 
 


 
 
 
 
 
 
 
 
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10.6.3 Adaptive Sample Size Re-Estimation 
Another objective of the 2nd interim analysis is to re-estimate the sample size based on the 
unblinded interim results.  
Proposed procedure at 2nd interim analysis (planned to include approximately 150 subjects) 
• unblinded analysis of the primary efficacy endpoint (“progression to level >4 of modified 
WHO ordinal COVID-19 scale by Day 14” as a binary endpoint)  
• calculation of conditional power (CP) given the interim results and calculated by assuming 
the interim estimates to be the true distribution parameters for the remaining part of the study 
• if CP < 4%: recommend early stop for futility 
• if one-sided p-value < 0.0005: recommend early stop for superior efficacy 
• if 50% < CP < 80% and one-sided p-value ≥ 0.0005:  
o continue the study with an increased total sample size N*, so that CP with a 
total of N* subjects is increased to 80%, same value as the (unconditional) 
desired power in the study design 
o N*, however, is limited to 600 (which is twice the original sample size 300) 
• if 4% ≤ CP ≤ 50%: continue the study without a change in sample size (otherwise, the 
sample size would need to be increased too much or the maximum sample size of 600 
would not be sufficient to come close to a CP of 80%. 
The table on the next page illustrated the proposed procedure for a number of possible results 
observed at the 2nd interim analysis.  
 
 


 
 
 
 
 
 
 
 
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Table with examples for the adaptive sample size procedure described above using the 
Cui/Hung/Wang (CHW) approach using a weighted (fixed weights determined by the stage-wise 
sample sizes planned at the design-stage) test for the final analysis: 
2nd IA results with n=150 
subjects (50 for SOC, 
100 for RESP301+SOC 
CP under 
observed trend 
for planned 300 
Total sample size 
required for CP 80% 
under observed trend 
CP under observed 
trend if total sample 
size capped by 600 
15 (30%) 
5 (5%) 
p < 0.0005  → early stop for superior efficacy 
15 (30%) 
10 (10%) 
99% 
Not applicable 
Not applicable 
15 (30%) 
15 (15%) 
90% 
Not applicable 
Not applicable 
15 (30%) 
18 (18%) 
66% 
393 
Not applicable 
15 (30%) 
19 (19%) 
55% 
483 
Not applicable 
15 (30%) 
21 (21%) 
34% 
[798] 
[67%] 
15 (30%) 
26 (26%) 
3.99% 
Early stop for futility 
12 (24%) 
10 (10%) 
92% 
Not applicable 
Not applicable 
12 (24%) 
12 (12%) 
77% 
321 
Not applicable 
12 (24%) 
14 (14%) 
54% 
498 
Not applicable 
12 (24%) 
15 (15%) 
42% 
[646] 
[77%] 
12 (24%) 
18 (18%) 
14% 
[1800] 
[31%] 
12 (24%) 
20 (20%) 
2.6% 
Early stop for futility 
10 (20%) 
8 (8%) 
85% 
Not applicable 
Not applicable 
10 (20%) 
10 (10%) 
64% 
412 
Not applicable 
10 (20%) 
11 (11%) 
50.4% 
534 
Not applicable 


 
 
 
 
 
 
 
 
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10 (20%) 
13 (13%) 
26% 
[1014] 
[55%] 
10 (20%) 
15 (15%) 
10% 
[2460] 
[23%] 
10 (20%) 
18 (18%) 
1.4% 
Early stop for futility 
Quantities in [ ] indicate theoretical values as sample size would not be increased per the 
currently proposed adaptive design.  
10.6.4 Overall Adaptive Design Performance 
Finally, the Cui/Hung/Wang (CHW) approach is compared to the Chen/DeMets/Lan (CDL) 
approach without pre-defined fixed weights for the final analysis (which is valid as sample size 
may only be increased if CP (obtained under observed trend) at the 2nd interim analysis exceeds 
50%).  
All results below are for the group-sequential design with adaptive sample size re-estimation 
procedure as described in previous sections and based on 10.000 simulated trials each. 
Scenario 1: true progression probabilities are 30% (SOC) and 15% (RESP301+SOC) 
CHW Simulation 0.3 
vs 0.15.html
 
CDL Simulation 0.3 
vs 0.15.html
 
Scenario 2: true progression probabilities are 24% (SOC) and 14% (RESP301+SOC) 
CHW Simulation 
0.24 vs 0.14.html  
CDL Simulation 0.24 
vs 0.14.html
 
Scenario 3: true progression probabilities are 30% (SOC) and 10% (RESP301+SOC) 
CHW Simulation 0.3 
vs 0.1.html
 
CDL Simulation 0.3 
vs 0.1.html
 
Scenario 4: true progression probabilities are 24% (SOC) and 20% (RESP301+SOC) 
CHW Simulation 
0.24 vs 0.2.html
 
CDL Simulation 0.24 
vs 0.2.html
 


 
 
 
 
 
 
 
 
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10.7 Appendix 7: Abbreviations 
ADE 
Adverse device effect 
AE 
adverse event 
ALT 
alanine aminotransferase 
ASADE 
Anticipated serious adverse device effect 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
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 
CP 
Conditional power 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
CRO 
contract research organization 
CV 
cardiovascular 
DMC 
Data Monitoring Committee 
DRE 
disease-related events 
ECG 
electrocardiogram 
ECMO 
Extra corporeal membrane oxygenation 
EDC 
electronic data capture 
EoS 
End of study 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 


 
 
 
 
 
 
 
 
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ITT 
Intent-to-treat 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LFT 
Liver function test 
mHb 
Methemoglobin 
NEWS 
National Early Warning Score 
NHS 
National Health Service 
NO 
Nitric oxide 
NO2 
Nitrogen dioxide 
NOx 
Oxide of nitrogen 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
PP 
Per protocol 
PT 
Prothrombin time 
QTcF 
QT interval corrected using Fridericia’s formula 
SADE 
Serious adverse device effect 
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 
TB 
Tuberculosis 
TID 
Three times daily 
ULN 
Upper limit of normal 
USADE 
Unanticipated serious adverse device effect 
WHO 
World Health Organization 
 
 
 


 
 
 
 
 
 
 
 
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11 References 
ACRO, 2020 
Association of clinical research organizations (ACRO). Considerations to Support Clinical Trial 
Monitoring Oversight During COVID-19, 13 March 2020. 
Akerström S et al, 2005 
Akerström S, Mousavi-Jazi M, Klingstr J, Leijon M, Lundkvist and Mirazimi A. Nitric oxide 
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. 
ATS/ACCP, 2003 
American Thoracic Society, American College of Chest Physicians. ATS/ACCP Statement on 
cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003; 167(2):211-77. 
Ari and Fink, 2020 
Ari A, Fink JB. Recent advances in aerosol devices for the delivery of inhaled medications. 
Expert Opinion on drug delivery. 2020; 17(2):133-44. 
Bialek et al, 2020 
Bialek S, Boundy E, Bowen V, Chow N, Cohn A, Dowling N, et al. Severe Outcomes Among 
Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 
2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-346. 
doi:10.15585/mmwr.mm6912e2 
Cao et al, 2020 
Cao B, Wang Y, Wen D, Liu W, Jingli Wang, Fan G et al. A Trial of Lopinavir–Ritonavir in 
Adults Hospitalized with Severe Covid-19. N Engl J Med 2020 March 18: doi: 
10.1056/NEJMoa2001282. [Epub ahead of print] 
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 


 
 
 
 
 
 
 
 
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at https://www.accessdata.fda.gov/cdrh_docs/pdf17/K170853.pdf (last accessed 16 April 2020) 
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consistency of performance of mesh nebulizers. Drug Delivery to the Lungs Conference. 2016; 
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brochures/industries/healthcare/rr2-full-noxivent-prescribing-
information.pdf?la=en&rev=caa0194a173a45edaeff44695b229ff9 (last accessed 16 April 2020) 
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Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of 
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Thirty Respiratory Limited 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
Final 
3 of 97 
05 Jun 2020 
 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Amendment 1.0 
Version 2.0 
05-Jun-2020 
Original Protocol 
Version 1.0 
01-May-2020 
 
Amendment 1.0 (05-Jun-2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment: 
The original protocol was updated to include important safety guidelines for study intervention 
administration for the first 10 participants (ie, up to the first independent data monitoring 
committee [IDMC] safety review). It was also updated to align with the IB Version 2.0, dated 
27 May 2020. Other changes, with brief rationale, are summarized in the following table. 
Section # and Name 
Description of Change 
Brief Rationale 
Global change 
Device name Philips 
InnoSpire Go was replaced 
with generic reference to a 
vibrating mesh nebulizer. 
The decision was made to keep 
the device generic for flexibility. 
Section 1.1 Synopsis 
and Section 4.1 Overall 
Design 
Clarified that participants 
were (male or female) adults. 
Wording of study design also 
clarified to include study 
intervention and minor 
clarification to text for 
screening period. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 4.1 Overall 
Design, Section 7.1, 
Discontinuation of 
Study Intervention 
Bullets specifying reasons for 
permanent discontinuation 
updated to reflect content of 
Section 7.1. 
Correction, for consistency 
across the protocol. 
Section 1.2 Schema 
Dose of study intervention 
corrected to 6.0 mL. Minor 
clarifications added in 
footnotes. 
Correction. 
Section 1.2 Schema 
Footnote 2 updated. 
Text added to make it clear that 
participants will be allowed 
sufficient time to consider their 
participation in the study. 
Section 1.1 Synopsis, 
Section 1.3 Schedule of 
Activities (SoA), 
Section 2.2.1 Risk 
Assessment, Section 4.1 
Overall Design, and 
Section 6.1 Study 
Intervention 
Administered 
The following statement was 
added: A staggered dosing 
approach will be used for the 
first 10 participants (up to the 
first IDMC safety review). 
RESP301 will be administered 
by intermittent inhalation to 
monitor the tolerability and 
response to RESP301 (see 
Sections 6.1 and 9.6). 
The time gap between 
consecutive doses in the 
3 times per day (TID) 
schedule was updated to “at 
least 6 hours” from “at least 
4 hours”.  
Updated to align with the 
Investigator Brochure (IB) 
Version 2.0, dated 27 May 2020. 


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Clinical Study Protocol 
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05 Jun 2020 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 SoA, Section 
5.2 Inclusion Criteria, 
Section 8.3.5 Pregnancy,  
Appendix 3, Clinical 
Laboratory Tests 
Addition of urine pregnancy 
test at screening. Requirement 
for all females of childbearing 
potential, including pregnant 
females, to consent to urine 
pregnancy testing at 
screening. Details of 
pregnancy follow-up 
procedures added. 
All women, including women of 
childbearing potential and 
pregnant women, are allowed in 
the study. Therefore, it is 
necessary to determine pregnancy 
status at study entry so that 
pregnant females can be followed 
to determine the outcome of the 
pregnancy. 
Section 1.3 SoA,  
Appendix 3, Clinical 
Laboratory Tests 
Deletion of tuberculosis (TB) 
screening test. Nitrite added to 
the protocol-required 
laboratory assessments (End 
of Study [EoS] only). 
Screening TB test is not 
mandatory for this study. Nitrite 
is to be measured for participants 
who are still hospitalized at EoS. 
Section 1.3 SoA and 
Section 7.1 Permanent 
discontinuation of Study 
Intervention 
Deletion of electrocardiogram 
(ECG) testing after screening. 
Clarified that significant 
changes in ECGs would be 
identified only as part of 
normal clinical follow-up. 
Only routine ECG monitoring is 
needed for this study. 
Section 2.1 Background, 
Section 11 References 
Text deleted from end of 
paragraph 12. References no 
longer cited were removed 
from Section 11. 
Removal of text that was specific 
to the Philips InnoSpire Go 
nebulizer. 
Table 2-1, Risk 
Assessment and 
Section 11 References 
The risk assessment table was 
updated to align with the 
above changes and IB. A new 
reference (Brannan et al, 
2005) was added to Section 11 
to support additional text 
around risk of bronchospasm. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 


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Clinical Study Protocol 
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05 Jun 2020 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 1.3 SoA, 
Section 4.1, Overall 
Design 
Visit window for Day 14 and 
Day 28 follow-up extended to 
(± 2 days). 
To allow more flexibility. 
Section 1.3 SoA 
Footnote 2 corrected to 
include weight and exclude 
ECG. Clarified that laboratory 
testing at EoS follow up is for 
nitrite and methemoglobin 
only. 
Correction and clarification. 
Section 1.3 SoA 
Footnote 6e corrected from 
‘Recording of SpO2 * pre-
nebulization on ambient air’ to 
‘Recording of SpO2 * on 
ambient air’. 
‘pre-nebulization’ was removed 
as SpO2 measurement on ambient 
air is required for both active and 
control group. 
Section 1.3 SoA 
Footnote 7 amended to clarify 
text that is applicable to 
participants in the active arm 
only. 
Clarification. 


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Clinical Study Protocol 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 SoA, 
Section 8.3 Adverse 
Events and Serious 
Adverse Events, 
Section 8.3.8 Medical 
Device Deficiencies, and 
Appendix 5: Medical 
Device Adverse Events 
(AEs) Adverse Device 
Effects (ADEs), Serious 
Adverse Events (SAEs) 
and Device 
Deficiencies: Definition 
and Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting 
Changes related to the 
removal of Appendix 5. 
Table 8-1 deleted. 
Appendix and table were not 
required because the nebulizer 
device used in the study is 
licensed and there is no 
requirement to collect data on the 
device. 
Section 2.1 Background 
Updated to include a 
description of the three 
mechanisms of action of 
RESP301 in fighting virus 
infection, including addition 
of new figure (Figure 2–1). 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 2.2.2 Benefit 
Assessment 
Clarification added regarding 
choice of nebulizer for this 
study. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 3 Objectives and 
Endpoints 
Safety endpoint for AEs 
amended to include both 
counts and cumulative 
incidence. 
Both types of data will be 
summarized. 


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Clinical Study Protocol 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3 Objectives and 
Endpoints, Section 9.4.4 
Tertiary/Exploratory 
Endpoint(s) 
Exploratory endpoint: 
timepoint for change from 
baseline measurement of 
fraction of inspired oxygen 
(FiO2) changed from Day 7 to 
Day 10.  
Correction; the endpoint should 
be measured at end of treatment. 
Section 4.4 End of Study 
Definition 
The following clarification 
was added to the definition: 
“End of the study is defined as 
the last participant’s last visit 
or follow up call.” 
Clarification of definition. 
Section 6.1 Study 
Intervention(s) 
Administered 
This section (including 
Table 6-1) was updated to 
include dosing instructions for 
the first 10 participants (ie, up 
to the first IDMC safety 
review). In the event of 
bronchospasm, rescue 
bronchodilator can be initiated 
if needed. A new figure was 
also added to clearly show the 
staggered approach (Figure 6–
1). The TID dosage was also 
clarified as every 8 hours with 
at least 6 hours between 
consecutive doses. Dosing 
Instructions were updated to 
clarify that nasal oxygen may 
be administered during 
nebulization if the participant 
is unable to tolerate 
nebulization without 
supplemental oxygen. 
Specific study drug 
administration guidelines 
(including the use of a rescue 
medication) were provided to 
monitor tolerability and response 
to RESP301 inhalation (as 
described in the risk-benefit table 
in Section 2.2.1) and to align 
with the IB, Version 2.0, dated 
27 May 2020. 


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Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
Final 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.1 
Preparation of Study 
Intervention Product 
Instructions for mixing the 
two solutions were updated. 
Further clarification on the 
delivered dose was added. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 6.5.1 Rescue 
Medication 
A new section was added to 
describe allowed 
bronchodilator rescue 
medication for participants 
treated before the first IDMC 
safety review (short acting 
beta agonist such as 
salbutamol/ albuterol 
according to investigational 
site standard practice for acute 
bronchospasm) 
Allowed rescue medication was 
added to minimize the risk of 
bronchospasm to participants, 
and to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 7.1 
Discontinuation of 
Study Intervention 
Rationale was added for 
additional monitoring and 
discontinuation guidance in 
case of bronchospasm. 
Table 7-1 added to provide 
additional clarification on the 
differences in signs and 
symptoms for acute 
bronchospasm and COVID-19 
progression. 
Safety guidance (including the 
use of a rescue medication) was 
updated to minimize the risk of 
bronchospasm to participants (as 
described in the risk-benefit table 
in Section 2.2.1) and to align 
with the IB Version 2.0, dated 
27 May 2020. 


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Clinical Study Protocol 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1 
Discontinuation of 
Study Intervention 
Section 7.2, Temporary 
Discontinuation of 
Study Intervention 
Subsequent subsections 
of renumbered to 
account for new 
Section 7.2. 
Heading updated to 
“Permanent” Discontinuation 
of Study Intervention. 
Text relating to temporary 
discontinuation moved to new 
Section 7.2. 
Text describing temporary 
discontinuation now moved into 
separate section for clarity and 
consistency. 
Section 8.3.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Corrected statement that AEs 
and SAEs will be collected 
from signing of informed 
consent and clarified that 
SAEs will be reported within 
24 hours of the Investigator 
becoming aware of the SAE, 
to align with Appendix 4 
(previously it stated ‘from 
randomization’). Deleted 
second paragraph. 
Internal document consistency. 
Section 8.3.6 Disease-
Related Events and/or 
Disease-Related 
Outcomes Not 
Qualifying as AEs or 
SAEs 
Loss of sense of taste and 
smell added to the list of 
common DREs in participants 
with COVID-19. 
Updated in line with updated 
World Health Guidelines. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.2 Sample Size 
Determination, 
Section 9.5 Interim 
Analyses, and 
Appendix 5, 
Section 10.5.1 Some 
General Design 
Considerations 
The timing of the interim 
analysis was changed from 
when 60 participants have 
completed the Day 7 
assessment to when 
60 participants have 
completed the Day 10 
assessment to make it 
consistent with the planned 
treatment duration and the 
SoA. 
Internal document consistency. 
Section 9.4.5.2 Clinical 
Laboratory Evaluation 
The following sentence was 
added:  
Participants who had urine 
pregnancy test at screening 
and the results will be listed. 
Updated to include pregnancy 
test data collection. 
Appendix 1, 
Section 10.1.3 Informed 
Consent Process, and 
Section 10.1.4 Data 
Protection 
Text added clarifying that a 
separate optional ICF will be 
provided for US participants 
who agree to tokenization. 
Added clarification that 
tokenization is for US 
participants only. 
Appendix 4, 
Section 10.4.3 
Recording of follow-up 
of AE and SAE, 
Section 10.4.4 Reporting 
of SAE 
Alignment of reporting details 
to state ‘Parexel Safety 
Services’ throughout 
appendix. Text was added to 
include paper SAE data 
collection tool. 
Internal document consistency 
and inclusion of paper SAE 
reporting data collection tool. 
Appendix 7, 
Abbreviations 
Heading number updated to 
reflect deletion of Appendix 6. 
Updated to reflect changes to 
abbreviations used in the 
document. 
Consistency. 


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Clinical Study Protocol 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 11 References 
Five new references were 
added to support the above 
updates (Basu et al, Benz et al, 
Brannen et al, Colosanti et al, 
and Saura et al). Two 
references were deleted as 
they are no longer cited. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Whole document 
Minor language and format 
changes. 
For improved clarity and 
readability. 


Thirty Respiratory Limited 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
Final 
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05 Jun 2020 
 
Table of Contents 
 
Protocol Amendment Summary of Changes Table ......................................................................... 3 
Table of Contents .......................................................................................................................... 13 
1 
Protocol Summary .................................................................................................................. 17 
1.1 
Synopsis .............................................................................................................................. 17 
1.2 
Schema ............................................................................................................................... 20 
1.3 
Schedule of Activities (SoA) .............................................................................................. 21 
2 
Introduction............................................................................................................................. 26 
2.1 
Background......................................................................................................................... 26 
2.2 
Benefit/Risk Assessment .................................................................................................... 29 
2.2.1 
Risk Assessment ............................................................................................................. 29 
2.2.2 
Benefit Assessment ......................................................................................................... 32 
2.2.3 
Overall Benefit: Risk Conclusion ................................................................................... 33 
3 
Objectives and Endpoints ....................................................................................................... 34 
4 
Study Design ........................................................................................................................... 35 
4.1 
Overall Design .................................................................................................................... 35 
4.2 
Scientific Rationale for Study Design ................................................................................ 36 
4.3 
Justification for Dose .......................................................................................................... 38 
4.4 
End of Study Definition...................................................................................................... 38 
5 
Study Population ..................................................................................................................... 38 
5.1 
Study Rationale .................................................................................................................. 38 
5.2 
Inclusion Criteria ................................................................................................................ 39 
5.3 
Exclusion Criteria ............................................................................................................... 40 
5.4 
Lifestyle Considerations ..................................................................................................... 41 
5.5 
Screen Failures ................................................................................................................... 41 
5.5.1 
Screening and Enrollment Log and Participant Identification Numbers ........................ 41 
6 
Study Intervention .................................................................................................................. 42 
6.1 
Study Intervention Administered ........................................................................................ 42 
6.1.1 
Medical Devices ............................................................................................................. 43 
6.1.2 
Device Training .............................................................................................................. 43 


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6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 43 
6.2.1 
Preparation of Study Intervention Product ..................................................................... 43 
6.2.2 
Storage and Accountability of Study Intervention ......................................................... 45 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 45 
6.4 
Study Intervention Compliance .......................................................................................... 46 
6.5 
Concomitant Therapy ......................................................................................................... 46 
6.5.1 
Rescue Medication ......................................................................................................... 47 
6.6 
Intervention After the End of the Study ............................................................................. 47 
7 
Discontinuation of Study Intervention and Participant Discontinuation ................................ 47 
7.1 
Permanent Discontinuation of Study Intervention ............................................................. 47 
7.2 
Temporary Discontinuation of Study Intervention ............................................................. 49 
7.3 
Participant Discontinuation/Withdrawal from the Study ................................................... 49 
7.4 
Loss of Participants to Follow-Up ...................................................................................... 50 
8 
Study Assessments and Procedures ........................................................................................ 50 
8.1 
Efficacy Assessments ......................................................................................................... 52 
8.1.1 
Modified WHO Ordinal Scale ........................................................................................ 52 
8.1.2 
Pulse Oximetry ............................................................................................................... 52 
8.1.3 
National Early Warning Score (NEWS) 2 ...................................................................... 53 
8.2 
Safety Assessments ............................................................................................................. 54 
8.2.1 
Physical Examinations .................................................................................................... 54 
8.2.2 
Vital Signs ...................................................................................................................... 54 
8.2.3 
Electrocardiograms ......................................................................................................... 55 
8.2.4 
Clinical Safety Laboratory Assessments ........................................................................ 55 
8.3 
Adverse Events and Serious Adverse Events ..................................................................... 55 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 56 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 56 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 56 
8.3.4 
Regulatory Reporting Requirements for SAE ................................................................ 56 
8.3.5 
Pregnancy ....................................................................................................................... 57 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs ............................................................................................................................... 58 
8.3.7 
Adverse Events of Special Interest (Not Applicable) ..................................................... 58 
8.3.8 
Medical Device Deficiencies (Not Applicable) .............................................................. 58 
8.4 
Tokenization (Optional) ...................................................................................................... 58 
8.5 
Treatment of Overdose (Not Applicable) ........................................................................... 59 


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8.6 
Pharmacokinetics (Not Applicable) .................................................................................... 59 
8.7 
Pharmacodynamics (Not Applicable) ................................................................................. 59 
8.8 
Genetics (Not Applicable) .................................................................................................. 59 
8.9 
Biomarkers (Not Applicable) ............................................................................................. 59 
8.10 Medical Resource Utilization and Health Economics (Not Applicable) ............................ 59 
9 
Statistical Considerations........................................................................................................ 60 
9.1 
Statistical Hypothesis ......................................................................................................... 60 
9.2 
Sample Size Determination ................................................................................................ 60 
9.3 
Populations for Analyses .................................................................................................... 60 
9.4 
Statistical Analyses ............................................................................................................. 61 
9.4.1 
General Considerations .................................................................................................. 61 
9.4.2 
Primary Endpoint ............................................................................................................ 62 
9.4.3 
Secondary Endpoint(s) ................................................................................................... 62 
9.4.4 
Tertiary/Exploratory Endpoint(s) ................................................................................... 63 
9.4.5 
Other Safety Analyses .................................................................................................... 63 
9.4.6 
Other Analyses ................................................................................................................ 65 
9.5 
Interim Analyses ................................................................................................................. 65 
9.6 
Data Monitoring Committee (DMC) .................................................................................. 66 
10 Supporting Documentation and Operational Considerations ................................................. 67 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 67 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 67 
10.1.2 
Financial Disclosure ....................................................................................................... 67 
10.1.3 
Informed Consent Process .............................................................................................. 67 
10.1.4 
Data Protection ............................................................................................................... 68 
10.1.5 
Committees Structure ..................................................................................................... 69 
10.1.6 
Data Quality Assurance .................................................................................................. 69 
10.1.7 
Source Documents .......................................................................................................... 70 
10.1.8 
Study and Site Start and Closure .................................................................................... 70 
10.1.9 
Publication Policy ........................................................................................................... 71 
10.1.10 Protocol Approval and Amendment ............................................................................... 71 
10.1.11 Liability and Insurance ................................................................................................... 72 
10.2 Appendix 2: The NEWS 2 Scoring System ....................................................................... 73 
10.3 Appendix 3: Clinical Laboratory Tests ............................................................................... 74 
10.4 Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 76 


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10.4.1 
Definition of AE ............................................................................................................. 76 
10.4.2 
Definition of SAE ........................................................................................................... 77 
10.4.3 
Recording and Follow-up of AE and SAE ..................................................................... 79 
10.4.4 
Reporting of SAE ........................................................................................................... 81 
10.5 Appendix 5: Statistical Design Considerations .................................................................. 84 
10.5.1 
Some General Design Considerations ............................................................................ 84 
10.5.2 
General Design Characteristics ...................................................................................... 87 
10.5.3 
Adaptive Sample Size Re-Estimation ............................................................................ 88 
10.5.4 
Overall Adaptive Design Performance ........................................................................... 90 
10.6 Appendix 6: Abbreviations ................................................................................................. 91 
11 References............................................................................................................................... 93 
Investigator Agreement Page ........................................................................................................ 97 
List of Figures 
Figure 1–1: 
Study Design ......................................................................................................... 20 
Figure 2–1: 
Mode of Action of RESP301 Against SARS-Cov-2 ............................................. 28 
Figure 6–1: 
Staggered Dosing Approach for the First 10 Participants ..................................... 43 
List of Tables 
Table 1-1 
Schedule of Activities (SoA) ................................................................................ 21 
Table 2-1 
Risk Assessment.................................................................................................... 29 
Table 3-1 
Objectives and Endpoints ..................................................................................... 34 
Table 6-1 
Study Intervention(s) Administered ...................................................................... 42 
Table 6-2 
Composition of Drug Product, Diluent and Admixture ........................................ 45 
Table 7-1 
Differences in Signs and Symptoms for Acute Bronchospasm and COVID-19 
Progression ............................................................................................................ 49 
Table 9-1 
Populations for Analysis ....................................................................................... 61 
Table 10-1 
Protocol-Required Laboratory Assessments ......................................................... 74 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: An 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 requiring supplemental oxygen 
(NOCoV2) 
Sponsor Protocol No.: RESP301-002 
Study Phase: Phase 2/Phase 3 
Sponsor: Thirty Respiratory Limited 
Rationale: 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design. Participants will be consented and randomized 2:1 to the 
Investigational arm or the Control arm. Participants randomized to the Investigational arm will 
receive inhaled RESP301 (6 mL) administered using a nebulizer 3 times a day (TID) for up to 
10 days in addition to the standard of care (SOC) while participants in the Control arm will 
receive SOC alone. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 4 in the 
modified World Health Organization 
(WHO) ordinal scale into levels >4 
• Proportion of participants who progress to 
level >4 of modified WHO ordinal scale 
due to COVID-19 by Day 14 
Key Secondary 
• To assess the effect of RESP301 as 
measured by room air SpO2 
• Change in room air SpO2 from baseline 
over time 
• To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
• Change in NEWS 2 symptom score from 
baseline over time 


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Overall Design: 
• Open-label, randomized, multicenter, parallel group, concurrent, controlled study using a 
sequential adaptive design to evaluate the efficacy and safety of RESP301 added to 
standard of care (SOC) in hospitalized patients with COVID-19 requiring supplemental 
oxygen. 
• Participants will be stratified by country and presence of risk factors for severe outcomes 
of COVID-19, based on comorbidities and age as detailed in Section 6.3. 
• The study treatment will be permanently discontinued prior to 10 days if the participant: 
o Improves to level 1 or 2 of the modified WHO ordinal scale; 
o Progresses to a level > 4 of the modified WHO ordinal scale; 
o Experiences an event that requires permanent discontinuation as described in 
Section 7.1. 
• An Independent Data Monitoring Committee (IDMC) will be responsible for closely 
reviewing the safety and efficacy data from interim analyses and for providing their 
recommendations on continuation of the study. The IDMC will meet after 10, 20, 60 and 
150 participants have completed the study (see Sections 9.5 and 9.6). 
• A staggered dosing approach will be used for the first 10 participants (up to the first 
IDMC safety review). Each RESP301 dose will be administered by intermittent 
inhalation to monitor the tolerability and response to RESP301 (see Sections 6.1 and 9.6). 
Disclosure Statement: This is a parallel group treatment study with two arms that are 
open-label. 
Number of Participants: 
Approximately 300 adult (male or female) participants will be randomly assigned to study 
intervention (200 to the Investigational arm and 100 to the Control arm). 
Intervention Groups and Duration: 
The total study duration for a participant from screening to last follow up will be up to 30 days 
(±2 days). The study will be divided into the following periods: 




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1.3 Schedule of Activities (SoA) 
Table 1-1 
Schedule of Activities (SoA) 
Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Informed consent 
X 
 
 
 
 
 
 
Optional tokenization 
ICF to be provided for 
a subset of 
participants in the 
United States (see 
Section 8.4) 
Confirmation of COVID-19 
infection by nasopharyngeal 
RT-PCR 3 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Recheck clinical 
status before 1st dose 
of study intervention 
Demographics 
X 
 
 
 
 
 
 
 
Physical examination including 
height and weight 
X 
 
 
X 
X 
 
X 2 
Full physical exam 
and height only at 
screening 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Pregnancy test (urine) 
X 
 
 
 
 
 
 
All women, including 
women of 
childbearing potential 
and pregnant women, 
may be enrolled in the 
study. Pregnancy 
status should be 
recorded (see 
Section 8.3.5). Note: 
Only females of child 
bearing potential and 
pregnant females need 
to undergo a screening 
pregnancy test. 
Medical history (includes 
substance usage) 
X 
 
 
 
 
 
 
History of substance 
usage or abuse to be 
recorded but is not 
exclusionary 
Medication history 
X 
 
 
 
 
 
 
In the prior 3 months 
Laboratory assessments 
(including liver chemistries) 4 
X 
X 
X 4 
X 
X 
 
X 2 
 
12-lead ECG  
X 
 
 
 
 
 
 
After resting supine 
for approximately 
5 minutes.  
QRS, QT, QTcF, PR, 
RR, rate 
Vital signs 5 
X 
X 
X 5 
X 
X 
 
X 
Within 15 minutes 
prior to study 
intervention 
administration 
Randomization 
 
X 
 
 
 
 
 
 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Study intervention, TID 6 
 
X 
X 
X 
 
 
 
A staggered dosing 
approach will be used 
for the first 
10 participants (up to 
the first IDMC safety 
review). Each 
RESP301 dose will be 
administered by 
intermittent inhalation 
to monitor the 
tolerability and 
response to RESP301 
(see Sections 6.1 and 
9.6). Where possible 
study intervention 
should be 
administered at 
approximately the 
same times each day 
At least 6 hours 
between 2 consecutive 
doses 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
 
Oxygen / respiratory assessment 7 
X 
X 
X 
X 
 
 
 
 
SpO2 on room air (after at least 
1 minute) prior to study 
intervention administration and 
immediately at the end of 
nebulization 6 
 
X 
X 
X 
 
 
 
See Section 8.1.2 
Modified WHO ordinal scale 
X 
X 
X 
X 
 
X 
X 
See Section 8.1.1 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
NEWS 2 assessment 7 
 
X 
X 
X 
 
 
 
Prior to study 
intervention in the 
morning. See 
Section 8.1.3 


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Abbreviations: AE=adverse event; aPTT= activated partial thromboplastin time; CBC=complete blood count; Chem 7=blood chemistry panel (sodium, 
potassium, chloride, bicarbonate/CO2, blood urea nitrogen, creatinine, glucose); CV=cardiovascular; ECG=electrocardiogram; LFTs=liver function tests; 
mHb=methemoglobin; PT/INR=prothrombin time/international normalized ratio; RT-PCR=reverse transcription-polymerase chain reaction; SAE=serious 
adverse event; TID=three times daily. 
1. Screening and randomization may be on the same day, providing all eligibility criteria are met.  
2. For participants who are already discharged at either the Day 14 or Day 28 (EoS) follow-up, there will be a phone call to check AEs/SAEs, 
concomitant medications, and modified WHO ordinal scale. At EoS, safety laboratory tests (nitrite and mHb only) and weight will be collected for 
participants in hospital only. 
3. COVID-19 infection must be confirmed and documented in chart with a positive result on a validated test. 
4. At Screening: CBC, chem 7, mHb, LFTs, coagulation (PT/INR, aPTT). 
On Day 1, Day 3, Day 7 and Day 10, or early withdrawal: CBC and chem 7 (per SOC). 
On Day 28: nitrite and mHb (participants in hospital at EoS only). 
5. Vital signs: temperature, heart rate, blood pressure, respiratory rate. Vital signs to be repeated as per SOC during treatment period. 
6. Study intervention comprises the following procedures which are to be done in order and as quickly as possible: 
a. 
Recording of oxygen flow level including mode (nasal cannula, mask) 
b. Recording of SpO2 and heart rate 
c. 
Discontinuation of supplemental oxygen administration * 
d. Close participant oversight by trained health care professional until SpO2 is stable on ambient air after one minute at least * 
e. 
Recording of SpO2 * pre-nebulization on ambient air 
f. 
Preparation of the admixture of RESP301* 
g. Administration of the nebulization via a vibrating mesh nebulizer while monitoring SpO2 and heart rate (alarms set to 89% and 120 beats / min, 
or as indicated by the Investigator, for stopping study intervention administration and resuming supplemental oxygen) * If the participant is 
unable to tolerate nebulization without supplemental oxygen, nasal oxygen may be administered during nebulization. 
h. Discontinuation of nebulization after 5 minutes or no product left in the device, whichever comes first * 
i. 
Recording of SpO2 * post nebulization on ambient air 
j. 
Resuming supplemental oxygen * 
k. Participant oversight until SpO2 is stable * 
l. 
Recording of SpO2 * 
* for participants on active treatment arm only 
7. Immediately before participant is discontinued from oxygen for study intervention administration (for participants on active treatment arm only) and 
assessment of SpO2 at room air. 


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2 Introduction 
2.1 Background 
Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by a novel coronavirus 
(SARS-CoV-2). COVID-19 was first described in Wuhan, China, in December 2019 and is now 
a global pandemic (Matos et al, 2020). Most of those affected have milder illness (80%), 15% 
will be severely ill (require oxygen) and 5% will require intensive care unit care (Novel 
Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020). Of those who are 
critically ill, most require early intubation and mechanical ventilation. Other complications 
include septic shock and multi-organ failure, including acute kidney injury and cardiac injury 
(Yang et al, 2020). Older age and comorbid diseases, such as chronic obstructive pulmonary 
disease (COPD), hypertension, and diabetes, increase risk of death (Huang et al, 2020; Zhou et 
al, 2020). The virus is highly contagious and spread via respiratory droplets, direct contact and, if 
aerosolized, airborne routes. The most common symptoms include fever, fatigue, dry cough, and 
shortness of breath.  
A critical early component of innate host defense 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 nitric oxide (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 nebulizer, 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. 


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RESP301 is a NO-generating liquid designed to release NO in situ in the upper airways and deep 
in the alveolar spaces. RESP301 is an admix solution of two precursor solutions mixed together 
at point of care for immediate inhaled administration via a CE marked handheld nebulizer and 
has specific advantages (see below) over inhaled NO gas in treating patients with COVID-19 
during the current pandemic. It has 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 nebulizer; 
• 
The formulation is nebulized 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 Sponsor has conducted a number of supportive in vitro studies to assess the activity of NO-
generating solutions against major respiratory viruses responsible for infections in humans. 
These studies include the following: 
• 
In vitro studies to demonstrate the effects of RESP301 on SARS-CoV-2 replication 
• 
In vitro study of RESP301 against influenza A (H1N1) and human rhinovirus 
• 
Determination of the anti-viral efficacy of NO-releasing formulations against two 
strains of virus (influenza A virus [H1N1] and human rhinovirus 16) 
• 
Anti-microbial activity of acidified nitrite solutions against intracellular drug sensitive 
and drug resistant Mycobacterium tuberculosis and M. abscessus infections 
• 
Anti-microbial activity of RESP301 when used alone and in combination with 
antibiotics 
Recent data from experiments at two independent laboratories using two different isolates of 
SARS-CoV-2 suggest that incubation with RESP301 for 36 to 48 hours reduced viral load to 
levels below the limit of detection of the assay at concentrations which were not associated with 
cytotoxicity. The limiting factor of the experiments was the slow growth rate of the viral 
controls; reduction in viral load was 2.2 and 4 Log10 median tissue culture infectious dose 
(TCID50).  
Studies of inhaled nebulized sodium nitrite (AIR001) in healthy subjects and in patients showed 
that inhaled acidified nitrite produces dose proportional plasma pharmacokinetics without 
accumulation following repeated administration, with low systemic blood levels of nitrite and 


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methemoglobin (<3%) (Rix et al, 2015). Inhaled nitrite (AIR001) at doses up to 90 mg three 
times daily (TID) displayed a good safety profile and is well tolerated (Parsley et al, 2013; 
Simon et al, 2016), thus supporting the investigation of RESP301 in the clinical setting. 
RESP301 delivers NO in a specifically focused way and with a unique mode of administration. 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. Whereas inhaled NO 
gas has been used to treat patients with virus-induced acute respiratory distress syndrome and is 
being tested currently in COVID-19 patients, it focuses on increasing vascular permeability and 
is not sufficiently targeted at the infection, it is rapidly dispelled with exhalation and is oxidized 
in air to toxic NO2. By comparison, RESP301 generates NO in a liquid environment that comes 
in direct contact with the virus and the virus-infected cells. As a result, RESP301 has a better 
targeted approach, and lower concentrations of NO are required, with a much more portable 
delivery system. An important environmental safety factor is that RESP301 produces negligible 
levels of NO2 generated and exhaled NO. 
In generating NO, RESP301 has at least three 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 (Figure 2–1). 
Figure 2–1: 
Mode of Action of RESP301 Against SARS-Cov-2 
 


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1. Nitric oxide 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), vital for the life-cycle of the virus, are targets for NO nitrosylation (Benz et al, 
2002; Colosanti et al, 1999). 
2. In coronaviruses like SARS-CoV-2, NO 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 receptor on the host cell. 
3. Nitric oxide can attack 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. Nitric oxide 
suppresses the virus-induced hyperactivity in the host cell and thereby deprives the virus 
of its crucial supply chain.  
RESP301 efficiently delivers with all three modes of action and is therefore considered an ideal 
candidate for clinical trials in COVID-19. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of RESP301 is 
provided in the Investigator’s Brochure. 
2.2 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. 
2.2.1 
Risk Assessment 
Table 2-1 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention RESP301 
Participants may need to be 
discontinued from 
supplemental oxygen for 
Study treatment is to be 
administered via a vibrating 
mesh nebulizer which is 
designed for oral inhalation. 
Participants unable to be 
safely discontinued from 
supplemental oxygen will be 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
several minutes to receive 
nebulized study treatment 
excluded (Exclusion 
criterion 2) 
Treatment administration is to 
be performed as quickly as 
possible (Section 1.3) 
Oxygen saturation (SpO2) 
and heart rate will be 
monitored throughout the 
study intervention 
administration (Section 1.3) 
In case of decrease in SpO2 or 
clinical signs of intolerance to 
nebulization, RESP301 
treatment may be paused 
temporarily and supplemental 
O2 resumed or the study 
treatment may be 
discontinued permanently 
(see Section 7.1) per 
Investigator assessment. 
Risk of methemoglobinemia 
Very low levels are produced 
but as methemoglobinemia 
has been reported with 
continuous NO gas 
administration, the risk 
cannot be firmly ruled out 
Participants with a history of 
methemoglobinemia will be 
excluded (Exclusion 
criterion 4) and 
methemoglobin (mHb) is 
included in safety laboratory 
tests (Section 1.3) 
Risk of clinical bronchial 
hyper-responsiveness related 
to nebulization 
Excipients in the nebulized 
RESP301 include mannitol 
which is a known bronchial 
Participants with a known 
history of moderate or severe 
bronchial hyperreactivity 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
irritant at the average dose of 
a positive mannitol test 
(239.0 ± 185.0 mg, Brannan 
et al, 2005). While the dose 
used in this study (54.66 mg) 
is lower than the average dose 
for a positive mannitol test, it 
has not yet been tested in 
COVID-19 patients and may 
potentially cause or 
exacerbate cough or 
bronchospasm in susceptible 
individuals in this specific 
population 
(such as in asthma) or 
presence of signs of 
significant bronchospasm on 
examination will be excluded 
from study participation 
(Exclusion criterion 5) 
For the first 10 participants 
treated before the first IDMC 
safety review (Section 9.6), 
RESP301 will be 
administered by intermittent 
inhalation until the intended 
dose is delivered 
(Section 6.1), so that the 
treatment can be quickly 
adjusted and rescue 
bronchodilator initiated if 
needed (Section 6.5.1) 
After reviewing safety data, 
the IDMC will decide 
whether the intermittent 
inhalation of RESP301 can be 
replaced by continuous 
inhalation. 
Study Procedures 
Nebulization 
The delivered dose of 
RESP301, estimated to be 
~40% of the masses listed in 
Table 6-2, can be affected by 
patient technique and 
inspiratory capacity leading 
Training will be provided to 
study staff to minimize 
variation in dose 


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Potential Risk of Clinical 
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Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
to inter- and intra-patient 
variation in actual doses of 
these ingredients, given the 
acute nature and high disease 
burden in this proposed 
clinical setting 
Other 
Risk of spreading SARS-
CoV-2 
SARS-CoV-2 is known to be 
transmissable via respiratory 
droplets and any interventions 
that may potentially increase 
cough or aerosolization of 
respiratory secretions of an 
infected patient may increase 
risk of spread of disease  
Proper personal protective 
equipment including 
appropriate mask, face shield, 
gown and gloves should be 
used at all times. When 
possible, the site staff should 
not remain in the room during 
study intervention 
administration (providing that 
continuous O2 monitoring can 
be conducted remotely and 
study intervention can be 
administered correctly) 
2.2.2 Benefit Assessment 
To date, no treatment of COVID-19 has demonstrated clinical efficacy. Patients and their 
physicians are critically in need for 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. 
Nitric Oxide is already marketed (e.g., INOmax®, NOXIVENT™, etc) in the United States (US) 
and other countries as a gas for continuous use in preterm and near-term (>34 weeks gestation) 
neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence 
of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents. 


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It is well tolerated, although under continuous use, a small number of cases of 
methemoglobinemia have been reported (NOXIVENT™ FDA Prescribing Information). 
Nitric oxide has been shown in vitro to inhibit the replication cycle of severe acute respiratory 
syndrome coronavirus (Akerström S et al, 2005). In addition, NO is a naturally occurring and 
potent antimicrobial agent in the human body, which is active against viruses, bacteria, fungus, 
and yeasts (Fang, 1997). In particular, NO inhibits replication in vitro in a number of respiratory 
viruses including influenza A and B (Rimmelzwaan et al, 1999, Regev-Shoshani et al, 2013), 
human rhinovirus (Sanders et al, 1998), and respiratory syncytial virus (Ali-Ahmad D et al, 
2003). 
The ability of RESP301 to have a marked antibacterial action is highly relevant in the context of 
treating patients with SARS-CoV-2 infection since superimposed bacterial infection is a critical 
factor and a major cause of morbidity and mortality. RESP301 would restore and replenish the 
NO deficiency in patients who have succumbed to SARS-CoV-2 infection. RESP301 also has 
key advantages over inhaled NO gas, as discussed in Section 2.1. 
A vibrating mesh nebulizer is advised for administration of RESP301. Amongst the suitable 
nebulizers, the device chosen for the study is a commercially available, CE-marked vibrating 
mesh device that delivers a mist of fine droplets in the size range required for pulmonary 
deposition (Mass Median Aerodynamic Diameter < 5 µm). This has been shown to be ideally 
suited for penetration deep into the alveolar spaces of the lung. As with all nebulizers in clinical 
use, there is a residual amount of drug that remains in the nebulizer so that not the full amount of 
drug is administered. The device operates continuously once initiated and automatically switch 
off once the medication has been delivered. The device may be used in pediatric and adult 
populations, as permitted by the prescribed medication, and is suitable for use in home 
environments or hospital/clinic settings. 
As testing inefficient product would distract sites from participating in other research efforts, two 
interim analysis for futility purpose have been planned. 
2.2.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this first-in-man 
study, the potential risks identified in association with RESP301 are justified by the anticipated 
benefits that may be afforded to participants with COVID-19. 


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3 Objectives and Endpoints 
Table 3-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 4 in the 
modified World Health Organization 
(WHO) ordinal scale into levels >4 
• Proportion of participants who progress to 
level >4 of modified WHO ordinal scale 
due to COVID-19 by Day 14 
Key Secondary 
• To assess the effect of RESP301 as 
measured by room air SpO2 
• Change in room air SpO2 from baseline 
over time 
• To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
• Change in NEWS 2 symptom score from 
baseline over time 
• To assess the treatment response on 
clinical status 
• Change from baseline on the modified 
WHO ordinal scale at each visit up to 
Day 28 
• Time to improvement to a lower level 
(<4) of modified WHO ordinal scale 
• Time to progression to a higher level (>4) 
of modified WHO ordinal scale 
Additional Secondary 
• To assess the treatment response on 
clinical status 
• Time to hospital discharge 
• Incidence of mortality by Day 28 
Safety 
• To assess the overall safety profile of 
RESP301 in COVID-19 participants 
• Clinical safety laboratory measurements 
• Physical examinations 
• Vital signs 
• Concomitant medications 
• Counts and cumulative incidence of: 
o Adverse events (AEs) 
o Serious adverse events (SAEs) 
o Severe AEs 


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After screening, eligible participants will be randomized to either RESP301+SOC or SOC alone 
on Day 1, and the study treatment will be initiated as applicable (Table 1-1). Screening and 
randomization may happen on the same day (Day 1).  
An individual administration of study intervention will be stopped, and supplemental oxygen 
resumed, if threshold limits of SpO2 89% or heart rate 120 beats/min (or as indicated by the 
Investigator) are exceeded (see Section 4.2 and Section 8.1.2). However, the participant may 
continue with subsequent doses if the Investigator judges that the benefit / risk ratio remains 
positive. In this case, the instruction to continue should be duly recorded in the participant’s 
hospital file and the subsequent nebulization should be closely monitored. Inhalation of study 
intervention should be completed within 20 minutes. A staggered dosing approach will be used 
for the first 10 participants (up to the first Independent Data Monitoring Committee [IDMC] 
safety review) to monitor tolerability and response to RESP301 (see Sections 6.1 and 9.6). 
The study treatment will be permanently discontinued prior to 10 days if the participant: 
• Improves to level 1 or 2 of the modified WHO ordinal scale; 
• Progresses to a level > 4 of the modified WHO ordinal scale; 
• Experiences an event that requires permanent discontinuation as described in Section 7.1. 
In the above cases, participants will be considered as ongoing in the study until the final Safety 
follow-up phone call (Day 28). Participants will be withdrawn from the study prior to Day 10 
(Early withdrawal) only if they withdraw consent.  
The total study duration for a participant from screening to last follow up will be up to 30 days 
(±2 days). 
Participants will be stratified by country and presence of risk factor(s) for severe outcomes of 
COVID-19, based on comorbidities and age, as detailed in Section 6.3. 
Two interim analyses are planned (see Section 9.5 for details). 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study. The IDMC will 
meet after 10, 20, 60 and 150 participants have completed the study (see Sections 9.5 and 9.6). 
4.2 Scientific Rationale for Study Design 
NO is a naturally occurring and potent antimicrobial agent in the human body which has been 
shown in vitro to inhibit replication of severe acute respiratory syndrome coronavirus 


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(Akerström S et al, 2005), including SARS-CoV2, and other respiratory viruses. NO as an 
inhaled gas is already marketed in the US and other countries (see Section 2.2.2) but has 
disadvantages over NO produced locally in the oropharynx or lung airways (lengthy treatment 
requiring NO canisters, the inhaled NO is expelled in exhalation, the NO gas oxidizes in air to 
form toxic NO2 which is a potential lung irritant and a contaminant in the patient’s environment, 
and the half-life of NO in air is short).  
RESP301 has potential advantages over inhaled NO gas: 
• 
RESP301 demonstrates powerful evidence in vitro as a broad-spectrum anti-microbial; 
• 
Treatment is quick, easy and portable using a standard handheld nebulizer; 
• 
The formulation is nebulized 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. 
In this study, the effect of RESP301 as an add on treatment to SOC will be evaluated for its 
efficacy in reducing rate of progression to a more severe level of COVID-19 and for safety by 
comparison with SOC alone in hospitalized COVID-19 patients. A sequential adaptive design 
was chosen in order to assess futility and sample size after interim analyses (see Section 9.5). 
The study design was developed in accordance with the latest WHO and regional regulatory 
agencies guidelines.  
Several risks factors for severe or fatal outcomes have been reported (Bialek et al, 2020; Huang 
et al, 2020; Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020; 
Rong-Hui et al, 2020; Zhou et al, 2020). To minimize bias, the results will be stratified according 
to the known risk factors as described in Section 6.3. 
In this study, measures will be in place to trigger discontinuation of study intervention at a SpO2 
limit pre-agreed at the site (see Section 8.1.2). There is no critical level of oxygen saturation 
below which tissue hypoxia occurs due to the large number of variables that contribute to 
hypoxia at the tissue and cellular level (temperature, pH, tissue blood flow). As a result, there is 
no consensus about what constitutes normal and abnormal oximetry (ATS/ACCP, 2003). To 
support and guide the team in charge of study intervention administration, a default value of 
SpO2=89% and heart rate (120 beats/min) has been proposed as a suitable limit of tolerance. 
However, for the reason stated above, this limit can be overruled by the Investigator in either 
direction. 


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Newly released guidelines for ongoing clinical trials during the COVID-19 pandemic have 
emphasized the need to reduce the burden on sites and clinical trial personnel/investigators 
whether they be administrative, site visit, or other burdens (ACRO, 2020; EMA, 2020; HRS, 
2020). Thus, without blinding and a placebo, along with minimal procedures, the additional 
burden on clinical staff has been reduced as much as possible. 
4.3 Justification for Dose 
Studies with nebulized sodium nitrite (AIR001) in healthy subjects and in patients have shown 
that inhaled nitrite produces dose proportional plasma pharmacokinetic without accumulation 
following repeated administration, with low systemic blood levels of nitrite and methemoglobin 
(<3%). Inhaled nitrite at doses up to 90 mg TID displayed a good safety profile and is well 
tolerated (Rix et al, 2015; Parsley et al, 2013; Simon et al, 2016).  
In this study, 6.0 mL RESP301 (delivered dose 62 mg) will be administered via a vibrating mesh 
nebulizer, TID with at least 6 hours between each dose. Each 6.0 mL dose for nebulization 
contains the masses described in Table 6-2. 
4.4 End of Study Definition 
A participant is considered to have completed the study if he/she has completed the Treatment 
Period and the Follow-up Period (through the Day 28 EoS Follow-up). End of the study is 
defined as the last participant’s last visit or follow up call. 
5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of male and female COVID-19 patients, including pregnant 
women and women of child bearing potential. Participants must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 
5.1 Study Rationale 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design to evaluate the efficacy and safety of RESP301 plus SOC versus 
SOC alone in hospitalized patients with COVID-19 requiring supplemental oxygen (WHO 
level 4). 


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Each constituent (see Section 6.2) of RESP301 is used as SOC for various conditions. Product 
application is straightforward, requiring a few minutes of inhalation using a standard nebulizer. 
RESP301 is likely to be beneficial in treating patients with COVID-19 who are not receiving 
ventilation but are using supplementary oxygen in order to maintain a safe level of SpO2. 
Considering the well-established and global use of NO and the device, and the current public 
health emergency resulting from the COVID-19 pandemic, a Phase2/3 study of RESP301 is 
considered reasonable in order to generate efficacy data in patients infected with COVID-19. 
5.2 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is ≥18 years of age, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participant has laboratory-confirmed SARS-CoV-2 infection as determined by reverse 
transcriptase polymerase chain reaction (RT-PCR) or other approved clinical testing prior 
to randomization. 
3. Participant is hospitalized in relation to COVID-19, requiring supplemental oxygen to 
maintain SpO2 at a safe level (WHO level 4). 
Sex 
4. Participant is male or female. All females of childbearing potential, including pregnant 
females, must consent to urine pregnancy testing at screening to be eligible for the study. 
(Females who are not of childbearing potential do not need to undergo a pregnancy test at 
screening). 
Informed Consent 
5. Participant is capable of giving signed informed consent as described in Appendix 1 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 


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5.3 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Rapidly deteriorating or likely to require escalation to high flow oxygen, invasive or 
non-invasive ventilatory support within 24 hours according to Investigator’s opinion. 
2. Unable to safely receive a nebulized treatment for approximately 4 minutes according to 
Investigator’s opinion. 
3. Unable to receive or considered ineligible for invasive or non-invasive ventilatory 
support. 
4. History of methemoglobinemia. 
5. Uncontrolled asthma or history of severe bronchospasm. 
6. Severe (requiring baseline oxygen therapy > 12 h/day prehospitalization) chronic 
respiratory disease (e.g., known COPD, pulmonary arterial hypertension, idiopathic 
pulmonary fibrosis, interstitial lung disease). 
7. Suspected or confirmed untreated, active tuberculosis. 
8. Severely immune-compromised participants in Investigator’s opinion. 
9. Recent (within 3 months) active coronary artery disease or decompensated heart failure 
(New York Heart Association class 3-4). 
10. Presence of tracheostomy. 
Prior/Concomitant Therapy 
11. Chronic (≥4 weeks) use of corticosteroids >10 mg/day of prednisone or equivalent within 
4 weeks of randomization. 
Prior/Concurrent Clinical Study Experience 
12. Participation in other clinical investigations utilizing investigational treatment or within 
30 days / 5 half-lives whichever is longer. 
Diagnostic Assessments 
13. Clinically significant abnormalities in clinical chemistry or hematology at screening, 
defined as: 


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• 
Platelet count <50,000 mm3 
• 
Alanine aminotransferase or aspartate aminotransferase >5 × upper limit of normal 
(ULN). 
• 
Estimated glomerular filtration rate <30 mL/min/1.73 m2 (modification of diet in renal 
disease formula) or requiring hemofiltration or dialysis. 
Other Exclusions 
14. Anticipated transfer to another hospital which is not a study site during the treatment 
period. 
15. Allergy to any of the components of the study intervention. 
5.4 Lifestyle Considerations 
No restrictions are required. 
5.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography and reason for screen 
failure (e.g., eligibility requirements failed). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
5.5.1 
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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6 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. 
6.1 Study Intervention Administered 
Table 6-1 
Study Intervention(s) Administered 
Study Treatment 
RESP301 + SOC 
Intervention Name: 
RESP301 
Type: 
Drug 
Dosage Formulation: 
Admixture for inhalation 
Unit Dose 
Strength(s): 
Delivered dose (62 mg) sodium nitrite (NaNO2) 
(6 mL of NO-generating admixture of 150 mM NaNO2, 50 mM mannitol and 100 mM 
citric acid) 
Dosage Level(s): 
One 6 mL-inhalation TID (every 8 hours) with at least 6 hours between 2 consecutive 
doses. 
Route of 
Administration: 
Inhalation 
IMP and NIMP: 
IMP 
Sourcing: 
RESP301 provided centrally by the Sponsor. 
Dosing Instructions: 
A vibrating mesh nebulizer will be used to administer the RESP301, under the 
direction of the study physician. 
Treatment is to commence within 5 minutes of RESP301 preparation.  
For the first 10 participants (up to the first IDMC safety review) RESP301 will be 
administered by intermittent inhalation to monitor tolerability and response to 
RESP301. After reviewing safety data, the IDMC will decide whether the intermittent 
inhalation of RESP301 can be replaced by a continuous inhalation. 
Before initiating each RESP301 inhalation, supplemental oxygen will be interrupted 
for a few minutes until SpO2 levels are stable. Depending on the extent of SpO2 
decrease, the RESP301 inhalation may be initiated or supplemental oxygen may be 
resumed at the discretion of the investigator. After treatment initiation, in case of SpO2 
decrease, RESP301 inhalation may be paused and supplemental oxygen resumed.  
If the participant is unable to tolerate nebulization without supplemental oxygen, nasal 
oxygen may be administered during nebulization. 
Packaging and 
Labeling: 
Study intervention will be provided as two separate vials: NaNO2/mannitol (3 mL) and 
citric acid buffered to pH 5.4 (3 mL), which will be labeled as required per country 
requirement.  
 
Staggered dosing approach for the first 10 participants: 
For the first 10 participants treated before the first IDMC safety review (Section 9.6), RESP301 
dose will be administered in a staggered approach: after 2 minutes of inhalation, treatment is 


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briefly paused to assess the participant. Provided there is no evidence of bronchospasm, 
treatment is continued for a further 2 minutes, after which treatment is again briefly paused for 
participant assessment. Thereafter, provided there is no evidence of bronchospasm and the 
participant is able to continue, the dose is completed (Figure 6–1), so that treatment can be 
quickly adjusted and rescue bronchodilator initiated if needed (Section 6.5.1). After reviewing 
safety data, the IDMC will decide whether the intermittent inhalation of RESP301 can be 
replaced by a continuous inhalation. 
Figure 6–1: 
Staggered Dosing Approach for the First 10 Participants 
 
  
6.1.1 
Medical Devices 
1. Medical device (not manufactured by or for Thirty Respiratory Limited) provided for use 
in this study will be an FDA-approved and CE marked vibrating mesh nebulizer.  
2. Instructions for medical device use will be provided in the User Manual. 
6.1.2 
Device Training 
Training will be provided to ensure all study staff are familiar with the device, including mixing 
the solutions, adding the admixture to the device and cleaning the device. 
6.2 Preparation, Handling, Storage, and Accountability 
6.2.1 
Preparation of Study Intervention Product 
RESP301 is prepared at bedside by mixing two sterile 3 mL solutions (one of NaNO2/mannitol 
and one of citric acid buffered to pH 5.4). The solution is to be nebulized immediately or within 


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5 minutes post mixing as per the instructions given in the SoA (Table 1-1) and, for the first 
10 participants, as in Section 6.1 above (staggered dosing). The first administration of study 
intervention should be provided under medical supervision. 
RESP301 is mixed in the nebulizer chamber before use following the steps below (see Table 6-2 
for details of composition): 
1. First the vial marked A (NaNO2 and mannitol) is opened and its contents are poured into 
the nebulizer chamber. 
2.  Next, the vial marked B (citric acid) is opened and its contents are poured into the 
nebulizer chamber. 
3. The nebulizer lid should be closed, and the nebulizer should be swirled gently for a few 
seconds to mix the two solutions. The nebulizer should not be inverted. 
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 of inhalation. 
This combined mildly acidified nitrite solution (6 mL) is inhaled through the mouth using a 
vibrating mesh nebulizer under the direction of a physician. The purpose of the acidified nitrite 
aerosol is to deliver NO to the participant. The delivered dose of RESP301, assessed via 
simulated tidal breathing is estimated to be ~40% of the masses listed below; it should be noted 
that delivered dose can be further affected by participant’s breathing pattern and inspiratory 
capacity and so inter- and intra-participant variation in actual doses of these ingredients may 
vary, given the acute nature and high disease burden in this proposed clinical setting. 


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Table 6-2 
Composition of Drug Product, Diluent and Admixture 
 
Material 
Function 
Quantity per vial 
Drug Product 
Sodium Nitrite 
Drug Substance 
62.10 mg 
Mannitol 
Excipient  
54.66 mg  
Sterile water for injection 
Diluent 
 
Total Volume 
 
3.0 mL 
Diluent 
Citric Acid  
Diluent 
115.28 mg 
Sterile water for injection 
Diluent 
 
Total Volume 
 
3.0 mL 
Acidified Drug 
Product Mixture 
(RESP301) 
Sodium Nitrite 
Drug Substance 
62.10 mg 
Mannitol 
Excipient  
54.66 mg  
Citric Acid  
Diluent 
115.28 mg 
Sterile water for injection 
Diluent 
 
Total Volume 
 
6.0 mL 
 
6.2.2 
Storage and Accountability of Study Intervention 
The Investigator or designee must document whether appropriate temperature conditions 
(<25°C) have been maintained during transit 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 authorized site 
staff may supply or administer study intervention. All study interventions 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 authorized 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). 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Investigator Manual. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; however, the specific intervention to be taken by a participant will be 
assigned using an interactive voice response system (IVRS)/interactive web response system 
(IWRS). The site will contact the IVRS/IWRS prior to the start of study intervention 


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administration for each participant. The site will record the intervention assignment on the 
applicable case report form (CRF), if required.  
Potential bias will be reduced using a central stratified randomization to assign participants into 
one of the study treatment arms, RESP301+SOC or SOC (control), with a randomization ratio of 
2:1. Participants will be stratified by country and presence of risk factors for severe outcomes of 
COVID-19, based on comorbidities and age as follows: 
1. Age >65 years 
2. Ongoing or currently treated diabetes mellitus 
3. Ongoing or currently treated hypertension 
4. Ongoing or currently treated cardiovascular disease 
5. Ongoing or currently treated chronic lung disease 
6. Cancer history of less than 3 years, basal cell skin carcinoma excluded 
7. Ongoing or currently treated chronic kidney disease 
Participants will be stratified as no risk factor (none of the above criteria), one risk factor (one 
single of the above) or high-risk factor (2 or more of the above). 
6.4 Study Intervention Compliance 
Participants will receive study intervention directly from the Investigator or designee, under 
medical supervision. The date and time of each inhalation will be recorded in the source 
documents and recorded in the CRF. The study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the study 
intervention. 
6.5 Concomitant Therapy 
During the study, participants will receive institutional SOC for the treatment of COVID-19. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency and route 


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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 
Rescue Medication 
For participants treated before the first safety review by the IDMC (Section 9.6), at the time of 
RESP301 treatment, a ready-to-use nebulization of a bronchodilator (short acting beta agonist 
such as salbutamol/albuterol according to investigational site standard practice for acute 
bronchospasm) may be administered to participants in case of bronchospasm. 
After reviewing safety data, the IDMC will decide whether the availability of rescue 
bronchodilator at the time of RESP301 treatment is still required. 
Although the use of rescue medications is allowable for the first 10 participants, the use of rescue 
medication should be delayed, if possible, for at least 2 minutes following each administration of 
study intervention. The date and time of rescue medication administration as well as the name of 
the rescue medication must be recorded. 
6.6 Intervention After the End of the Study 
After the end of the study, participants may continue their SOC (if any). Study intervention for 
COVID-19 will not continue beyond this study. 
7 Discontinuation of Study Intervention and Participant Discontinuation 
7.1 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 the Day 14 and Day 28 safety follow-ups. See the SoA 
(Table 1-1) for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
Study intervention will be permanently discontinued prior to 10 days if the participant: 
• Improves to level 1 or 2 of the modified WHO ordinal scale; 
• Progresses to a level > 4 of the modified WHO ordinal scale. 
Additionally, study intervention should be permanently discontinued in the following 
circumstances: 


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1. Discontinuation of study intervention for abnormal liver tests should be considered if the 
Investigator believes that it is in best interest of the participant. 
2. If, as part of normal clinical follow-up, a clinically significant change in ECG is 
identified, the Investigators should exercise their clinical judgement to decide whether 
continuing study intervention administration is in the best interest of safety of the 
participant. 
3. AE/SAE if the Investigator believes that it is in best interest of the participant, including 
the following: 
• Development of significant bronchospasm * or worsening of cough that is not tolerated 
by the participant and leads to immediate discontinuation of the nebulization. 
• Progressive COVID-19 requiring initiation of non-invasive or invasive ventilation or high 
flow oxygen. 
• Development of mHb level above 3%. 
• Inability to safely continue receiving study intervention due to compromised respiratory 
status while off supplemental oxygen and receiving nebulized therapy (manifest by drop 
in SpO2, increased respiratory rate or clinical other findings). 
Refer to the SoA (Table 1-1) for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
* Inhaled citric acid and inhaled mannitol provoke bronchospasm in patients with bronchial 
hyperresponsiveness in a dose dependent pattern. Although the concentrations of mannitol and 
citric acid are below the provocative dose and concentration inducing bronchospasm, there is a 
theoretical risk that a participant may develop acute bronchospasm during the use of RESP301. 
Participants should therefore be monitored during RESP301 administration. In case of clinical 
intolerance or saturation decrease, nebulization should be immediately discontinued (see 
Section 7.2). Further clarification of the differences in signs and symptoms for acute 
bronchospasm and COVID-19 progression are provided in Table 7-1. 


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Table 7-1 
Differences in Signs and Symptoms for Acute Bronchospasm and 
COVID-19 Progression 
 
Acute bronchospasm related to 
inhaled bronchial irritant  
Progression of COVID-19 lung 
disease to acute respiratory 
failure  
Mechanism 
Acute contraction of bronchial muscles 
resulting in bronchial obstruction 
resulting in increased ventilatory load 
Cytokine storm resulting in alveolar 
damage resulting in gas transfer 
impairment 
Onset 
Within minutes (<15 minutes) 
following inhalation (no late phase 
since it is not an allergic IgE mediated 
reaction) 
Within hours or days and not related to 
nebulization  
Clinical auscultatory signs 
Wheezing (almost all cases) 
Bilateral rales (inconstant) 
Patient history 
Asthma or respiratory allergy  
Age > 65 years, increased BMI, high 
blood pressure, cardiac diseases, etc. 
Reversibility with inhaled 
beta mimetics 
Within minutes 
No 
Abbreviations: BMI=body mass index; IgE=immunoglobulin E. 
 
7.2 Temporary Discontinuation of Study Intervention 
Brief temporary discontinuation of study intervention is permitted during the study, providing 
inhalation of study intervention is completed within 20 minutes.  
Study intervention should be temporarily discontinued in the following circumstance: 
1. Clinical intolerance to nebulization. 
An individual administration of study treatment will be stopped, and supplemental 
oxygen resumed, if threshold limits of SpO2 89% or heart rate 120 beats/min (or as 
indicated by the Investigator) are exceeded (see Sections 4.2 and 8.1.2).  
The participant may continue with subsequent doses if the Investigator judges that the benefit / 
risk ratio remains positive. In this case, the instruction to continue should be duly recorded in the 
participant’s hospital file and the subsequent nebulization should be closely monitored.  
Refer to Section 6.1 for information on staggered dosing in the first 10 participants. 
7.3 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, behavioral, or 


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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. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
At the time of discontinuing from the study, if possible, an early discontinuation assessment 
should be conducted, as shown in the SoA (Table 1-1). 
7.4 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. The following actions must be taken if a participant cannot be contacted at Day 14 or 
Day 28: 
• 
The site must attempt to contact the participant and counsel the participant on the 
importance of maintaining the assigned schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• 
In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant (where possible, 
three telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record/CRF. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
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. 


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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 utilized 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 1-1). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 20 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Informed Consent 
Informed consent must be documented according to Appendix 1, Section 10.1.3.  
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or designee to ensure 
that the participant qualifies for the study. 
Participant Identification Card 
All participants will be given a participant identification card identifying them as participants in 
a research study. The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency. The Investigator or qualified designee will 
provide the participant with a participant identification card immediately after the participant 
provides written informed consent. At the time of intervention allocation/randomization, site 
personnel will add the intervention/randomization number to the participant identification card. 
Medical History 
A medical history will be obtained by the Investigator or qualified designee. The medical history 
will collect all active conditions and any condition diagnosed that the Investigator considers to be 
clinically relevant. Details regarding the disease for which the participant has enrolled in this 
study will be recorded separately and not listed as medical history. 


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Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 3 months prior to screening. This should include a 
history of hypertension medication, in particular angiotensin-converting enzyme inhibitors and 
angiotensin receptor blockers. 
The Investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the last assessment. Concomitant medications will be recorded on an 
ongoing basis during the study (or longer if related to an SAE). 
8.1 Efficacy Assessments 
8.1.1 
Modified WHO Ordinal Scale 
A modified WHO ordinal scale will be used for consistency with the recent study of 
lopinavir-ritonavir in adults hospitalized with severe COVID-19 (Cao et al, 2020), to record the 
participant’s status at the time of assessment. The modified WHO ordinal scale includes the 
following levels: 
1. Not hospitalized, no limitations on activities; 
2. Not hospitalized, limitation on activities; 
3. Hospitalized, not requiring supplemental oxygen; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 
6. Hospitalized, on invasive mechanical ventilation or extra corporeal membrane 
oxygenation (ECMO); 
7. Death. 
8.1.2 
Pulse Oximetry 
Pulse oximetry measurements will be performed to evaluate SpO2 as outlined in the SoA 
(Table 1-1) and in accordance with the site standard operating procedures, on a medical-grade 
medical device. Measurements will be taken with a probe on fingertip or earlobe and recorded as 
percent oxygenated hemoglobin. Supplemental oxygen used at the time of assessment and 
method of oxygen delivery will be collected and documented along with the SpO2. 


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Prior to administration of study intervention, supplemental oxygen will be held for at least a 
minute and SpO2 checked in order to ensure participant may safely receive the study 
intervention. For safety reasons, since due to the current pandemic it cannot be guaranteed that 
study intervention will be consistently administered under direct medical supervision, the study 
Investigators should provide study personnel who are able to monitor the participant and their 
SpO2 and ensure that should it decrease to a threshold, this would trigger immediate 
discontinuation. By default, unless overruled by the study Investigator, this SpO2 threshold is set 
to 89%. This threshold should be entered into the saturation monitoring device to trigger an 
alarm during nebulization. 
FiO2 will be measured per site standard practice and recorded in the eCRF. The device used to 
administer oxygen should also be recorded. 
8.1.3 
National Early Warning Score (NEWS) 2 
The NEWS 2 will be measured prior to study intervention in the morning according to the SoA 
in Table 1-1. 
The NEWS is based on a simple aggregate scoring system in which a score is allocated to 
physiological measurements, already recorded in routine practice, when patients present to, or 
are being monitored in hospital (RCP, 2012). Six simple physiological parameters form the basis 
of the scoring system: 
1. Respiration rate 
2. Oxygen saturation 
3. Systolic blood pressure 
4. Pulse rate 
5. Level of consciousness or new confusion* 
6. Temperature 
*The patient has new-onset confusion, disorientation and/or agitation, where previously their 
mental state was normal – this may be subtle. The patient may respond to questions coherently, 
but there is some confusion, disorientation and/or agitation. This would score 3 or 4 on the 
Glasgow Coma Scale (rather than the normal 5 for verbal response), and scores 3 on the NEWS 
system. 
A score is allocated to each parameter as they are measured, with the magnitude of the score 
reflecting how extremely the parameter varies from the norm (zero for ‘normal’; maximum 


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score 3). The score is then aggregated. The score is increased by 2 points for people requiring 
supplemental oxygen to maintain their recommended oxygen saturation. This is a pragmatic 
approach, with a key emphasis on system-wide standardization and the use of physiological 
parameters that are already routinely measured in National Health Service (NHS) hospitals and 
in prehospital care, recorded on a standardized clinical chart – the NEWS 2 chart (Refer to 
Appendix 2: The NEWS 2 Scoring System). 
Reproduced from: Royal College of Physicians. National Early Warning Score (NEWS) 2: 
Standardising the assessment of acute-illness severity in the NHS. Updated report of a working 
party. London: RCP, 2017 (RCP, 2017). 
8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1-1). 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
head/ear/eyes/nose/throat, cardiovascular, respiratory, gastrointestinal, lymphatic, skin and 
neurological systems. Height (screening only) and weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
8.2.2 
Vital Signs 
Vital signs to be collected as outlined in the SoA (Table 1-1) and include body temperature, heart 
rate, blood pressure, and respiratory rate. 
Body temperature will be assessed per the local practice (temporal or otic are preferred sites), 
and site will be recorded. Pulse rate, respiratory rate, and blood pressure will also be assessed per 
site SOC. Where possible the same methods should be used throughout the study for an 
individual participant. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). During study 
intervention administration, an alarm threshold should be set for heart rate at 120 beats/min (or 
as indicated by the Investigator), as outlined in the SoA (Table 1-1). 
Vital signs (to be taken before blood collection for laboratory tests) will be measured after the 
participant has been sitting for 5 minutes. 


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8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (Table 1-1) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals for 
local reading.  
8.2.4 
Clinical Safety Laboratory Assessments 
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA 
(Table 1-1) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically abnormal during participation in the study 
or within 4 days after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator 
or Medical Monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, where possible, and the 
Sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the Laboratory Manual and the SoA (Table 1-1). 
• 
If laboratory values from laboratory assessments not specified in the protocol and 
performed at the institution’s local laboratory result in the need for a change in 
participant management or are considered clinically relevant by the Investigator (e.g., 
are considered to be an SAE or an AE), then the results must be recorded in the CRF. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 4. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized 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 


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up AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue the study intervention (see Section 7). 
8.3.1 
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 1-1). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
Investigator becoming aware of the SAE, as indicated in Appendix 4. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obliged to actively seek AEs or SAEs after the conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 
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 4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.3.3 
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, stabilization, 
until the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.4). Further information on follow-up procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Appendix 4) 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. 


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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 IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
All women, including women of childbearing potential are allowed in the study. Urine pregnancy 
test will be performed on female participants of childbearing potential and pregnant females at 
screening. Females who are not of child bearing potential do not need to undergo a screening 
pregnancy test. 
Pregnant females will be followed to determine the outcome of the pregnancy: 
• The Investigator will collect any follow-up information on the participant and the neonate 
and the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of the pregnancy will be reported, regardless of fetal state (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered to be SAEs. Any post-study 
pregnancy-related SAE considered reasonably related to study intervention by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting. 


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8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
The following disease-related events (DREs) are common in participants with COVID-19 and 
can be serious/life-threatening: 
• 
Fever 
• 
Cough* 
• 
Dyspnea* 
• 
Asthenia 
• 
Loss of sense of taste and smell 
* A cough or dyspnea episode related to study intervention administration does not meet the 
definition of a DRE and should be reported as an AE. 
Because these events are typically associated with the disease under study, they will not be 
reported as AEs. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an SAE (instead of a DRE): 
• 
The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant. 
OR 
• 
The Investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.3.7 
Adverse Events of Special Interest (Not Applicable) 
No AEs of special interest are defined for this study. 
8.3.8 
Medical Device Deficiencies (Not Applicable) 
The medical device to be used in this study is a vibrating mesh nebulizer 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. 
8.4 Tokenization (Optional) 
Tokenization is the process of converting a piece of data into a random string of characters 
known as a token. Tokenization protects sensitive data by substituting non-sensitive data. The 


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token serves merely as a reference to the original data, but cannot be utilized to determine those 
values. The advantage of tokens is that there is no mathematical relationship to the real data that 
they represent. The real data values cannot be obtained through reversal, and hence, a breach 
renders the information invaluable. Tokens are being increasingly used to secure varying types of 
sensitive information. In particular, personal identifiable information such as healthcare 
information, email addresses and account numbers are such examples. From a security 
perspective, tokenization significantly reduces risk based on the fact that sensitive data cannot be 
breached if it is not there in the first place. 
Tokenization applies only to US participants who agree and sign the optional ICF. The piece of 
personal data needed to generate the token will be collected to create a unique, de-identified 
token. This token would be instrumental to enrich and aggregate other study participants’ data 
coming from different sources for the purpose of future research. The benefit of linking data in 
general, is that the data set that is created can be used to answer a variety of healthcare- and 
therapy-related questions that could not otherwise be answered through conventional means. 
8.5 Treatment of Overdose (Not Applicable) 
There is no risk of overdose. 
8.6 Pharmacokinetics (Not Applicable) 
Pharmacokinetic parameters are not evaluated in this study. 
8.7 Pharmacodynamics (Not Applicable) 
Pharmacodynamic parameters are not evaluated in this study. 
8.8 Genetics (Not Applicable) 
Pharmacogenomics are not evaluated in this study. 
8.9 Biomarkers (Not Applicable) 
Biomarkers are not evaluated in this study. 
8.10 Medical Resource Utilization and Health Economics (Not Applicable) 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 


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9 Statistical Considerations 
9.1 Statistical Hypothesis 
RESP301 reduces the rate of progression to level 5 and above in the modified WHO ordinal 
scale in COVID-19 (see Section 8.1.1). 
This represents a composite endpoint of (i) death (level 7), (ii) hospitalized, on invasive 
mechanical ventilation or ECMO (level 6), or (iii) hospitalized, on non-invasive ventilation or 
high-flow oxygen devices (level 5). 
9.2 Sample Size Determination 
A total of 300 hospitalized participants with confirmed COVID-19 will be randomized 2:1 to 
receive RESP301+SOC (200 participants) or SOC alone (100 participants). 
The comparison between the treatment arms for the primary endpoint will have approximately 
80% power and alpha level 0.025 (one-sided) to demonstrate significant reductions (15% versus 
30%) of the primary endpoint between RESP001+SOC and the Control arm (SOC), a 50% 
relative reduction for the proportion of participants who progress to level >4 (see definition of 
the primary endpoint). 
Two interim analyses are planned (see Section 9.5 for details): 
1. The first IDMC interim analysis will take place after the first 60 participants have 
completed Day 10 of the study to evaluate whether the study can be stopped for futility 
based on change from baseline in room air SpO2. For a final decision to stop the study for 
futility the results on other endpoints will be considered as well. 
2. The second interim analysis will take place after 150 participants have completed Day 14 
post-randomization based on event rate for the primary endpoint. The purpose of the 
second interim analysis will be futility as well as a potential sample size re-estimation in 
case the actual results differ from the original assumptions. 
In addition to the review of efficacy data, safety will be assessed at each of the interim analysis 
by the IDMC. Further details are provided in Appendix 5. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 


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Table 9-1 
Populations for Analysis 
Population (Analysis Set) 
Description 
Intent-To-Treat (ITT) 
Population 
The ITT Population will include all randomized participants. The 
ITT participants will be analyzed according to randomized 
treatment, irrespective of the actual treatment received. 
Participants who withdraw from treatment early will be followed 
for the assessment of the Day 14 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 randomized participants who inhale any 
amount of study intervention or are randomized to the control 
arm. The SP will be analyzed according to the actual treatment 
received. This set will be used for the safety analyses. 
 
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 primary efficacy endpoint. 
9.4 Statistical Analyses 
Below is a description of planned statistical analyses. Further details are presented in the 
Statistical Analysis Plan (SAP). 
9.4.1 
General Considerations 
All statistical analyses will be conducted using SAS, Version 9.4 or later. Baseline characteristics 
will be summarized by treatment arm. For continuous measures the mean and standard deviation 
(SD) will be summarized. Categorical variables will be described by the proportion in each 
category. In addition, 95% confidence intervals (CIs) will be computed as indicated. 
All the categorical variables including the primary endpoint will be summarized by treatment 
with the numbers and percentages of the participants. Treatment difference will be tested using a 
Cochran–Mantel–Haenszel test stratified by 1) country and 2) participant’s clinical status at 
Baseline. For the categorical endpoints, relative risk and its 95% CI will be presented. 
All of the continuous variables, including the changes from Baseline, will be summarized by 
treatment with the means, SD, medians and the ranges. The mixed model with repeated 


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measurements /analysis of covariance model with treatment, country, participant’s clinical status 
at Baseline and visit as the model term, and Baseline value as the covariate will be used to test 
for the significance of the treatment difference. Least square means, standard errors, 95% CIs 
and p-values will be presented. 
Time to event endpoints will be analyzed using the Cox Proportional Hazard model with 
treatment, participant’s clinical status at Baseline and country as the model term. The hazard 
ratio of RESP301+SOC versus SOC will be presented along with 95% CI and p-value from the 
model. The Kaplan-Meier curves of the time to events will be presented by treatment for each 
applicable endpoint. 
Handling of missing data 
If participants are discharged from the hospital prior to Day 14 due to improvement of the 
clinical status and their status on Day 14 cannot be obtained, their status on Day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. Depending on the 
reasons for missing data on the primary endpoint up to Day 14, additional sensitivity analyses 
will be performed. Further details on handling on missing data will be provided in the SAP. 
9.4.2 
Primary Endpoint 
The primary endpoint is the proportion of participants who progress to level >4 of the modified 
WHO ordinal scale due to COVID-19 by Day 14. 
9.4.3 
Secondary Endpoint(s) 
The key secondary endpoints are: 
1. Change from baseline on the modified WHO ordinal scale at each visit up to Day 28 
2. Change in room air SpO2 from baseline over time 
3. Change in NEWS 2 symptom score from baseline over time 
4. Time to improvement to a lower level (<4) of the modified WHO ordinal scale 
5. Time to progression to a higher level (>4) of the modified WHO ordinal scale 
Additional secondary endpoints are: 
1. Time to hospital discharge 
2. Incidence of mortality by Day 28 


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will be summarized by study day. If more than one laboratory result is reported per study visit 
per parameter, the last non-missing result will be selected for change from Baseline analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the Investigator. The number of participants with a non-missing 
result, the number and percentage of participants with a clinically significant result less than the 
lower limit of normal, non-clinically significant result more than the ULN, and clinically 
significant result more than the ULN will be summarized by study visit. If more than one 
laboratory result is reported per study day per parameter, the result yielding the most severe 
classification will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study day per parameters, the result yielding the 
most severe classification will be selected for analysis.  
Participants who had urine pregnancy test at screening and the results will be listed. 
Participants with clinically significant abnormal laboratory test results will be listed. This listing 
will include all results of the laboratory parameter that was abnormal and determined to be 
clinically significant by the Investigator for a participant across study visit. 
9.4.5.3 
Vital Signs 
Baseline is defined as the last non‑missing value obtained in screening and prior to the first 
exposure to study drug. Actual values and changes from Baseline in vital signs will be 
summarized by study day and study time point. All vital sign data will be presented in patient 
listings. 
Vital sign values will be classified according to the clinical significance as determined by the 
Investigator. The number of participants with a non-missing result, the number and percentage of 
participants with a non-clinically significant result, and clinically significant result will be 
summarized by study visit and study time point. If more than one vital sign result is reported per 
study day and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis. 
Participants with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the Investigator to be clinically 
significant for a participant across study time points. 


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9.4.5.4 
Physical Examination 
Abnormal physical examination findings will be listed. 
9.4.6 
Other Analyses 
Other analyses may be added to the SAP as applicable. 
9.5 Interim Analyses 
Two interim analyses will be performed.  
1. The first analysis will be conducted when about 60 participants (40 participants in the 
RESP301+SOC arm and 20 participants in the SOC arm) have completed the Day 10 
assessment. The purpose of this analysis is to evaluate efficacy of RESP301 with the 
application of a futility criterion based on the results on SpO2 change from baseline on 
Day 10. The following futility criterion will be used for this first interim analysis: 
If the difference in the percentage of participants with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints 
will be considered as well.  
As no other modification of the study at the time of the first interim analysis is considered, 
no adjustment of the alpha level is required. 
2. The second interim analysis will be conducted after 150 participants (100 participants in 
the RESP301+SOC arm and 50 participants in the SOC arm) have completed the Day 14 
assessment. The purpose of this analysis is the assessment of futility or a sample size 
re-estimation in case the actual results differ from the original assumptions for the power 
calculations of the study, related to the percentage of participants meeting the primary 
endpoint in the control arm and/or the relative treatment benefit achieved in the 
RESP301+SOC arm compared to the SOC arm. 
To account for the multiple testing due to the second interim analysis an adjustment for 
the type I error alpha will be applied using the Haybittle-Peto approach which would 
spend one sided alpha=0.0005 at the second interim analysis and leave one-sided nominal 
alpha of 0.0249 for the final analysis. The futility criterion for the second interim analysis 
will be based on the conditional power (CP) for the final results based on the assumption 
that the remainder of the study will follow the same trend as observed in the interim 
analysis. If CP at the time of the second interim analysis is less than 20% consideration 


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will be given to stop the study for futility. At the same time sample size re-estimation will 
be performed to achieve 80% power at the end of the study. The methodology for the 
adjustment and the procedure to maintain the type I error level will be described in greater 
detail in the SAP. 
Detailed information, including the boundaries futility and characteristics for the sample size 
re-estimation at the time of the interim analyses will be provided in the SAP and Data 
Monitoring Committee (DMC) Charter. Further details are also provided in Appendix 5. 
9.6 Data Monitoring Committee (DMC) 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study. The IDMC will 
meet to review after 10 and 20 participants have completed as well as at the time of the interim 
analyses (ie, after 60 and 150 participants have completed; see Section 9.5). 
The detailed procedures and criteria of the interim analyses will be described in the DMC 
Charter. 


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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 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. 
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. 
10.1.2 Financial Disclosure 
Information on financial disclosure can be found in the Investigator Site File. 
10.1.3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. 


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Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
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 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
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 currently enrolled in 
the study. 
For US participants who agree to tokenization, a separate optional ICF will be provided. 
10.1.4 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 authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Data Protection for Tokenization information is addressed in the separate optional ICF (for US 
participants only). 


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10.1.5 Committees Structure 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study (see Sections 9.5 
and 9.6). 
10.1.6 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. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized 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. 


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• All data generated by the site personnel will be captured electronically at each study 
center using eCRFs. Data from external sources (such as laboratory data) will be 
imported into the database. Once the eCRF clinical data have been submitted to the 
central server at the independent data center, 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. Once all 
source data verification is complete and all queries are closed, the monitor will freeze the 
eCRF page. 
• 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. 
10.1.7 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. 
10.1.8 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 visit 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. 


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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 contract research 
organization(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 
10.1.9 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 multicenter 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. 
10.1.10 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). In the US: Following approval, the protocol 


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amendment(s) will be submitted to the Investigational New Drug application under which the 
study is being conducted. 
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. 
10.1.11 Liability and Insurance 
10.1.11.1 Access to Source Data 
Access to source data is described in the Clinical Site contract. 


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10.2 Appendix 2: The NEWS 2 Scoring System 
Chart 1: The NEWS 2 scoring system 
 
Abbreviations: CVPU: C=new onset confusion, disorientation or agitation, V=responds to voice, P=responds to 
pain, U=unresponsive; SpO2=oxygen saturation. 
Source: Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of 
acute-illness severity in the NHS. Updated report of a working party. London: RCP, 2017. 
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2 
 










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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
(Applies only during the safety follow up period for participants who may have 
been discharged during the treatment period, ie, between Day 1 and Day 10) 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are considered 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective intervention of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive intervention 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 










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However, as far as possible all points on the SAE form should be covered in the initial report, or 
the completed SAE form itself must be emailed or faxed to the Parexel Safety Services. In 
addition, the event must be documented in the electronic CRF/EDC system. 
After receipt of the initial report, Parexel Safety Services will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the event. 
Parexel will be responsible for all information processing and reporting according to local legal 
requirements. Where necessary, Investigators will inform regulatory authorities in their own 
countries. 
 


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10.5 Appendix 5: Statistical Design Considerations 
10.5.1 Some General Design Considerations 
1. Binary primary endpoint: progression to critical stage/death up to Day 14 
• to be analyzed by a Cochran-Mantel-Haenszel (CMH) stratified for the factors used in 
the stratified randomization 
• subjects who withdraw from study treatment will be followed up until their primary 
endpoint outcome is known (i.e., up to Day 14 or progression to critical stage/death, 
whatever is first) 
• it is, therefore, not clear what current protocol synopsis text could mean: If subjects 
are discharged from the hospital prior to day 14 due to improvement of the clinical 
status and their status on day 14 cannot be obtained, their status on day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. and what 
the implications on statistical study characteristics could be. Further discussion is 
needed.  
2. Timing of the two planned interim analyses with stopping options is stated as 
There are 2 interim analyses planned, the first interim analysis after the first 60 participants 
have completed day 10 of the observation period … and a second interim analysis after 150 
participants have completed day 14 of the observation period. 
With the current text for the timing of the first interim analysis, it is not clear how many 
subjects will have been randomized at least 14 days prior to the interim data cut-off date and 
can therefore provide data for the binary primary endpoint (“progression to critical 
stage/death up to Day 14”).  
For such a binary endpoint, Parexel does not recommend including any participant 
randomized less than 14 days prior to the interim data cut-off date (note this would be 
different to a study with a time-to-event endpoint) as 
• for such participants not yet progressed, the outcome up to Day 14 is unknown and 
should not be imputed as “not progressed up to Day 14” 
• for such participants progressed prior to Day 14, the outcome is known but their 
inclusion would bias the estimation of progression probability up to Day 14 in a 
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In order to set up the adaptive group-sequential study design, the following assumptions have 
been used: 
• first interim analysis: a total of ≈ 39 participants randomized at least 14 days prior to 
data cut-off date 
• second interim analysis: a total of ≈ 50% of the initially planned number of 
participants randomized at least 14 days prior to data cut-off date. 
3. Non-binding DMC guidance for stopping the study for futility at the first interim analysis 
is stated as: 
If the difference in the percentage of participants with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, a benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints will 
be considered as well. 
As the main futility stopping criterion is based on improvement in SpO2 (and not on the 
primary efficacy endpoint), this first interim analysis will be “ignored” in these statistical 
considerations for an adaptive group-sequential design. We may revisit the first interim 
analysis at a later point in time when more information is available.  
4. Non-binding DMC guidance for stopping the study for futility at the second interim 
analysis stated as:  
The futility criterion for the second interim analysis will be based on the conditional power 
(CP) for the final results based on the assumption that the remainder of the study will follow 
the same trend as observed in the interim analysis. If CP at the time of the second interim 
analysis is less than 20% consideration will be given to stop the study for futility. 
5. Current DMC guidance for stopping the study for superior efficacy at the second interim 
analysis is stated as: 
To account for the multiple testing due to the second interim analysis an adjustment for the 
type-I-error probability will be applied using the Haybittle-Peto approach with one sided 
alpha=0.0005 at the second interim analysis and leave one-sided nominal alpha of 0.0249 
for the final analysis. 
6. For initial sample size calculation, the following additional assumptions / features from 
the protocol have been used 
• progression probability up to Day 14 for Standard of Care (SOC): 30% 


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• progression probability up to Day 14 for RESP301+SOC: 15%  
• desired power assuming the alternative hypothesis stated above: 80% 
• 2:1 randomization 
7. Method for adaptation of the sample size based on the second interim analysis data is 
stated as 
A sample size re-estimation will be performed to achieve 80% conditional power at the end 
of the study. The methodology for the adjustment and the procedure to maintain the type-I-
error level will be described in greater detail in an appendix to the protocol.  The maximum 
increase of the sample size will be limited to a total number of 600 randomized subjects.  
Parexel has put a suggestions with some fictitious interim data for illustration in 
Section 10.5.3; that section also illustrates by simulations the Cui/Hung/Wang (CWH) 
approach using a weighted (weights fixed at the design-stage) test for the final analysis 
versus the Chen/DeMets/Lan (CDL) approach without such weights at the final analysis. 
 
 


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10.5.2 General Design Characteristics 
Parexel proposes to base non-binding futility stopping criteria on conditional power criteria. 
Conditional power (CP) is the conditional probability for achieving statistically significant 
superiority of RESP301+SOC over SOC at the final analysis, given the interim results and 
calculated by assuming the interim estimates to be the true distribution parameters for the 
remaining part of the study (an alternative would be predictive power (PP), a Bayesian version of 
CP where prior distributions and observed interim results are combined to obtain the probability 
for achieving statistically significant superiority of gimsilumab over placebo at the final 
analysis).  
Randomization 2:1 
Group-Sequential Design 
1st Interim Analysis (IA) 
N ≈ 39 for D14 
2nd IA 
≈ 50% for D14 
Futility criterion 1st IA 
Based on SpO2 
Futility criterion 2nd IA 
Superior efficacy criterion 2nd IA 
CP < 4% 
p < 0.0005 
Total sample size required for 80% power 
300 
Futility stopping probability at 2nd IA under 
“No effect” 
1st IA: NA 
2nd IA: 70% 
Futility stopping probability at 2nd IA under 
“Planned effect 30% vs 15%” 
1st IA: NA 
2nd IA: 6% 
Superiority stopping probability at 2nd IA 
under “Planned effect 30% vs 15%” 
10% 
Superiority stopping probability at 2nd IA 
under “30% vs 10%” 
28% 
 


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10.5.3 Adaptive Sample Size Re-Estimation 
Another objective of the 2nd interim analysis is to re-estimate the sample size based on the 
unblinded interim results.  
Proposed procedure at 2nd interim analysis (planned to include approximately 150 subjects) 
• unblinded analysis of the primary efficacy endpoint (“progression to level >4 of modified 
WHO ordinal COVID-19 scale by Day 14” as a binary endpoint)  
• calculation of conditional power (CP) given the interim results and calculated by assuming 
the interim estimates to be the true distribution parameters for the remaining part of the study 
• if CP < 4%: recommend early stop for futility 
• if one-sided p-value < 0.0005: recommend early stop for superior efficacy 
• if 50% < CP < 80% and one-sided p-value ≥ 0.0005:  
o continue the study with an increased total sample size N*, so that CP with a 
total of N* subjects is increased to 80%, same value as the (unconditional) 
desired power in the study design 
o N*, however, is limited to 600 (which is twice the original sample size 300) 
• if 4% ≤ CP ≤ 50%: continue the study without a change in sample size (otherwise, the 
sample size would need to be increased too much or the maximum sample size of 600 
would not be sufficient to come close to a CP of 80%. 
The table on the next page illustrated the proposed procedure for a number of possible results 
observed at the 2nd interim analysis.  
 
 


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Table with examples for the adaptive sample size procedure described above using the 
Cui/Hung/Wang (CHW) approach using a weighted (fixed weights determined by the stage-wise 
sample sizes planned at the design-stage) test for the final analysis: 
2nd IA results with n=150 
subjects (50 for SOC, 
100 for RESP301+SOC 
CP under 
observed trend 
for planned 300 
Total sample size 
required for CP 80% 
under observed trend 
CP under observed 
trend if total sample 
size capped by 600 
15 (30%) 
5 (5%) 
p < 0.0005  → early stop for superior efficacy 
15 (30%) 
10 (10%) 
99% 
Not applicable 
Not applicable 
15 (30%) 
15 (15%) 
90% 
Not applicable 
Not applicable 
15 (30%) 
18 (18%) 
66% 
393 
Not applicable 
15 (30%) 
19 (19%) 
55% 
483 
Not applicable 
15 (30%) 
21 (21%) 
34% 
[798] 
[67%] 
15 (30%) 
26 (26%) 
3.99% 
Early stop for futility 
12 (24%) 
10 (10%) 
92% 
Not applicable 
Not applicable 
12 (24%) 
12 (12%) 
77% 
321 
Not applicable 
12 (24%) 
14 (14%) 
54% 
498 
Not applicable 
12 (24%) 
15 (15%) 
42% 
[646] 
[77%] 
12 (24%) 
18 (18%) 
14% 
[1800] 
[31%] 
12 (24%) 
20 (20%) 
2.6% 
Early stop for futility 
10 (20%) 
8 (8%) 
85% 
Not applicable 
Not applicable 
10 (20%) 
10 (10%) 
64% 
412 
Not applicable 
10 (20%) 
11 (11%) 
50.4% 
534 
Not applicable 


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10 (20%) 
13 (13%) 
26% 
[1014] 
[55%] 
10 (20%) 
15 (15%) 
10% 
[2460] 
[23%] 
10 (20%) 
18 (18%) 
1.4% 
Early stop for futility 
Quantities in [ ] indicate theoretical values as sample size would not be increased per the 
currently proposed adaptive design.  
10.5.4 Overall Adaptive Design Performance 
Finally, the Cui/Hung/Wang (CHW) approach is compared to the Chen/DeMets/Lan (CDL) 
approach without pre-defined fixed weights for the final analysis (which is valid as sample size 
may only be increased if CP (obtained under observed trend) at the second interim analysis 
exceeds 50%).  
All the results below are for the group-sequential design with adaptive sample size re-estimation 
procedure as described in previous sections and based on 10.000 simulated trials each. 
Scenario 1: true progression probabilities are 30% (SOC) and 15% (RESP301+SOC) 
Scenario 2: true progression probabilities are 24% (SOC) and 14% (RESP301+SOC) 
Scenario 3: true progression probabilities are 30% (SOC) and 10% (RESP301+SOC) 
Scenario 4: true progression probabilities are 24% (SOC) and 20% (RESP301+SOC) 


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10.6 Appendix 6: Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
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 
CP 
Conditional power 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
CRO 
contract research organization 
CV 
cardiovascular 
DMC 
Data Monitoring Committee 
DRE 
disease-related events 
ECG 
electrocardiogram 
ECMO 
Extra corporeal membrane oxygenation 
EDC 
electronic data capture 
EoS 
End of study 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
interactive voice response system 


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IWRS 
interactive web response system 
LFT 
Liver function test 
mHb 
Methemoglobin 
NEWS 
National Early Warning Score 
NHS 
National Health Service 
NO 
Nitric oxide 
NO2 
Nitrogen dioxide 
NOx 
Oxide of nitrogen 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
PP 
Per protocol 
PT 
Prothrombin time 
QTcF 
QT interval corrected using Fridericia’s formula 
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 
Three times daily 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 
 
 


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Final Amendment 2 (Version 3.0) 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Amendment 2.0 
Version 3.0 
10-Jun-2020 
Amendment 1.0 
Version 2.0 
05-Jun-2020 
Original Protocol 
Version 1.0 
01-May-2020 
 
Amendment 2.0 (10-Jun-2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment: 
The protocol was updated to clarify that staggered dosing is required for all participants treated 
before completion of the first Independent Data Monittoring Committee (IDMC) review, and to 
clarify exclusionary criteria and monitoring of methemoglobin (mHb). Information was added to 
ensure that investigators are aware of the potential risk of interaction between nitric oxide (NO) 
and other NO donor agents. Other changes, with brief rationale, are summarized in the following 
table. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA) 
Footnote 4 updated to include mHb 
assessment at the same time points as 
hematology and clinical chemistry 
assessments. 
For monitoring and 
assessment of mHb 
against the 
discontinuation criteria. 
Section 2.2.1 Risk 
Assessment 
Section 5.3 Exclusion 
criteria 
Table 2-1 updated to include 
exclusionary mHb >1%. 
Exclusion criterion 13 updated to 
specify that mHb >1% is exclusionary. 
The normal reference 
range for mHb is 0-1% 
(Longo et al, 2011).  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1 Overall 
Design 
Section 6.1 Study 
Intervention 
Administered 
Section 9.6 Data 
Monitoring Committee 
(DMC) 
Due to the urgency of the pandemic, if 
participants become eligible for the 
study during the IDMC review of the 
first 10 participants then they may be 
recruited. However, their 
administration of RESP301 will be 
staggered in the same way as for the 
first 10 participants.  
Once the IDMC review has been 
completed, and provided there are no 
safety concerns, further recruitment 
will continue as per protocol. The 
Sponsor and contract research 
organization (CRO) confirm that the 
report from the IDMC will be sent in a 
timely manner to all participating sites 
and investigators. 
The staggered dosing 
approach will be used 
for all participants 
enrolled up to 
completion of the first 
IDMC safety review, to 
ensure appropriate safety 
procedures are in place 
for the first participants 
recruited into the study. 
Section 6.5.1 Potential 
Drug Interactions 
A new section was added to describe 
NO donor agents that may increase the 
risk of developing 
methemoglobinemia.  
To ensure that 
investigators are aware 
of the potential risk of 
interaction between NO 
and other NO donor 
agents. 
Section 7.1 Permanent 
Discontinuation of 
Study Intervention 
Addition of Hy’s law discontinuation 
criteria to the first bullet. 
To ensure consistency 
with Appendix 10.3. 
Whole document 
Minor language and format changes. 
For improved clarity and 
readability. 


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Table of Contents 
 
Protocol Amendment Summary of Changes Table ......................................................................... 3 
Table of Contents ............................................................................................................................ 5 
1 
Protocol Summary .................................................................................................................... 9 
1.1 
Synopsis ................................................................................................................................ 9 
1.2 
Schema ............................................................................................................................... 12 
1.3 
Schedule of Activities (SoA) .............................................................................................. 13 
2 
Introduction............................................................................................................................. 18 
2.1 
Background......................................................................................................................... 18 
2.2 
Benefit/Risk Assessment .................................................................................................... 21 
2.2.1 
Risk Assessment ............................................................................................................. 21 
2.2.2 
Benefit Assessment ......................................................................................................... 24 
2.2.3 
Overall Benefit: Risk Conclusion ................................................................................... 26 
3 
Objectives and Endpoints ....................................................................................................... 26 
4 
Study Design ........................................................................................................................... 27 
4.1 
Overall Design .................................................................................................................... 27 
4.2 
Scientific Rationale for Study Design ................................................................................ 29 
4.3 
Justification for Dose .......................................................................................................... 30 
4.4 
End of Study Definition...................................................................................................... 30 
5 
Study Population ..................................................................................................................... 30 
5.1 
Study Rationale .................................................................................................................. 30 
5.2 
Inclusion Criteria ................................................................................................................ 31 
5.3 
Exclusion Criteria ............................................................................................................... 32 
5.4 
Lifestyle Considerations ..................................................................................................... 33 
5.5 
Screen Failures ................................................................................................................... 33 
5.5.1 
Screening and Enrollment Log and Participant Identification Numbers ........................ 33 
6 
Study Intervention .................................................................................................................. 34 
6.1 
Study Intervention Administered ........................................................................................ 34 
6.1.1 
Medical Devices ............................................................................................................. 35 
6.1.2 
Device Training .............................................................................................................. 36 


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6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 36 
6.2.1 
Preparation of Study Intervention Product ..................................................................... 36 
6.2.2 
Storage and Accountability of Study Intervention ......................................................... 37 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 37 
6.4 
Study Intervention Compliance .......................................................................................... 38 
6.5 
Concomitant Therapy ......................................................................................................... 38 
6.5.1 
Potential Drug Interactions ............................................................................................. 39 
6.5.2 
Rescue Medication ......................................................................................................... 39 
6.6 
Intervention After the End of the Study ............................................................................. 39 
7 
Discontinuation of Study Intervention and Participant Discontinuation ................................ 39 
7.1 
Permanent Discontinuation of Study Intervention ............................................................. 39 
7.2 
Temporary Discontinuation of Study Intervention ............................................................. 41 
7.3 
Participant Discontinuation/Withdrawal from the Study ................................................... 42 
7.4 
Loss of Participants to Follow-Up ...................................................................................... 42 
8 
Study Assessments and Procedures ........................................................................................ 42 
8.1 
Efficacy Assessments ......................................................................................................... 44 
8.1.1 
Modified WHO Ordinal Scale ........................................................................................ 44 
8.1.2 
Pulse Oximetry ............................................................................................................... 44 
8.1.3 
National Early Warning Score (NEWS) 2 ...................................................................... 45 
8.2 
Safety Assessments ............................................................................................................. 46 
8.2.1 
Physical Examinations .................................................................................................... 46 
8.2.2 
Vital Signs ...................................................................................................................... 46 
8.2.3 
Electrocardiograms ......................................................................................................... 47 
8.2.4 
Clinical Safety Laboratory Assessments ........................................................................ 47 
8.3 
Adverse Events and Serious Adverse Events ..................................................................... 47 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 48 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 48 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 48 
8.3.4 
Regulatory Reporting Requirements for SAE ................................................................ 48 
8.3.5 
Pregnancy ....................................................................................................................... 49 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs ............................................................................................................................... 50 
8.3.7 
Adverse Events of Special Interest (Not Applicable) ..................................................... 50 
8.3.8 
Medical Device Deficiencies (Not Applicable) .............................................................. 50 
8.4 
Tokenization (Optional) ...................................................................................................... 50 


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8.5 
Treatment of Overdose (Not Applicable) ........................................................................... 51 
8.6 
Pharmacokinetics (Not Applicable) .................................................................................... 51 
8.7 
Pharmacodynamics (Not Applicable) ................................................................................. 51 
8.8 
Genetics (Not Applicable) .................................................................................................. 51 
8.9 
Biomarkers (Not Applicable) ............................................................................................. 51 
8.10 Medical Resource Utilization and Health Economics (Not Applicable) ............................ 51 
9 
Statistical Considerations........................................................................................................ 52 
9.1 
Statistical Hypothesis ......................................................................................................... 52 
9.2 
Sample Size Determination ................................................................................................ 52 
9.3 
Populations for Analyses .................................................................................................... 52 
9.4 
Statistical Analyses ............................................................................................................. 53 
9.4.1 
General Considerations .................................................................................................. 53 
9.4.2 
Primary Endpoint ............................................................................................................ 54 
9.4.3 
Secondary Endpoint(s) ................................................................................................... 54 
9.4.4 
Tertiary/Exploratory Endpoint(s) ................................................................................... 55 
9.4.5 
Other Safety Analyses .................................................................................................... 55 
9.4.6 
Other Analyses ................................................................................................................ 57 
9.5 
Interim Analyses ................................................................................................................. 57 
9.6 
Data Monitoring Committee (DMC) .................................................................................. 58 
10 Supporting Documentation and Operational Considerations ................................................. 59 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 59 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 59 
10.1.2 
Financial Disclosure ....................................................................................................... 59 
10.1.3 
Informed Consent Process .............................................................................................. 59 
10.1.4 
Data Protection ............................................................................................................... 60 
10.1.5 
Committees Structure ..................................................................................................... 61 
10.1.6 
Data Quality Assurance .................................................................................................. 61 
10.1.7 
Source Documents .......................................................................................................... 62 
10.1.8 
Study and Site Start and Closure .................................................................................... 62 
10.1.9 
Publication Policy ........................................................................................................... 63 
10.1.10 Protocol Approval and Amendment ............................................................................... 63 
10.1.11 Liability and Insurance ................................................................................................... 64 
10.2 Appendix 2: The NEWS 2 Scoring System ....................................................................... 65 
10.3 Appendix 3: Clinical Laboratory Tests ............................................................................... 66 


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10.4 Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 68 
10.4.1 
Definition of AE ............................................................................................................. 68 
10.4.2 
Definition of SAE ........................................................................................................... 69 
10.4.3 
Recording and Follow-up of AE and SAE ..................................................................... 71 
10.4.4 
Reporting of SAE ........................................................................................................... 73 
10.5 Appendix 5: Statistical Design Considerations .................................................................. 76 
10.5.1 
Some General Design Considerations ............................................................................ 76 
10.5.2 
General Design Characteristics ...................................................................................... 79 
10.5.3 
Adaptive Sample Size Re-Estimation ............................................................................ 80 
10.5.4 
Overall Adaptive Design Performance ........................................................................... 82 
10.6 Appendix 6: Abbreviations ................................................................................................. 83 
10.7 Appendix 7: Protocol Amendment History ........................................................................ 85 
10.7.1 
Protocol Amendment 1.0, 05 Jun 2020 .......................................................................... 85 
11 References............................................................................................................................... 94 
Investigator Agreement Page ........................................................................................................ 98 
List of Figures 
Figure 1–1: 
Study Design ......................................................................................................... 12 
Figure 2–1: 
Mode of Action of RESP301 Against SARS-Cov-2 ............................................. 20 
Figure 6-1: 
Staggered Dosing Approach for the First 10 Participants ..................................... 35 
List of Tables 
Table 1-1 
Schedule of Activities (SoA) ................................................................................ 13 
Table 2-1 
Risk Assessment.................................................................................................... 21 
Table 3-1 
Objectives and Endpoints ..................................................................................... 26 
Table 6-1 
Study Intervention(s) Administered ...................................................................... 34 
Table 6-2 
Composition of Drug Product, Diluent and Admixture ........................................ 37 
Table 7-1 
Differences in Signs and Symptoms for Acute Bronchospasm and COVID-19 
Progression ............................................................................................................ 41 
Table 9-1 
Populations for Analysis ....................................................................................... 53 
Table 10-1 
Protocol-Required Laboratory Assessments ......................................................... 66 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: An 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 requiring supplemental oxygen 
(NOCoV2) 
Sponsor Protocol No.: RESP301-002 
Study Phase: Phase 2/Phase 3 
Sponsor: Thirty Respiratory Limited 
Rationale: 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design. Participants will be consented and randomized 2:1 to the 
Investigational arm or the Control arm. Participants randomized to the Investigational arm will 
receive inhaled RESP301 (6 mL) administered using a nebulizer 3 times a day (TID) for up to 
10 days in addition to the standard of care (SOC) while participants in the Control arm will 
receive SOC alone. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 4 in the 
modified World Health Organization 
(WHO) ordinal scale into levels >4 
• Proportion of participants who progress to 
level >4 of modified WHO ordinal scale 
due to COVID-19 by Day 14 
Key Secondary 
• To assess the effect of RESP301 as 
measured by room air SpO2 
• Change in room air SpO2 from baseline 
over time 
• To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
• Change in NEWS 2 symptom score from 
baseline over time 


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Overall Design: 
• Open-label, randomized, multicenter, parallel group, concurrent, controlled study using a 
sequential adaptive design to evaluate the efficacy and safety of RESP301 added to 
standard of care (SOC) in hospitalized patients with COVID-19 requiring supplemental 
oxygen. 
• Participants will be stratified by country and presence of risk factors for severe outcomes 
of COVID-19, based on comorbidities and age as detailed in Section 6.3. 
• The study treatment will be permanently discontinued prior to 10 days if the participant: 
o Improves to level 1 or 2 of the modified WHO ordinal scale; 
o Progresses to a level > 4 of the modified WHO ordinal scale; 
o Experiences an event that requires permanent discontinuation as described in 
Section 7.1. 
• An Independent Data Monitoring Committee (IDMC) will be responsible for closely 
reviewing the safety and efficacy data from interim analyses and for providing their 
recommendations on continuation of the study. The IDMC will meet after 10, 20, 60 and 
150 participants have completed the study (see Sections 9.5 and 9.6). 
• A staggered dosing approach will be used for the first 10 participants (up to the first 
IDMC safety review). Each RESP301 dose will be administered by intermittent 
inhalation to monitor the tolerability and response to RESP301 (see Sections 6.1 and 9.6). 
Disclosure Statement: This is a parallel group treatment study with two arms that are 
open-label. 
Number of Participants: 
Approximately 300 adult (male or female) participants will be randomly assigned to study 
intervention (200 to the Investigational arm and 100 to the Control arm). 
Intervention Groups and Duration: 
The total study duration for a participant from screening to last follow up will be up to 30 days 
(±2 days). The study will be divided into the following periods: 




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1.3 Schedule of Activities (SoA) 
Table 1-1 
Schedule of Activities (SoA) 
Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Informed consent 
X 
 
 
 
 
 
 
Optional tokenization 
ICF to be provided for 
a subset of 
participants in the 
United States (see 
Section 8.4) 
Confirmation of COVID-19 
infection by nasopharyngeal 
RT-PCR 3 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Recheck clinical 
status before 1st dose 
of study intervention 
Demographics 
X 
 
 
 
 
 
 
 
Physical examination including 
height and weight 
X 
 
 
X 
X 
 
X 2 
Full physical exam 
and height only at 
screening 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Pregnancy test (urine) 
X 
 
 
 
 
 
 
All women, including 
women of 
childbearing potential 
and pregnant women, 
may be enrolled in the 
study. Pregnancy 
status should be 
recorded (see 
Section 8.3.5). Note: 
Only females of child 
bearing potential and 
pregnant females need 
to undergo a screening 
pregnancy test. 
Medical history (includes 
substance usage) 
X 
 
 
 
 
 
 
History of substance 
usage or abuse to be 
recorded but is not 
exclusionary 
Medication history 
X 
 
 
 
 
 
 
In the prior 3 months 
Laboratory assessments 
(including liver chemistries) 4 
X 4 
X 4 
X  
(Days 3 and 
7 only) 4 
X 4 
X 4 
 
X 2,4 
 
12-lead ECG  
X 
 
 
 
 
 
 
After resting supine 
for approximately 
5 minutes.  
QRS, QT, QTcF, PR, 
RR, rate 
Vital signs 5 
X 
X 
X 5 
X 
X 
 
X 
Within 15 minutes 
prior to study 
intervention 
administration 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Randomization 
 
X 
 
 
 
 
 
 
Study intervention, TID 6 
 
X 
X 
X 
 
 
 
A staggered dosing 
approach will be used 
for the first 
10 participants (up to 
the first IDMC safety 
review). Each 
RESP301 dose will be 
administered by 
intermittent inhalation 
to monitor the 
tolerability and 
response to RESP301 
(see Sections 6.1 and 
9.6). Where possible 
study intervention 
should be 
administered at 
approximately the 
same times each day 
At least 6 hours 
between 2 consecutive 
doses 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
 
Oxygen / respiratory assessment 7 
X 
X 
X 
X 
 
 
 
 
SpO2 on room air (after at least 
1 minute) prior to study 
intervention administration and 
immediately at the end of 
nebulization 6 
 
X 
X 
X 
 
 
 
See Section 8.1.2 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Modified WHO ordinal scale 
X 
X 
X 
X 
 
X 
X 
See Section 8.1.1 
NEWS 2 assessment 7 
 
X 
X 
X 
 
 
 
Prior to study 
intervention in the 
morning. See 
Section 8.1.3 


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Abbreviations: AE=adverse event; aPTT= activated partial thromboplastin time; CBC=complete blood count; Chem 7=blood chemistry panel (sodium, 
potassium, chloride, bicarbonate/CO2, blood urea nitrogen, creatinine, glucose); CV=cardiovascular; ECG=electrocardiogram; IDMC=Independent Data 
Monitoring Committee; LFTs=liver function tests; mHb=methemoglobin; PT/INR=prothrombin time/international normalized ratio; RT-PCR=reverse 
transcription-polymerase chain reaction; SAE=serious adverse event; TID=three times daily. 
1. Screening and randomization may be on the same day, providing all eligibility criteria are met.  
2. For participants who are already discharged at either the Day 14 or Day 28 (EoS) follow-up, there will be a phone call to check AEs/SAEs, 
concomitant medications, and modified WHO ordinal scale. At EoS, safety laboratory tests (nitrite and mHb only) and weight will be collected for 
participants in hospital only. 
3. COVID-19 infection must be confirmed and documented in chart with a positive result on a validated test. 
4. At Screening: CBC, chem 7, mHb, LFTs, and coagulation (PT/INR, aPTT). 
On Day 1, Day 3, Day 7 and Day 10, or early withdrawal: CBC, chem 7 (per SOC), and mHb. 
On Day 28: nitrite and mHb (participants in hospital at EoS only). 
5. Vital signs: temperature, heart rate, blood pressure, respiratory rate. Vital signs to be repeated as per SOC during treatment period. 
6. Study intervention comprises the following procedures which are to be done in order and as quickly as possible: 
a. 
Recording of oxygen flow level including mode (nasal cannula, mask) 
b. Recording of SpO2 and heart rate 
c. 
Discontinuation of supplemental oxygen administration * 
d. Close participant oversight by trained health care professional until SpO2 is stable on ambient air after one minute at least * 
e. 
Recording of SpO2 * pre-nebulization on ambient air 
f. 
Preparation of the admixture of RESP301* 
g. Administration of the nebulization via a vibrating mesh nebulizer while monitoring SpO2 and heart rate (alarms set to 89% and 120 beats / min, 
or as indicated by the Investigator, for stopping study intervention administration and resuming supplemental oxygen) * If the participant is 
unable to tolerate nebulization without supplemental oxygen, nasal oxygen may be administered during nebulization. 
h. Discontinuation of nebulization after 5 minutes or no product left in the device, whichever comes first * 
i. 
Recording of SpO2 * post nebulization on ambient air 
j. 
Resuming supplemental oxygen * 
k. Participant oversight until SpO2 is stable * 
l. 
Recording of SpO2 * 
* for participants on active treatment arm only 
7. Immediately before participant is discontinued from oxygen for study intervention administration (for participants on active treatment arm only) and 
assessment of SpO2 at room air. 


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2 Introduction 
2.1 Background 
Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by a novel coronavirus 
(SARS-CoV-2). COVID-19 was first described in Wuhan, China, in December 2019 and is now 
a global pandemic (Matos et al, 2020). Most of those affected have milder illness (80%), 15% 
will be severely ill (require oxygen) and 5% will require intensive care unit care (Novel 
Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020). Of those who are 
critically ill, most require early intubation and mechanical ventilation. Other complications 
include septic shock and multi-organ failure, including acute kidney injury and cardiac injury 
(Yang et al, 2020). Older age and comorbid diseases, such as chronic obstructive pulmonary 
disease (COPD), hypertension, and diabetes, increase risk of death (Huang et al, 2020; Zhou et 
al, 2020). The virus is highly contagious and spread via respiratory droplets, direct contact and, if 
aerosolized, airborne routes. The most common symptoms include fever, fatigue, dry cough, and 
shortness of breath.  
A critical early component of innate host defense 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 nebulizer, 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. 


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RESP301 is a NO-generating liquid designed to release NO in situ in the upper airways and deep 
in the alveolar spaces. RESP301 is an admixture solution of two precursor solutions mixed 
together at point of care for immediate inhaled administration via a CE marked handheld 
nebulizer and has specific advantages (see below) over inhaled NO gas in treating patients with 
COVID-19 during the current pandemic. It has 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 nebulizer; 
• 
The formulation is nebulized 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 Sponsor has conducted a number of supportive in vitro studies to assess the activity of NO-
generating solutions against major respiratory viruses responsible for infections in humans. 
These studies include the following: 
• 
In vitro studies to demonstrate the effects of RESP301 on SARS-CoV-2 replication 
• 
In vitro study of RESP301 against influenza A (H1N1) and human rhinovirus 
• 
Determination of the anti-viral efficacy of NO-releasing formulations against two 
strains of virus (influenza A virus [H1N1] and human rhinovirus 16) 
• 
Anti-microbial activity of acidified nitrite solutions against intracellular drug sensitive 
and drug resistant Mycobacterium tuberculosis and M. abscessus infections 
• 
Anti-microbial activity of RESP301 when used alone and in combination with 
antibiotics 
Recent data from experiments at two independent laboratories using two different isolates of 
SARS-CoV-2 suggest that incubation with RESP301 for 36 to 48 hours reduced viral load to 
levels below the limit of detection of the assay at concentrations which were not associated with 
cytotoxicity. The limiting factor of the experiments was the slow growth rate of the viral 
controls; reduction in viral load was 2.2 and 4 Log10 median tissue culture infectious dose 
(TCID50).  
Studies of inhaled nebulized sodium nitrite (AIR001) in healthy subjects and in patients showed 
that inhaled acidified nitrite produces dose proportional plasma pharmacokinetics without 
accumulation following repeated administration, with low systemic blood levels of nitrite and 


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methemoglobin (<3%) (Rix et al, 2015). Inhaled nitrite (AIR001) at doses up to 90 mg three 
times daily (TID) displayed a good safety profile and is well tolerated (Parsley et al, 2013; 
Simon et al, 2016), thus supporting the investigation of RESP301 in the clinical setting. 
RESP301 delivers NO in a specifically focused way and with a unique mode of administration. 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. Whereas inhaled NO 
gas has been used to treat patients with virus-induced acute respiratory distress syndrome and is 
being tested currently in COVID-19 patients, it focuses on increasing vascular permeability and 
is not sufficiently targeted at the infection, it is rapidly dispelled with exhalation and is oxidized 
in air to toxic NO2. By comparison, RESP301 generates NO in a liquid environment that comes 
in direct contact with the virus and the virus-infected cells. As a result, RESP301 has a better 
targeted approach, and lower concentrations of NO are required, with a much more portable 
delivery system. An important environmental safety factor is that RESP301 produces negligible 
levels of NO2 generated and exhaled NO. 
In generating NO, RESP301 has at least three 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 (Figure 2–1). 
Figure 2–1: 
Mode of Action of RESP301 Against SARS-Cov-2 


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1. Nitric oxide 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), vital for the life-cycle of the virus, are targets for NO nitrosylation (Benz et al, 
2002; Colosanti et al, 1999). 
2. In coronaviruses like SARS-CoV-2, NO 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 receptor on the host cell. 
3. Nitric oxide can attack 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. Nitric oxide 
suppresses the virus-induced hyperactivity in the host cell and thereby deprives the virus 
of its crucial supply chain.  
RESP301 efficiently delivers with all three modes of action and is therefore considered an ideal 
candidate for clinical trials in COVID-19. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of RESP301 is 
provided in the Investigator’s Brochure. 
2.2 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. 
2.2.1 
Risk Assessment 
Table 2-1 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention RESP301 
Participants may need to be 
discontinued from 
supplemental oxygen for 
Study treatment is to be 
administered via a vibrating 
mesh nebulizer which is 
designed for oral inhalation. 
Participants unable to be 
safely discontinued from 
supplemental oxygen will be 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
several minutes to receive 
nebulized study treatment 
excluded (Exclusion 
criterion 2) 
Treatment administration is to 
be performed as quickly as 
possible (Section 1.3) 
Oxygen saturation (SpO2) 
and heart rate will be 
monitored throughout the 
study intervention 
administration (Section 1.3) 
In case of decrease in SpO2 or 
clinical signs of intolerance to 
nebulization, RESP301 
treatment may be paused 
temporarily and supplemental 
O2 resumed or the study 
treatment may be 
discontinued permanently 
(see Section 7.1) per 
Investigator assessment. 
Risk of methemoglobinemia 
Very low levels are produced 
but as methemoglobinemia 
has been reported with 
continuous NO gas 
administration, the risk 
cannot be firmly ruled out 
Participants with a history of 
methemoglobinemia will be 
excluded (Exclusion 
criterion 4), methemoglobin 
(mHb) level >1% is 
exclusionary (exclusion 
criterion 13), and mHb is 
included in safety laboratory 
tests (Section 1.3) 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Risk of clinical bronchial 
hyper-responsiveness related 
to nebulization 
Excipients in the nebulized 
RESP301 include mannitol 
which is a known bronchial 
irritant at the average dose of 
a positive mannitol test 
(239.0 ± 185.0 mg, Brannan 
et al, 2005). While the dose 
used in this study (54.66 mg) 
is lower than the average dose 
for a positive mannitol test, it 
has not yet been tested in 
COVID-19 patients and may 
potentially cause or 
exacerbate cough or 
bronchospasm in susceptible 
individuals in this specific 
population 
Participants with a known 
history of moderate or severe 
bronchial hyperreactivity 
(such as in asthma) or 
presence of signs of 
significant bronchospasm on 
examination will be excluded 
from study participation 
(Exclusion criterion 5) 
For the first 10 participants 
treated before the first 
Independent Data Monitoring 
Committee (IDMC) safety 
review (Section 9.6), 
RESP301 will be 
administered by intermittent 
inhalation until the intended 
dose is delivered 
(Section 6.1), so that the 
treatment can be quickly 
adjusted and rescue 
bronchodilator initiated if 
needed (Section 6.5.2) 
After reviewing safety data, 
the IDMC will decide 
whether the intermittent 
inhalation of RESP301 can be 
replaced by continuous 
inhalation. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Procedures 
Nebulization 
The delivered dose of 
RESP301, estimated to be 
~40% of the masses listed in 
Table 6-2, can be affected by 
patient technique and 
inspiratory capacity leading 
to inter- and intra-patient 
variation in actual doses of 
these ingredients, given the 
acute nature and high disease 
burden in this proposed 
clinical setting 
Training will be provided to 
study staff to minimize 
variation in dose 
Other 
Risk of spreading SARS-
CoV-2 
SARS-CoV-2 is known to be 
transmissable via respiratory 
droplets and any interventions 
that may potentially increase 
cough or aerosolization of 
respiratory secretions of an 
infected patient may increase 
risk of spread of disease  
Proper personal protective 
equipment including 
appropriate mask, face shield, 
gown and gloves should be 
used at all times. When 
possible, the site staff should 
not remain in the room during 
study intervention 
administration (providing that 
continuous O2 monitoring can 
be conducted remotely and 
study intervention can be 
administered correctly) 
2.2.2 Benefit Assessment 
To date, no treatment of COVID-19 has demonstrated clinical efficacy. Patients and their 
physicians are critically in need for treatments that decrease the risk of severe levels of disease, 


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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. 
Nitric Oxide is already marketed (e.g., INOmax®, NOXIVENT™, etc) in the United States (US) 
and other countries as a gas for continuous use in preterm and near-term (>34 weeks gestation) 
neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence 
of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents. 
It is well tolerated, although under continuous use, a small number of cases of 
methemoglobinemia have been reported (NOXIVENT™ FDA Prescribing Information). 
Nitric oxide has been shown in vitro to inhibit the replication cycle of severe acute respiratory 
syndrome coronavirus (Akerström S et al, 2005). In addition, NO is a naturally occurring and 
potent antimicrobial agent in the human body, which is active against viruses, bacteria, fungus, 
and yeasts (Fang, 1997). In particular, NO inhibits replication in vitro in a number of respiratory 
viruses including influenza A and B (Rimmelzwaan et al, 1999, Regev-Shoshani et al, 2013), 
human rhinovirus (Sanders et al, 1998), and respiratory syncytial virus (Ali-Ahmad D et al, 
2003). 
The ability of RESP301 to have a marked antibacterial action is highly relevant in the context of 
treating patients with SARS-CoV-2 infection since superimposed bacterial infection is a critical 
factor and a major cause of morbidity and mortality. RESP301 would restore and replenish the 
NO deficiency in patients who have succumbed to SARS-CoV-2 infection. RESP301 also has 
key advantages over inhaled NO gas, as discussed in Section 2.1. 
A vibrating mesh nebulizer is advised for administration of RESP301. Amongst the suitable 
nebulizers, the device chosen for the study is a commercially available, CE-marked vibrating 
mesh device that delivers a mist of fine droplets in the size range required for pulmonary 
deposition (Mass Median Aerodynamic Diameter < 5 µm). This has been shown to be ideally 
suited for penetration deep into the alveolar spaces of the lung. As with all nebulizers in clinical 
use, there is a residual amount of drug that remains in the nebulizer so that not the full amount of 
drug is administered. The device operates continuously once initiated and automatically switch 
off once the medication has been delivered. The device may be used in pediatric and adult 
populations, as permitted by the prescribed medication, and is suitable for use in home 
environments or hospital/clinic settings. 
As testing inefficient product would distract sites from participating in other research efforts, two 
interim analysis for futility purpose have been planned. 


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2.2.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this first-in-man 
study, the potential risks identified in association with RESP301 are justified by the anticipated 
benefits that may be afforded to participants with COVID-19. 
3 Objectives and Endpoints 
Table 3-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 4 in the 
modified World Health Organization 
(WHO) ordinal scale into levels >4 
• Proportion of participants who progress to 
level >4 of modified WHO ordinal scale 
due to COVID-19 by Day 14 
Key Secondary 
• To assess the effect of RESP301 as 
measured by room air SpO2 
• Change in room air SpO2 from baseline 
over time 
• To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
• Change in NEWS 2 symptom score from 
baseline over time 
• To assess the treatment response on 
clinical status 
• Change from baseline on the modified 
WHO ordinal scale at each visit up to 
Day 28 
• Time to improvement to a lower level 
(<4) of modified WHO ordinal scale 
• Time to progression to a higher level (>4) 
of modified WHO ordinal scale 
Additional Secondary 
• To assess the treatment response on 
clinical status 
• Time to hospital discharge 
• Incidence of mortality by Day 28 
Safety 
• To assess the overall safety profile of 
RESP301 in COVID-19 participants 
• Clinical safety laboratory measurements 
• Physical examinations 
• Vital signs 


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• 
Efficacy follow-up: Day 14 and Day 28 (±2 days) 
• 
Safety follow-up: 28 days after treatment initiation; with the participant being contacted 
by phone call, if not still hospitalized, on Day 28 (±2 days) 
After screening, eligible participants will be randomized to either RESP301+SOC or SOC alone 
on Day 1, and the study treatment will be initiated as applicable (Table 1-1). Screening and 
randomization may happen on the same day (Day 1).  
An individual administration of study intervention will be stopped, and supplemental oxygen 
resumed, if threshold limits of SpO2 89% or heart rate 120 beats/min (or as indicated by the 
Investigator) are exceeded (see Section 4.2 and Section 8.1.2). However, the participant may 
continue with subsequent doses if the Investigator judges that the benefit / risk ratio remains 
positive. In this case, the instruction to continue should be duly recorded in the participant’s 
hospital file and the subsequent nebulization should be closely monitored. Inhalation of study 
intervention should be completed within 20 minutes. A staggered dosing approach will be used 
for the first 10 participants (and enrolment up to completion of the first IDMC safety review) to 
monitor tolerability and response to RESP301 (see Sections 6.1 and 9.6). 
The study treatment will be permanently discontinued prior to 10 days if the participant: 
• Improves to level 1 or 2 of the modified WHO ordinal scale; 
• Progresses to a level > 4 of the modified WHO ordinal scale; 
• Experiences an event that requires permanent discontinuation as described in Section 7.1. 
In the above cases, participants will be considered as ongoing in the study until the final Safety 
follow-up phone call (Day 28). Participants will be withdrawn from the study prior to Day 10 
(Early withdrawal) only if they withdraw consent.  
The total study duration for a participant from screening to last follow up will be up to 30 days 
(±2 days). 
Participants will be stratified by country and presence of risk factor(s) for severe outcomes of 
COVID-19, based on comorbidities and age, as detailed in Section 6.3. 
Two interim analyses are planned (see Section 9.5 for details). 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study. The IDMC will 
meet after 10, 20, 60 and 150 participants have completed the study (see Sections 9.5 and 9.6). 


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4.2 Scientific Rationale for Study Design 
NO is a naturally occurring and potent antimicrobial agent in the human body which has been 
shown in vitro to inhibit replication of severe acute respiratory syndrome coronavirus 
(Akerström S et al, 2005), including SARS-CoV2, and other respiratory viruses. NO as an 
inhaled gas is already marketed in the US and other countries (see Section 2.2.2) but has 
disadvantages over NO produced locally in the oropharynx or lung airways (lengthy treatment 
requiring NO canisters, the inhaled NO is expelled in exhalation, the NO gas oxidizes in air to 
form toxic NO2 which is a potential lung irritant and a contaminant in the patient’s environment, 
and the half-life of NO in air is short).  
RESP301 has potential advantages over inhaled NO gas: 
• 
RESP301 demonstrates powerful evidence in vitro as a broad-spectrum anti-microbial; 
• 
Treatment is quick, easy and portable using a standard handheld nebulizer; 
• 
The formulation is nebulized 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. 
In this study, the effect of RESP301 as an add on treatment to SOC will be evaluated for its 
efficacy in reducing rate of progression to a more severe level of COVID-19 and for safety by 
comparison with SOC alone in hospitalized COVID-19 patients. A sequential adaptive design 
was chosen in order to assess futility and sample size after interim analyses (see Section 9.5). 
The study design was developed in accordance with the latest WHO and regional regulatory 
agencies guidelines.  
Several risks factors for severe or fatal outcomes have been reported (Bialek et al, 2020; Huang 
et al, 2020; Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020; 
Rong-Hui et al, 2020; Zhou et al, 2020). To minimize bias, the results will be stratified according 
to the known risk factors as described in Section 6.3. 
In this study, measures will be in place to trigger discontinuation of study intervention at a SpO2 
limit pre-agreed at the site (see Section 8.1.2). There is no critical level of oxygen saturation 
below which tissue hypoxia occurs due to the large number of variables that contribute to 
hypoxia at the tissue and cellular level (temperature, pH, tissue blood flow). As a result, there is 
no consensus about what constitutes normal and abnormal oximetry (ATS/ACCP, 2003). To 
support and guide the team in charge of study intervention administration, a default value of 


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SpO2=89% and heart rate (120 beats/min) has been proposed as a suitable limit of tolerance. 
However, for the reason stated above, this limit can be overruled by the Investigator in either 
direction. 
Newly released guidelines for ongoing clinical trials during the COVID-19 pandemic have 
emphasized the need to reduce the burden on sites and clinical trial personnel/investigators 
whether they be administrative, site visit, or other burdens (ACRO, 2020; EMA, 2020; HRS, 
2020). Thus, without blinding and a placebo, along with minimal procedures, the additional 
burden on clinical staff has been reduced as much as possible. 
4.3 Justification for Dose 
Studies with nebulized sodium nitrite (AIR001) in healthy subjects and in patients have shown 
that inhaled nitrite produces dose proportional plasma pharmacokinetic without accumulation 
following repeated administration, with low systemic blood levels of nitrite and methemoglobin 
(<3%). Inhaled nitrite at doses up to 90 mg TID displayed a good safety profile and is well 
tolerated (Rix et al, 2015; Parsley et al, 2013; Simon et al, 2016).  
In this study, 6.0 mL RESP301 (delivered dose 62 mg) will be administered via a vibrating mesh 
nebulizer, TID with at least 6 hours between each dose. Each 6.0 mL dose for nebulization 
contains the masses described in Table 6-2. 
4.4 End of Study Definition 
A participant is considered to have completed the study if he/she has completed the Treatment 
Period and the Follow-up Period (through the Day 28 EoS Follow-up). End of the study is 
defined as the last participant’s last visit or follow up call. 
5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of male and female COVID-19 patients, including pregnant 
women and women of child bearing potential. Participants must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 
5.1 Study Rationale 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design to evaluate the efficacy and safety of RESP301 plus SOC versus 


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SOC alone in hospitalized patients with COVID-19 requiring supplemental oxygen (WHO 
level 4). 
Each constituent (see Section 6.2) of RESP301 is used as SOC for various conditions. Product 
application is straightforward, requiring a few minutes of inhalation using a standard nebulizer. 
RESP301 is likely to be beneficial in treating patients with COVID-19 who are not receiving 
ventilation but are using supplementary oxygen in order to maintain a safe level of SpO2. 
Considering the well-established and global use of NO and the device, and the current public 
health emergency resulting from the COVID-19 pandemic, a Phase2/3 study of RESP301 is 
considered reasonable in order to generate efficacy data in patients infected with COVID-19. 
5.2 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is ≥18 years of age, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participant has laboratory-confirmed SARS-CoV-2 infection as determined by reverse 
transcriptase polymerase chain reaction (RT-PCR) or other approved clinical testing prior 
to randomization. 
3. Participant is hospitalized in relation to COVID-19, requiring supplemental oxygen to 
maintain SpO2 at a safe level (WHO level 4). 
Sex 
4. Participant is male or female. All females of childbearing potential, including pregnant 
females, must consent to urine pregnancy testing at screening to be eligible for the study. 
(Females who are not of childbearing potential do not need to undergo a pregnancy test at 
screening). 
Informed Consent 
5. Participant is capable of giving signed informed consent as described in Appendix 1 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 


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5.3 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Rapidly deteriorating or likely to require escalation to high flow oxygen, invasive or 
non-invasive ventilatory support within 24 hours according to Investigator’s opinion. 
2. Unable to safely receive a nebulized treatment for approximately 4 minutes according to 
Investigator’s opinion. 
3. Unable to receive or considered ineligible for invasive or non-invasive ventilatory 
support. 
4. History of methemoglobinemia. 
5. Uncontrolled asthma or history of severe bronchospasm. 
6. Severe (requiring baseline oxygen therapy > 12 h/day prehospitalization) chronic 
respiratory disease (e.g., known COPD, pulmonary arterial hypertension, idiopathic 
pulmonary fibrosis, interstitial lung disease). 
7. Suspected or confirmed untreated, active tuberculosis. 
8. Severely immune-compromised participants in Investigator’s opinion. 
9. Recent (within 3 months) active coronary artery disease or decompensated heart failure 
(New York Heart Association class 3-4). 
10. Presence of tracheostomy. 
Prior/Concomitant Therapy 
11. Chronic (≥4 weeks) use of corticosteroids >10 mg/day of prednisone or equivalent within 
4 weeks of randomization. 
Prior/Concurrent Clinical Study Experience 
12. Participation in other clinical investigations utilizing investigational treatment or within 
30 days / 5 half-lives whichever is longer. 


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Diagnostic Assessments 
13. Clinically significant abnormalities in clinical chemistry or hematology at screening, 
defined as: 
• 
Methemoglobin level >1% (Longo et al, 2011) 
• 
Platelet count <50,000 mm3 
• 
Alanine aminotransferase or aspartate aminotransferase >5 × upper limit of normal 
(ULN). 
• 
Estimated glomerular filtration rate <30 mL/min/1.73 m2 (modification of diet in renal 
disease formula) or requiring hemofiltration or dialysis. 
Other Exclusions 
14. Anticipated transfer to another hospital which is not a study site during the treatment 
period. 
15. Allergy to any of the components of the study intervention. 
5.4 Lifestyle Considerations 
No restrictions are required. 
5.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography and reason for screen 
failure (e.g., eligibility requirements failed). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
5.5.1 
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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6 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. 
6.1 Study Intervention Administered 
Table 6-1 
Study Intervention(s) Administered 
Study Treatment 
RESP301 + SOC 
Intervention Name: 
RESP301 
Type: 
Drug 
Dosage Formulation: 
Admixture for inhalation 
Unit Dose 
Strength(s): 
Delivered dose (62 mg) sodium nitrite (NaNO2) 
(6 mL of NO-generating admixture of 150 mM NaNO2, 50 mM mannitol and 100 mM 
citric acid) 
Dosage Level(s): 
One 6 mL-inhalation TID (every 8 hours) with at least 6 hours between 2 consecutive 
doses. 
Route of 
Administration: 
Inhalation 
IMP and NIMP: 
IMP 
Sourcing: 
RESP301 provided centrally by the Sponsor. 
Dosing Instructions: 
A vibrating mesh nebulizer will be used to administer the RESP301, under the 
direction of the study physician. 
Treatment is to commence within 5 minutes of RESP301 preparation.  
For the first 10 participants (and enrolment up to completion of the first IDMC safety 
review) RESP301 will be administered by intermittent inhalation to monitor 
tolerability and response to RESP301. After reviewing safety data, the IDMC will 
decide whether the intermittent inhalation of RESP301 can be replaced by a continuous 
inhalation. 
Before initiating each RESP301 inhalation, supplemental oxygen will be interrupted 
for a few minutes until SpO2 levels are stable. Depending on the extent of SpO2 
decrease, the RESP301 inhalation may be initiated or supplemental oxygen may be 
resumed at the discretion of the investigator. After treatment initiation, in case of SpO2 
decrease, RESP301 inhalation may be paused and supplemental oxygen resumed.  
If the participant is unable to tolerate nebulization without supplemental oxygen, nasal 
oxygen may be administered during nebulization. 
Packaging and 
Labeling: 
Study intervention will be provided as two separate vials: NaNO2/mannitol (3 mL) and 
citric acid buffered to pH 5.4 (3 mL), which will be labeled as required per country 
requirement.  
 


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Staggered dosing approach for the first 10 participants: 
For the first 10 participants treated, and enrolment up to completion of the first IDMC safety 
review (Section 9.6), RESP301 dose will be administered in a staggered approach: after 2 
minutes of inhalation, treatment is briefly paused to assess the participant. Provided there is no 
evidence of bronchospasm, treatment is continued for a further 2 minutes, after which treatment 
is again briefly paused for participant assessment. Thereafter, provided there is no evidence of 
bronchospasm and the participant is able to continue, the dose is completed (Figure 6-1), so that 
treatment can be quickly adjusted and rescue bronchodilator initiated if needed (Section 6.5.2). 
After reviewing safety data, the IDMC will decide whether the intermittent inhalation of 
RESP301 can be replaced by a continuous inhalation (see also Section 9.6). Due to the urgency 
of the pandemic, if participants become eligible for the study during the IDMC review of the first 
10 participants then they may be recruited; however, their administration of RESP301 will be 
staggered in the same way as for the first 10 participants.  
Figure 6-1: 
Staggered Dosing Approach for the First 10 Participants 
 
  
6.1.1 
Medical Devices 
1. Medical device (not manufactured by or for Thirty Respiratory Limited) provided for use 
in this study will be an FDA-approved and CE marked vibrating mesh nebulizer.  
2. Instructions for medical device use will be provided in the User Manual. 


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6.1.2 
Device Training 
Training will be provided to ensure all study staff are familiar with the device, including mixing 
the solutions, adding the admixture to the device and cleaning the device. 
6.2 Preparation, Handling, Storage, and Accountability 
6.2.1 
Preparation of Study Intervention Product 
RESP301 is prepared at bedside by mixing two sterile 3 mL solutions (one of NaNO2/mannitol 
and one of citric acid buffered to pH 5.4). The solution is to be nebulized immediately or within 
5 minutes post mixing as per the instructions given in the SoA (Table 1-1) and, for the first 
10 participants, as in Section 6.1 above (staggered dosing). The first administration of study 
intervention should be provided under medical supervision. 
RESP301 is mixed in the nebulizer chamber before use following the steps below (see Table 6-2 
for details of composition): 
1. First the vial marked A (NaNO2 and mannitol) is opened and its contents are poured into 
the nebulizer chamber. 
2.  Next, the vial marked B (citric acid) is opened and its contents are poured into the 
nebulizer chamber. 
3. The nebulizer lid should be closed, and the nebulizer should be swirled gently for a few 
seconds to mix the two solutions. The nebulizer should not be inverted. 
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 of inhalation. 
This combined mildly acidified nitrite solution (6 mL) is inhaled through the mouth using a 
vibrating mesh nebulizer under the direction of a physician. The purpose of the acidified nitrite 
aerosol is to deliver NO to the participant. The delivered dose of RESP301, assessed via 
simulated tidal breathing is estimated to be ~40% of the masses listed below; it should be noted 
that delivered dose can be further affected by participant’s breathing pattern and inspiratory 
capacity and so inter- and intra-participant variation in actual doses of these ingredients may 
vary, given the acute nature and high disease burden in this proposed clinical setting. 


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Table 6-2 
Composition of Drug Product, Diluent and Admixture 
 
Material 
Function 
Quantity per vial 
Drug Product 
Sodium Nitrite 
Drug Substance 
62.10 mg 
Mannitol 
Excipient  
54.66 mg  
Sterile water for injection 
Diluent 
 
Total Volume 
 
3.0 mL 
Diluent 
Citric Acid  
Diluent 
115.28 mg 
Sterile water for injection 
Diluent 
 
Total Volume 
 
3.0 mL 
Acidified Drug 
Product Mixture 
(RESP301) 
Sodium Nitrite 
Drug Substance 
62.10 mg 
Mannitol 
Excipient  
54.66 mg  
Citric Acid  
Diluent 
115.28 mg 
Sterile water for injection 
Diluent 
 
Total Volume 
 
6.0 mL 
 
6.2.2 
Storage and Accountability of Study Intervention 
The Investigator or designee must document whether appropriate temperature conditions 
(<25°C) have been maintained during transit 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 authorized site 
staff may supply or administer study intervention. All study interventions 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 authorized 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). 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Investigator Manual. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; however, the specific intervention to be taken by a participant will be 
assigned using an interactive voice response system (IVRS)/interactive web response system 
(IWRS). The site will contact the IVRS/IWRS prior to the start of study intervention 


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administration for each participant. The site will record the intervention assignment on the 
applicable case report form (CRF), if required.  
Potential bias will be reduced using a central stratified randomization to assign participants into 
one of the study treatment arms, RESP301+SOC or SOC (control), with a randomization ratio of 
2:1. Participants will be stratified by country and presence of risk factors for severe outcomes of 
COVID-19, based on comorbidities and age as follows: 
1. Age >65 years 
2. Ongoing or currently treated diabetes mellitus 
3. Ongoing or currently treated hypertension 
4. Ongoing or currently treated cardiovascular disease 
5. Ongoing or currently treated chronic lung disease 
6. Cancer history of less than 3 years, basal cell skin carcinoma excluded 
7. Ongoing or currently treated chronic kidney disease 
Participants will be stratified as no risk factor (none of the above criteria), one risk factor (one 
single of the above) or high-risk factor (2 or more of the above). 
6.4 Study Intervention Compliance 
Participants will receive study intervention directly from the Investigator or designee, under 
medical supervision. The date and time of each inhalation will be recorded in the source 
documents and recorded in the CRF. The study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the study 
intervention. 
6.5 Concomitant Therapy 
During the study, participants will receive institutional SOC for the treatment of COVID-19. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency and route 


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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 
Potential Drug Interactions 
Investigators should be aware of the potential interaction between NO generated by RESP301 
and that generated from NO donor agents, such as prilocaine, sodium nitroprusside, and 
nitroglycerine, that may increase the risk of developing methemoglobinemia. 
6.5.2 
Rescue Medication 
For participants treated before completion of the first safety review by the IDMC (Section 9.6), 
at the time of RESP301 treatment, a ready-to-use nebulization of a bronchodilator (short acting 
beta agonist such as salbutamol/albuterol according to investigational site standard practice for 
acute bronchospasm) may be administered to participants in case of bronchospasm. 
After reviewing safety data, the IDMC will decide whether the availability of rescue 
bronchodilator at the time of RESP301 treatment is still required. 
Although the use of rescue medications is allowable for the first 10 participants, the use of rescue 
medication should be delayed, if possible, for at least 2 minutes following each administration of 
study intervention. The date and time of rescue medication administration as well as the name of 
the rescue medication must be recorded. 
6.6 Intervention After the End of the Study 
After the end of the study, participants may continue their SOC (if any). Study intervention for 
COVID-19 will not continue beyond this study. 
7 Discontinuation of Study Intervention and Participant Discontinuation 
7.1 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 the Day 14 and Day 28 safety follow-ups. See the SoA 
(Table 1-1) for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
Study intervention will be permanently discontinued prior to 10 days if the participant: 
• Improves to level 1 or 2 of the modified WHO ordinal scale; 


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• Progresses to a level > 4 of the modified WHO ordinal scale. 
Additionally, study intervention should be permanently discontinued in the following 
circumstances: 
1. Discontinuation of study intervention for abnormal liver tests should be considered if the 
Investigator believes that it is in best interest of the participant. The development of 
alanine aminotransferase (ALT) ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct 
bilirubin) or ALT ≥3 × ULN and international normalized ratio (INR) >1.5, if INR is 
measured, which may indicate severe liver injury (according to Hy’s Law), must be 
reported as an SAE and the study intervention discontinued. 
2. If, as part of normal clinical follow-up, a clinically significant change in ECG is 
identified, the Investigators should exercise their clinical judgement to decide whether 
continuing study intervention administration is in the best interest of safety of the 
participant. 
3. AE/SAE if the Investigator believes that it is in best interest of the participant, including 
the following: 
• Development of significant bronchospasm * or worsening of cough that is not tolerated 
by the participant and leads to immediate discontinuation of the nebulization. 
• Progressive COVID-19 requiring initiation of non-invasive or invasive ventilation or high 
flow oxygen. 
• Development of mHb level above 3%. 
• Inability to safely continue receiving study intervention due to compromised respiratory 
status while off supplemental oxygen and receiving nebulized therapy (manifest by drop 
in SpO2, increased respiratory rate or clinical other findings). 
Refer to the SoA (Table 1-1) for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
* Inhaled citric acid and inhaled mannitol provoke bronchospasm in patients with bronchial 
hyperresponsiveness in a dose dependent pattern. Although the concentrations of mannitol and 
citric acid are below the provocative dose and concentration inducing bronchospasm, there is a 
theoretical risk that a participant may develop acute bronchospasm during the use of RESP301. 
Participants should therefore be monitored during RESP301 administration. In case of clinical 


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intolerance or saturation decrease, nebulization should be immediately discontinued (see 
Section 7.2). Further clarification of the differences in signs and symptoms for acute 
bronchospasm and COVID-19 progression are provided in Table 7-1. 
Table 7-1 
Differences in Signs and Symptoms for Acute Bronchospasm and 
COVID-19 Progression 
 
Acute bronchospasm related to 
inhaled bronchial irritant  
Progression of COVID-19 lung 
disease to acute respiratory 
failure  
Mechanism 
Acute contraction of bronchial muscles 
resulting in bronchial obstruction 
resulting in increased ventilatory load 
Cytokine storm resulting in alveolar 
damage resulting in gas transfer 
impairment 
Onset 
Within minutes (<15 minutes) 
following inhalation (no late phase 
since it is not an allergic IgE mediated 
reaction) 
Within hours or days and not related to 
nebulization  
Clinical auscultatory signs 
Wheezing (almost all cases) 
Bilateral rales (inconstant) 
Patient history 
Asthma or respiratory allergy  
Age > 65 years, increased BMI, high 
blood pressure, cardiac diseases, etc. 
Reversibility with inhaled 
beta mimetics 
Within minutes 
No 
Abbreviations: BMI=body mass index; IgE=immunoglobulin E. 
 
7.2 Temporary Discontinuation of Study Intervention 
Brief temporary discontinuation of study intervention is permitted during the study, providing 
inhalation of study intervention is completed within 20 minutes.  
Study intervention should be temporarily discontinued in the following circumstance: 
1. Clinical intolerance to nebulization. 
An individual administration of study treatment will be stopped, and supplemental 
oxygen resumed, if threshold limits of SpO2 89% or heart rate 120 beats/min (or as 
indicated by the Investigator) are exceeded (see Sections 4.2 and 8.1.2).  
The participant may continue with subsequent doses if the Investigator judges that the benefit / 
risk ratio remains positive. In this case, the instruction to continue should be duly recorded in the 
participant’s hospital file and the subsequent nebulization should be closely monitored.  
Refer to Section 6.1 for information on staggered dosing in the first 10 participants. 


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7.3 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, behavioral, 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. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
At the time of discontinuing from the study, if possible, an early discontinuation assessment 
should be conducted, as shown in the SoA (Table 1-1). 
7.4 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. The following actions must be taken if a participant cannot be contacted at Day 14 or 
Day 28: 
• 
The site must attempt to contact the participant and counsel the participant on the 
importance of maintaining the assigned schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• 
In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant (where possible, 
three telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record/CRF. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
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. 


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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 utilized 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 1-1). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 20 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Informed Consent 
Informed consent must be documented according to Appendix 1, Section 10.1.3.  
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or designee to ensure 
that the participant qualifies for the study. 
Participant Identification Card 
All participants will be given a participant identification card identifying them as participants in 
a research study. The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency. The Investigator or qualified designee will 
provide the participant with a participant identification card immediately after the participant 
provides written informed consent. At the time of intervention allocation/randomization, site 
personnel will add the intervention/randomization number to the participant identification card. 
Medical History 
A medical history will be obtained by the Investigator or qualified designee. The medical history 
will collect all active conditions and any condition diagnosed that the Investigator considers to be 


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clinically relevant. Details regarding the disease for which the participant has enrolled in this 
study will be recorded separately and not listed as medical history. 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 3 months prior to screening. This should include a 
history of hypertension medication, in particular angiotensin-converting enzyme inhibitors and 
angiotensin receptor blockers. 
The Investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the last assessment. Concomitant medications will be recorded on an 
ongoing basis during the study (or longer if related to an SAE). 
8.1 Efficacy Assessments 
8.1.1 
Modified WHO Ordinal Scale 
A modified WHO ordinal scale will be used for consistency with the recent study of 
lopinavir-ritonavir in adults hospitalized with severe COVID-19 (Cao et al, 2020), to record the 
participant’s status at the time of assessment. The modified WHO ordinal scale includes the 
following levels: 
1. Not hospitalized, no limitations on activities; 
2. Not hospitalized, limitation on activities; 
3. Hospitalized, not requiring supplemental oxygen; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 
6. Hospitalized, on invasive mechanical ventilation or extra corporeal membrane 
oxygenation (ECMO); 
7. Death. 
8.1.2 
Pulse Oximetry 
Pulse oximetry measurements will be performed to evaluate SpO2 as outlined in the SoA 
(Table 1-1) and in accordance with the site standard operating procedures, on a medical-grade 
medical device. Measurements will be taken with a probe on fingertip or earlobe and recorded as 


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percent oxygenated hemoglobin. Supplemental oxygen used at the time of assessment and 
method of oxygen delivery will be collected and documented along with the SpO2. 
Prior to administration of study intervention, supplemental oxygen will be held for at least a 
minute and SpO2 checked in order to ensure participant may safely receive the study 
intervention. For safety reasons, since due to the current pandemic it cannot be guaranteed that 
study intervention will be consistently administered under direct medical supervision, the study 
Investigators should provide study personnel who are able to monitor the participant and their 
SpO2 and ensure that should it decrease to a threshold, this would trigger immediate 
discontinuation. By default, unless overruled by the study Investigator, this SpO2 threshold is set 
to 89%. This threshold should be entered into the saturation monitoring device to trigger an 
alarm during nebulization. 
FiO2 will be measured per site standard practice and recorded in the eCRF. The device used to 
administer oxygen should also be recorded. 
8.1.3 
National Early Warning Score (NEWS) 2 
The NEWS 2 will be measured prior to study intervention in the morning according to the SoA 
in Table 1-1. 
The NEWS is based on a simple aggregate scoring system in which a score is allocated to 
physiological measurements, already recorded in routine practice, when patients present to, or 
are being monitored in hospital (RCP, 2012). Six simple physiological parameters form the basis 
of the scoring system: 
1. Respiration rate 
2. Oxygen saturation 
3. Systolic blood pressure 
4. Pulse rate 
5. Level of consciousness or new confusion* 
6. Temperature 
*The patient has new-onset confusion, disorientation and/or agitation, where previously their 
mental state was normal – this may be subtle. The patient may respond to questions coherently, 
but there is some confusion, disorientation and/or agitation. This would score 3 or 4 on the 
Glasgow Coma Scale (rather than the normal 5 for verbal response), and scores 3 on the NEWS 
system. 


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A score is allocated to each parameter as they are measured, with the magnitude of the score 
reflecting how extremely the parameter varies from the norm (zero for ‘normal’; maximum 
score 3). The score is then aggregated. The score is increased by 2 points for people requiring 
supplemental oxygen to maintain their recommended oxygen saturation. This is a pragmatic 
approach, with a key emphasis on system-wide standardization and the use of physiological 
parameters that are already routinely measured in National Health Service (NHS) hospitals and 
in prehospital care, recorded on a standardized clinical chart – the NEWS 2 chart (Refer to 
Appendix 2: The NEWS 2 Scoring System). 
Reproduced from: Royal College of Physicians. National Early Warning Score (NEWS) 2: 
Standardising the assessment of acute-illness severity in the NHS. Updated report of a working 
party. London: RCP, 2017 (RCP, 2017). 
8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1-1). 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
head/ear/eyes/nose/throat, cardiovascular, respiratory, gastrointestinal, lymphatic, skin and 
neurological systems. Height (screening only) and weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
8.2.2 
Vital Signs 
Vital signs to be collected as outlined in the SoA (Table 1-1) and include body temperature, heart 
rate, blood pressure, and respiratory rate. 
Body temperature will be assessed per the local practice (temporal or otic are preferred sites), 
and site will be recorded. Pulse rate, respiratory rate, and blood pressure will also be assessed per 
site SOC. Where possible the same methods should be used throughout the study for an 
individual participant. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). During study 
intervention administration, an alarm threshold should be set for heart rate at 120 beats/min (or 
as indicated by the Investigator), as outlined in the SoA (Table 1-1). 


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Vital signs (to be taken before blood collection for laboratory tests) will be measured after the 
participant has been sitting for 5 minutes. 
8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (Table 1-1) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals for 
local reading.  
8.2.4 
Clinical Safety Laboratory Assessments 
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA 
(Table 1-1) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically abnormal during participation in the study 
or within 4 days after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator 
or Medical Monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, where possible, and the 
Sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the Laboratory Manual and the SoA (Table 1-1). 
• 
If laboratory values from laboratory assessments not specified in the protocol and 
performed at the institution’s local laboratory result in the need for a change in 
participant management or are considered clinically relevant by the Investigator (e.g., 
are considered to be an SAE or an AE), then the results must be recorded in the CRF. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 4. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 


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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 AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue the study intervention (see Section 7). 
8.3.1 
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 1-1). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
Investigator becoming aware of the SAE, as indicated in Appendix 4. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obliged to actively seek AEs or SAEs after the conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 
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 4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.3.3 
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, stabilization, 
until the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.4). Further information on follow-up procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Appendix 4) 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. 


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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 IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
All women, including women of childbearing potential are allowed in the study. Urine pregnancy 
test will be performed on female participants of childbearing potential and pregnant females at 
screening. Females who are not of child bearing potential do not need to undergo a screening 
pregnancy test. 
Pregnant females will be followed to determine the outcome of the pregnancy: 
• The Investigator will collect any follow-up information on the participant and the neonate 
and the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of the pregnancy will be reported, regardless of fetal state (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered to be SAEs. Any post-study 
pregnancy-related SAE considered reasonably related to study intervention by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting. 


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8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
The following disease-related events (DREs) are common in participants with COVID-19 and 
can be serious/life-threatening: 
• 
Fever 
• 
Cough* 
• 
Dyspnea* 
• 
Asthenia 
• 
Loss of sense of taste and smell 
* A cough or dyspnea episode related to study intervention administration does not meet the 
definition of a DRE and should be reported as an AE. 
Because these events are typically associated with the disease under study, they will not be 
reported as AEs. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an SAE (instead of a DRE): 
• 
The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant. 
OR 
• 
The Investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.3.7 
Adverse Events of Special Interest (Not Applicable) 
No AEs of special interest are defined for this study. 
8.3.8 
Medical Device Deficiencies (Not Applicable) 
The medical device to be used in this study is a vibrating mesh nebulizer 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. 
8.4 Tokenization (Optional) 
Tokenization is the process of converting a piece of data into a random string of characters 
known as a token. Tokenization protects sensitive data by substituting non-sensitive data. The 


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token serves merely as a reference to the original data, but cannot be utilized to determine those 
values. The advantage of tokens is that there is no mathematical relationship to the real data that 
they represent. The real data values cannot be obtained through reversal, and hence, a breach 
renders the information invaluable. Tokens are being increasingly used to secure varying types of 
sensitive information. In particular, personal identifiable information such as healthcare 
information, email addresses and account numbers are such examples. From a security 
perspective, tokenization significantly reduces risk based on the fact that sensitive data cannot be 
breached if it is not there in the first place. 
Tokenization applies only to US participants who agree and sign the optional ICF. The piece of 
personal data needed to generate the token will be collected to create a unique, de-identified 
token. This token would be instrumental to enrich and aggregate other study participants’ data 
coming from different sources for the purpose of future research. The benefit of linking data in 
general, is that the data set that is created can be used to answer a variety of healthcare- and 
therapy-related questions that could not otherwise be answered through conventional means. 
8.5 Treatment of Overdose (Not Applicable) 
There is no risk of overdose. 
8.6 Pharmacokinetics (Not Applicable) 
Pharmacokinetic parameters are not evaluated in this study. 
8.7 Pharmacodynamics (Not Applicable) 
Pharmacodynamic parameters are not evaluated in this study. 
8.8 Genetics (Not Applicable) 
Pharmacogenomics are not evaluated in this study. 
8.9 Biomarkers (Not Applicable) 
Biomarkers are not evaluated in this study. 
8.10 Medical Resource Utilization and Health Economics (Not Applicable) 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 


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9 Statistical Considerations 
9.1 Statistical Hypothesis 
RESP301 reduces the rate of progression to level 5 and above in the modified WHO ordinal 
scale in COVID-19 (see Section 8.1.1). 
This represents a composite endpoint of (i) death (level 7), (ii) hospitalized, on invasive 
mechanical ventilation or ECMO (level 6), or (iii) hospitalized, on non-invasive ventilation or 
high-flow oxygen devices (level 5). 
9.2 Sample Size Determination 
A total of 300 hospitalized participants with confirmed COVID-19 will be randomized 2:1 to 
receive RESP301+SOC (200 participants) or SOC alone (100 participants). 
The comparison between the treatment arms for the primary endpoint will have approximately 
80% power and alpha level 0.025 (one-sided) to demonstrate significant reductions (15% versus 
30%) of the primary endpoint between RESP001+SOC and the Control arm (SOC), a 50% 
relative reduction for the proportion of participants who progress to level >4 (see definition of 
the primary endpoint). 
Two interim analyses are planned (see Section 9.5 for details): 
1. The first IDMC interim analysis will take place after the first 60 participants have 
completed Day 10 of the study to evaluate whether the study can be stopped for futility 
based on change from baseline in room air SpO2. For a final decision to stop the study for 
futility the results on other endpoints will be considered as well. 
2. The second interim analysis will take place after 150 participants have completed Day 14 
post-randomization based on event rate for the primary endpoint. The purpose of the 
second interim analysis will be futility as well as a potential sample size re-estimation in 
case the actual results differ from the original assumptions. 
In addition to the review of efficacy data, safety will be assessed at each of the interim analysis 
by the IDMC. Further details are provided in Appendix 5. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 


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Table 9-1 
Populations for Analysis 
Population (Analysis Set) 
Description 
Intent-To-Treat (ITT) 
Population 
The ITT Population will include all randomized participants. The 
ITT participants will be analyzed according to randomized 
treatment, irrespective of the actual treatment received. 
Participants who withdraw from treatment early will be followed 
for the assessment of the Day 14 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 randomized participants who inhale any 
amount of study intervention or are randomized to the control 
arm. The SP will be analyzed according to the actual treatment 
received. This set will be used for the safety analyses. 
 
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 primary efficacy endpoint. 
9.4 Statistical Analyses 
Below is a description of planned statistical analyses. Further details are presented in the 
Statistical Analysis Plan (SAP). 
9.4.1 
General Considerations 
All statistical analyses will be conducted using SAS, Version 9.4 or later. Baseline characteristics 
will be summarized by treatment arm. For continuous measures the mean and standard deviation 
(SD) will be summarized. Categorical variables will be described by the proportion in each 
category. In addition, 95% confidence intervals (CIs) will be computed as indicated. 
All the categorical variables including the primary endpoint will be summarized by treatment 
with the numbers and percentages of the participants. Treatment difference will be tested using a 
Cochran–Mantel–Haenszel test stratified by 1) country and 2) participant’s clinical status at 
Baseline. For the categorical endpoints, relative risk and its 95% CI will be presented. 
All of the continuous variables, including the changes from Baseline, will be summarized by 
treatment with the means, SD, medians and the ranges. The mixed model with repeated 


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measurements /analysis of covariance model with treatment, country, participant’s clinical status 
at Baseline and visit as the model term, and Baseline value as the covariate will be used to test 
for the significance of the treatment difference. Least square means, standard errors, 95% CIs 
and p-values will be presented. 
Time to event endpoints will be analyzed using the Cox Proportional Hazard model with 
treatment, participant’s clinical status at Baseline and country as the model term. The hazard 
ratio of RESP301+SOC versus SOC will be presented along with 95% CI and p-value from the 
model. The Kaplan-Meier curves of the time to events will be presented by treatment for each 
applicable endpoint. 
Handling of missing data 
If participants are discharged from the hospital prior to Day 14 due to improvement of the 
clinical status and their status on Day 14 cannot be obtained, their status on Day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. Depending on the 
reasons for missing data on the primary endpoint up to Day 14, additional sensitivity analyses 
will be performed. Further details on handling on missing data will be provided in the SAP. 
9.4.2 
Primary Endpoint 
The primary endpoint is the proportion of participants who progress to level >4 of the modified 
WHO ordinal scale due to COVID-19 by Day 14. 
9.4.3 
Secondary Endpoint(s) 
The key secondary endpoints are: 
1. Change from baseline on the modified WHO ordinal scale at each visit up to Day 28 
2. Change in room air SpO2 from baseline over time 
3. Change in NEWS 2 symptom score from baseline over time 
4. Time to improvement to a lower level (<4) of the modified WHO ordinal scale 
5. Time to progression to a higher level (>4) of the modified WHO ordinal scale 
Additional secondary endpoints are: 
1. Time to hospital discharge 
2. Incidence of mortality by Day 28 


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will be summarized by study day. If more than one laboratory result is reported per study visit 
per parameter, the last non-missing result will be selected for change from Baseline analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the Investigator. The number of participants with a non-missing 
result, the number and percentage of participants with a clinically significant result less than the 
lower limit of normal, non-clinically significant result more than the ULN, and clinically 
significant result more than the ULN will be summarized by study visit. If more than one 
laboratory result is reported per study day per parameter, the result yielding the most severe 
classification will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study day per parameters, the result yielding the 
most severe classification will be selected for analysis.  
Participants who had urine pregnancy test at screening and the results will be listed. 
Participants with clinically significant abnormal laboratory test results will be listed. This listing 
will include all results of the laboratory parameter that was abnormal and determined to be 
clinically significant by the Investigator for a participant across study visit. 
9.4.5.3 
Vital Signs 
Baseline is defined as the last non‑missing value obtained in screening and prior to the first 
exposure to study drug. Actual values and changes from Baseline in vital signs will be 
summarized by study day and study time point. All vital sign data will be presented in patient 
listings. 
Vital sign values will be classified according to the clinical significance as determined by the 
Investigator. The number of participants with a non-missing result, the number and percentage of 
participants with a non-clinically significant result, and clinically significant result will be 
summarized by study visit and study time point. If more than one vital sign result is reported per 
study day and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis. 
Participants with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the Investigator to be clinically 
significant for a participant across study time points. 


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9.4.5.4 
Physical Examination 
Abnormal physical examination findings will be listed. 
9.4.6 
Other Analyses 
Other analyses may be added to the SAP as applicable. 
9.5 Interim Analyses 
Two interim analyses will be performed.  
1. The first analysis will be conducted when about 60 participants (40 participants in the 
RESP301+SOC arm and 20 participants in the SOC arm) have completed the Day 10 
assessment. The purpose of this analysis is to evaluate efficacy of RESP301 with the 
application of a futility criterion based on the results on SpO2 change from baseline on 
Day 10. The following futility criterion will be used for this first interim analysis: 
If the difference in the percentage of participants with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints 
will be considered as well.  
As no other modification of the study at the time of the first interim analysis is considered, 
no adjustment of the alpha level is required. 
2. The second interim analysis will be conducted after 150 participants (100 participants in 
the RESP301+SOC arm and 50 participants in the SOC arm) have completed the Day 14 
assessment. The purpose of this analysis is the assessment of futility or a sample size 
re-estimation in case the actual results differ from the original assumptions for the power 
calculations of the study, related to the percentage of participants meeting the primary 
endpoint in the control arm and/or the relative treatment benefit achieved in the 
RESP301+SOC arm compared to the SOC arm. 
To account for the multiple testing due to the second interim analysis an adjustment for 
the type I error alpha will be applied using the Haybittle-Peto approach which would 
spend one sided alpha=0.0005 at the second interim analysis and leave one-sided nominal 
alpha of 0.0249 for the final analysis. The futility criterion for the second interim analysis 
will be based on the conditional power (CP) for the final results based on the assumption 
that the remainder of the study will follow the same trend as observed in the interim 
analysis. If CP at the time of the second interim analysis is less than 20% consideration 


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will be given to stop the study for futility. At the same time sample size re-estimation will 
be performed to achieve 80% power at the end of the study. The methodology for the 
adjustment and the procedure to maintain the type I error level will be described in greater 
detail in the SAP. 
Detailed information, including the boundaries futility and characteristics for the sample size 
re-estimation at the time of the interim analyses will be provided in the SAP and Data 
Monitoring Committee (DMC) Charter. Further details are also provided in Appendix 5. 
9.6 Data Monitoring Committee (DMC) 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study. The IDMC will 
meet to review after 10 and 20 participants have completed as well as at the time of the interim 
analyses (ie, after 60 and 150 participants have completed; see Section 9.5). 
Due to the urgency of the pandemic, if participants become eligible for the study during the 
IDMC review of the first 10 participants then they may be recruited. However, their 
administration of RESP301 will be staggered in the same way as for the first 10 participants (see 
also Section 6.1). Once the IDMC review has been completed, and provided there are no safety 
concerns, further recruitment will continue as per protocol. The Sponsor and CRO confirm that 
the report from the IDMC will be sent in a timely manner to all participating sites and 
investigators. 
The detailed procedures and criteria of the interim analyses will be described in the DMC 
Charter. 


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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 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. 
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. 
10.1.2 Financial Disclosure 
Information on financial disclosure can be found in the Investigator Site File. 
10.1.3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. 


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Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
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 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
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 currently enrolled in 
the study. 
For US participants who agree to tokenization, a separate optional ICF will be provided. 
10.1.4 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 authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Data Protection for Tokenization information is addressed in the separate optional ICF (for US 
participants only). 


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10.1.5 Committees Structure 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study (see Sections 9.5 
and 9.6). 
10.1.6 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. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations [CROs]). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized 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. 


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• All data generated by the site personnel will be captured electronically at each study 
center using eCRFs. Data from external sources (such as laboratory data) will be 
imported into the database. Once the eCRF clinical data have been submitted to the 
central server at the independent data center, 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. Once all 
source data verification is complete and all queries are closed, the monitor will freeze the 
eCRF page. 
• 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. 
10.1.7 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. 
10.1.8 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 visit 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. 


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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 
10.1.9 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 multicenter 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. 
10.1.10 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). In the US: Following approval, the protocol 


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amendment(s) will be submitted to the Investigational New Drug application under which the 
study is being conducted. 
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. 
10.1.11 Liability and Insurance 
10.1.11.1 Access to Source Data 
Access to source data is described in the Clinical Site contract. 


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10.2 Appendix 2: The NEWS 2 Scoring System 
Chart 1: The NEWS 2 scoring system 
 
Abbreviations: CVPU: C=new onset confusion, disorientation or agitation, V=responds to voice, P=responds to 
pain, U=unresponsive; SpO2=oxygen saturation. 
Source: Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of 
acute-illness severity in the NHS. Updated report of a working party. London: RCP, 2017. 
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2 
 










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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
(Applies only during the safety follow up period for participants who may have 
been discharged during the treatment period, ie, between Day 1 and Day 10) 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are considered 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective intervention of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive intervention 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 










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However, as far as possible all points on the SAE form should be covered in the initial report, or 
the completed SAE form itself must be emailed or faxed to the Parexel Safety Services. In 
addition, the event must be documented in the electronic CRF/EDC system. 
After receipt of the initial report, Parexel Safety Services will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the event. 
Parexel will be responsible for all information processing and reporting according to local legal 
requirements. Where necessary, Investigators will inform regulatory authorities in their own 
countries. 
 


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10.5 Appendix 5: Statistical Design Considerations 
10.5.1 Some General Design Considerations 
1. Binary primary endpoint: progression to critical stage/death up to Day 14 
• to be analyzed by a Cochran-Mantel-Haenszel (CMH) stratified for the factors used in 
the stratified randomization 
• subjects who withdraw from study treatment will be followed up until their primary 
endpoint outcome is known (i.e., up to Day 14 or progression to critical stage/death, 
whatever is first) 
• it is, therefore, not clear what current protocol synopsis text could mean: If subjects 
are discharged from the hospital prior to day 14 due to improvement of the clinical 
status and their status on day 14 cannot be obtained, their status on day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. and what 
the implications on statistical study characteristics could be. Further discussion is 
needed.  
2. Timing of the two planned interim analyses with stopping options is stated as 
There are 2 interim analyses planned, the first interim analysis after the first 60 participants 
have completed day 10 of the observation period … and a second interim analysis after 150 
participants have completed day 14 of the observation period. 
With the current text for the timing of the first interim analysis, it is not clear how many 
subjects will have been randomized at least 14 days prior to the interim data cut-off date and 
can therefore provide data for the binary primary endpoint (“progression to critical 
stage/death up to Day 14”).  
For such a binary endpoint, Parexel does not recommend including any participant 
randomized less than 14 days prior to the interim data cut-off date (note this would be 
different to a study with a time-to-event endpoint) as 
• for such participants not yet progressed, the outcome up to Day 14 is unknown and 
should not be imputed as “not progressed up to Day 14” 
• for such participants progressed prior to Day 14, the outcome is known but their 
inclusion would bias the estimation of progression probability up to Day 14 in a 
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In order to set up the adaptive group-sequential study design, the following assumptions have 
been used: 
• first interim analysis: a total of ≈ 39 participants randomized at least 14 days prior to 
data cut-off date 
• second interim analysis: a total of ≈ 50% of the initially planned number of 
participants randomized at least 14 days prior to data cut-off date. 
3. Non-binding DMC guidance for stopping the study for futility at the first interim analysis 
is stated as: 
If the difference in the percentage of participants with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, a benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints will 
be considered as well. 
As the main futility stopping criterion is based on improvement in SpO2 (and not on the 
primary efficacy endpoint), this first interim analysis will be “ignored” in these statistical 
considerations for an adaptive group-sequential design. We may revisit the first interim 
analysis at a later point in time when more information is available.  
4. Non-binding DMC guidance for stopping the study for futility at the second interim 
analysis stated as:  
The futility criterion for the second interim analysis will be based on the conditional power 
(CP) for the final results based on the assumption that the remainder of the study will follow 
the same trend as observed in the interim analysis. If CP at the time of the second interim 
analysis is less than 20% consideration will be given to stop the study for futility. 
5. Current DMC guidance for stopping the study for superior efficacy at the second interim 
analysis is stated as: 
To account for the multiple testing due to the second interim analysis an adjustment for the 
type-I-error probability will be applied using the Haybittle-Peto approach with one sided 
alpha=0.0005 at the second interim analysis and leave one-sided nominal alpha of 0.0249 
for the final analysis. 
6. For initial sample size calculation, the following additional assumptions / features from 
the protocol have been used 
• progression probability up to Day 14 for Standard of Care (SOC): 30% 


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• progression probability up to Day 14 for RESP301+SOC: 15%  
• desired power assuming the alternative hypothesis stated above: 80% 
• 2:1 randomization 
7. Method for adaptation of the sample size based on the second interim analysis data is 
stated as 
A sample size re-estimation will be performed to achieve 80% conditional power at the end 
of the study. The methodology for the adjustment and the procedure to maintain the type-I-
error level will be described in greater detail in an appendix to the protocol.  The maximum 
increase of the sample size will be limited to a total number of 600 randomized subjects.  
Parexel has put a suggestions with some fictitious interim data for illustration in 
Section 10.5.3; that section also illustrates by simulations the Cui/Hung/Wang (CWH) 
approach using a weighted (weights fixed at the design-stage) test for the final analysis 
versus the Chen/DeMets/Lan (CDL) approach without such weights at the final analysis. 
 
 


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10.5.2 General Design Characteristics 
Parexel proposes to base non-binding futility stopping criteria on conditional power criteria. 
Conditional power (CP) is the conditional probability for achieving statistically significant 
superiority of RESP301+SOC over SOC at the final analysis, given the interim results and 
calculated by assuming the interim estimates to be the true distribution parameters for the 
remaining part of the study (an alternative would be predictive power (PP), a Bayesian version of 
CP where prior distributions and observed interim results are combined to obtain the probability 
for achieving statistically significant superiority of gimsilumab over placebo at the final 
analysis).  
Randomization 2:1 
Group-Sequential Design 
1st Interim Analysis (IA) 
N ≈ 39 for D14 
2nd IA 
≈ 50% for D14 
Futility criterion 1st IA 
Based on SpO2 
Futility criterion 2nd IA 
Superior efficacy criterion 2nd IA 
CP < 4% 
p < 0.0005 
Total sample size required for 80% power 
300 
Futility stopping probability at 2nd IA under 
“No effect” 
1st IA: NA 
2nd IA: 70% 
Futility stopping probability at 2nd IA under 
“Planned effect 30% vs 15%” 
1st IA: NA 
2nd IA: 6% 
Superiority stopping probability at 2nd IA 
under “Planned effect 30% vs 15%” 
10% 
Superiority stopping probability at 2nd IA 
under “30% vs 10%” 
28% 
 


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10.5.3 Adaptive Sample Size Re-Estimation 
Another objective of the 2nd interim analysis is to re-estimate the sample size based on the 
unblinded interim results.  
Proposed procedure at 2nd interim analysis (planned to include approximately 150 subjects) 
• unblinded analysis of the primary efficacy endpoint (“progression to level >4 of modified 
WHO ordinal COVID-19 scale by Day 14” as a binary endpoint)  
• calculation of conditional power (CP) given the interim results and calculated by assuming 
the interim estimates to be the true distribution parameters for the remaining part of the study 
• if CP < 4%: recommend early stop for futility 
• if one-sided p-value < 0.0005: recommend early stop for superior efficacy 
• if 50% < CP < 80% and one-sided p-value ≥ 0.0005:  
o continue the study with an increased total sample size N*, so that CP with a 
total of N* subjects is increased to 80%, same value as the (unconditional) 
desired power in the study design 
o N*, however, is limited to 600 (which is twice the original sample size 300) 
• if 4% ≤ CP ≤ 50%: continue the study without a change in sample size (otherwise, the 
sample size would need to be increased too much or the maximum sample size of 600 
would not be sufficient to come close to a CP of 80%. 
The table on the next page illustrated the proposed procedure for a number of possible results 
observed at the 2nd interim analysis.  
 
 


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Table with examples for the adaptive sample size procedure described above using the 
Cui/Hung/Wang (CHW) approach using a weighted (fixed weights determined by the stage-wise 
sample sizes planned at the design-stage) test for the final analysis: 
2nd IA results with n=150 
subjects (50 for SOC, 
100 for RESP301+SOC 
CP under 
observed trend 
for planned 300 
Total sample size 
required for CP 80% 
under observed trend 
CP under observed 
trend if total sample 
size capped by 600 
15 (30%) 
5 (5%) 
p < 0.0005   early stop for superior efficacy 
15 (30%) 
10 (10%) 
99% 
Not applicable 
Not applicable 
15 (30%) 
15 (15%) 
90% 
Not applicable 
Not applicable 
15 (30%) 
18 (18%) 
66% 
393 
Not applicable 
15 (30%) 
19 (19%) 
55% 
483 
Not applicable 
15 (30%) 
21 (21%) 
34% 
[798] 
[67%] 
15 (30%) 
26 (26%) 
3.99% 
Early stop for futility 
12 (24%) 
10 (10%) 
92% 
Not applicable 
Not applicable 
12 (24%) 
12 (12%) 
77% 
321 
Not applicable 
12 (24%) 
14 (14%) 
54% 
498 
Not applicable 
12 (24%) 
15 (15%) 
42% 
[646] 
[77%] 
12 (24%) 
18 (18%) 
14% 
[1800] 
[31%] 
12 (24%) 
20 (20%) 
2.6% 
Early stop for futility 
10 (20%) 
8 (8%) 
85% 
Not applicable 
Not applicable 
10 (20%) 
10 (10%) 
64% 
412 
Not applicable 
10 (20%) 
11 (11%) 
50.4% 
534 
Not applicable 


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10 (20%) 
13 (13%) 
26% 
[1014] 
[55%] 
10 (20%) 
15 (15%) 
10% 
[2460] 
[23%] 
10 (20%) 
18 (18%) 
1.4% 
Early stop for futility 
Quantities in [ ] indicate theoretical values as sample size would not be increased per the 
currently proposed adaptive design.  
10.5.4 Overall Adaptive Design Performance 
Finally, the Cui/Hung/Wang (CHW) approach is compared to the Chen/DeMets/Lan (CDL) 
approach without pre-defined fixed weights for the final analysis (which is valid as sample size 
may only be increased if CP (obtained under observed trend) at the second interim analysis 
exceeds 50%).  
All the results below are for the group-sequential design with adaptive sample size re-estimation 
procedure as described in previous sections and based on 10.000 simulated trials each. 
Scenario 1: true progression probabilities are 30% (SOC) and 15% (RESP301+SOC) 
Scenario 2: true progression probabilities are 24% (SOC) and 14% (RESP301+SOC) 
Scenario 3: true progression probabilities are 30% (SOC) and 10% (RESP301+SOC) 
Scenario 4: true progression probabilities are 24% (SOC) and 20% (RESP301+SOC) 


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10.6 Appendix 6: Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
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 
CP 
Conditional power 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
CRO 
contract research organization 
CV 
cardiovascular 
DMC 
Data Monitoring Committee 
DRE 
disease-related events 
ECG 
electrocardiogram 
ECMO 
Extra corporeal membrane oxygenation 
EDC 
electronic data capture 
EoS 
End of study 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
interactive voice response system 


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IWRS 
interactive web response system 
LFT 
Liver function test 
mHb 
Methemoglobin 
NEWS 
National Early Warning Score 
NHS 
National Health Service 
NO 
Nitric oxide 
NO2 
Nitrogen dioxide 
NOx 
Oxide of nitrogen 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
PP 
Per protocol 
PT 
Prothrombin time 
QTcF 
QT interval corrected using Fridericia’s formula 
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 
Three times daily 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 
 
 


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10.7 Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.7.1 Protocol Amendment 1.0, 05 Jun 2020 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment: 
The original protocol was updated to include important safety guidelines for study intervention 
administration for the first 10 participants (ie, up to the first independent data monitoring 
committee [IDMC] safety review). It was also updated to align with the IB Version 2.0, dated 
27 May 2020. Other changes, with brief rationale, are summarized in the following table. 
Section # and Name 
Description of Change 
Brief Rationale 
Global change 
Device name Philips 
InnoSpire Go was replaced 
with generic reference to a 
vibrating mesh nebulizer. 
The decision was made to keep 
the device generic for flexibility. 
Section 1.1 Synopsis 
and Section 4.1 Overall 
Design 
Clarified that participants 
were (male or female) adults. 
Wording of study design also 
clarified to include study 
intervention and minor 
clarification to text for 
screening period. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 1.1 Synopsis, 
Section 4.1 Overall 
Design, Section 7.1, 
Discontinuation of 
Study Intervention 
Bullets specifying reasons for 
permanent discontinuation 
updated to reflect content of 
Section 7.1. 
Correction, for consistency 
across the protocol. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema 
Dose of study intervention 
corrected to 6.0 mL. Minor 
clarifications added in 
footnotes. 
Correction. 
Section 1.2 Schema 
Footnote 2 updated. 
Text added to make it clear that 
participants will be allowed 
sufficient time to consider their 
participation in the study. 
Section 1.1 Synopsis, 
Section 1.3 Schedule of 
Activities (SoA), 
Section 2.2.1 Risk 
Assessment, Section 4.1 
Overall Design, and 
Section 6.1 Study 
Intervention 
Administered 
The following statement was 
added: A staggered dosing 
approach will be used for the 
first 10 participants (up to the 
first IDMC safety review). 
RESP301 will be administered 
by intermittent inhalation to 
monitor the tolerability and 
response to RESP301 (see 
Sections 6.1 and 9.6). 
The time gap between 
consecutive doses in the 
3 times per day (TID) 
schedule was updated to “at 
least 6 hours” from “at least 
4 hours”.  
Updated to align with the 
Investigator Brochure (IB) 
Version 2.0, dated 27 May 2020. 
Section 1.3 SoA, Section 
5.2 Inclusion Criteria, 
Section 8.3.5 Pregnancy,  
Appendix 3, Clinical 
Laboratory Tests 
Addition of urine pregnancy 
test at screening. Requirement 
for all females of childbearing 
potential, including pregnant 
females, to consent to urine 
pregnancy testing at 
screening. Details of 
pregnancy follow-up 
procedures added. 
All women, including women of 
childbearing potential and 
pregnant women, are allowed in 
the study. Therefore, it is 
necessary to determine pregnancy 
status at study entry so that 
pregnant females can be followed 
to determine the outcome of the 
pregnancy. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 SoA,  
Appendix 3, Clinical 
Laboratory Tests 
Deletion of tuberculosis (TB) 
screening test. Nitrite added to 
the protocol-required 
laboratory assessments (End 
of Study [EoS] only). 
Screening TB test is not 
mandatory for this study. Nitrite 
is to be measured for participants 
who are still hospitalized at EoS. 
Section 1.3 SoA and 
Section 7.1 Permanent 
discontinuation of Study 
Intervention 
Deletion of electrocardiogram 
(ECG) testing after screening. 
Clarified that significant 
changes in ECGs would be 
identified only as part of 
normal clinical follow-up. 
Only routine ECG monitoring is 
needed for this study. 
Section 2.1 Background, 
Section 11 References 
Text deleted from end of 
paragraph 12. References no 
longer cited were removed 
from Section 11. 
Removal of text that was specific 
to the Philips InnoSpire Go 
nebulizer. 
Table 2-1, Risk 
Assessment and 
Section 11 References 
The risk assessment table was 
updated to align with the 
above changes and IB. A new 
reference (Brannan et al, 
2005) was added to Section 11 
to support additional text 
around risk of bronchospasm. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 1.1 Synopsis, 
Section 1.3 SoA, 
Section 4.1, Overall 
Design 
Visit window for Day 14 and 
Day 28 follow-up extended to 
(± 2 days). 
To allow more flexibility. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 SoA 
Footnote 2 corrected to 
include weight and exclude 
ECG. Clarified that laboratory 
testing at EoS follow up is for 
nitrite and methemoglobin 
only. 
Correction and clarification. 
Section 1.3 SoA 
Footnote 6e corrected from 
‘Recording of SpO2 * pre-
nebulization on ambient air’ to 
‘Recording of SpO2 * on 
ambient air’. 
‘pre-nebulization’ was removed 
as SpO2 measurement on ambient 
air is required for both active and 
control group. 
Section 1.3 SoA 
Footnote 7 amended to clarify 
text that is applicable to 
participants in the active arm 
only. 
Clarification. 
Section 1.3 SoA, 
Section 8.3 Adverse 
Events and Serious 
Adverse Events, 
Section 8.3.8 Medical 
Device Deficiencies, and 
Appendix 5: Medical 
Device Adverse Events 
(AEs) Adverse Device 
Effects (ADEs), Serious 
Adverse Events (SAEs) 
and Device 
Deficiencies: Definition 
and Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting 
Changes related to the 
removal of Appendix 5. 
Table 8-1 deleted. 
Appendix and table were not 
required because the nebulizer 
device used in the study is 
licensed and there is no 
requirement to collect data on the 
device. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.1 Background 
Updated to include a 
description of the three 
mechanisms of action of 
RESP301 in fighting virus 
infection, including addition 
of new figure (Figure 2–1). 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 2.2.2 Benefit 
Assessment 
Clarification added regarding 
choice of nebulizer for this 
study. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 3 Objectives and 
Endpoints 
Safety endpoint for AEs 
amended to include both 
counts and cumulative 
incidence. 
Both types of data will be 
summarized. 
Section 3 Objectives and 
Endpoints, Section 9.4.4 
Tertiary/Exploratory 
Endpoint(s) 
Exploratory endpoint: 
timepoint for change from 
baseline measurement of 
fraction of inspired oxygen 
(FiO2) changed from Day 7 to 
Day 10.  
Correction; the endpoint should 
be measured at end of treatment. 
Section 4.4 End of Study 
Definition 
The following clarification 
was added to the definition: 
“End of the study is defined as 
the last participant’s last visit 
or follow up call.” 
Clarification of definition. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 Study 
Intervention(s) 
Administered 
This section (including 
Table 6-1) was updated to 
include dosing instructions for 
the first 10 participants (ie, up 
to the first IDMC safety 
review). In the event of 
bronchospasm, rescue 
bronchodilator can be initiated 
if needed. A new figure was 
also added to clearly show the 
staggered approach 
(Figure 6-1). The TID dosage 
was also clarified as every 8 
hours with at least 6 hours 
between consecutive doses. 
Dosing Instructions were 
updated to clarify that nasal 
oxygen may be administered 
during nebulization if the 
participant is unable to 
tolerate nebulization without 
supplemental oxygen. 
Specific study drug 
administration guidelines 
(including the use of a rescue 
medication) were provided to 
monitor tolerability and response 
to RESP301 inhalation (as 
described in the risk-benefit table 
in Section 2.2.1) and to align 
with the IB, Version 2.0, dated 
27 May 2020. 
Section 6.2.1 
Preparation of Study 
Intervention Product 
Instructions for mixing the 
two solutions were updated. 
Further clarification on the 
delivered dose was added. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.1 Rescue 
Medication 
A new section was added to 
describe allowed 
bronchodilator rescue 
medication for participants 
treated before the first IDMC 
safety review (short acting 
beta agonist such as 
salbutamol/ albuterol 
according to investigational 
site standard practice for acute 
bronchospasm) 
Allowed rescue medication was 
added to minimize the risk of 
bronchospasm to participants, 
and to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 7.1 
Discontinuation of 
Study Intervention 
Rationale was added for 
additional monitoring and 
discontinuation guidance in 
case of bronchospasm. 
Table 7-1 added to provide 
additional clarification on the 
differences in signs and 
symptoms for acute 
bronchospasm and COVID-19 
progression. 
Safety guidance (including the 
use of a rescue medication) was 
updated to minimize the risk of 
bronchospasm to participants (as 
described in the risk-benefit table 
in Section 2.2.1) and to align 
with the IB Version 2.0, dated 
27 May 2020. 
Section 7.1 
Discontinuation of 
Study Intervention 
Section 7.2, Temporary 
Discontinuation of 
Study Intervention 
Subsequent subsections 
of renumbered to 
account for new 
Section 7.2. 
Heading updated to 
“Permanent” Discontinuation 
of Study Intervention. 
Text relating to temporary 
discontinuation moved to new 
Section 7.2. 
Text describing temporary 
discontinuation now moved into 
separate section for clarity and 
consistency. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Corrected statement that AEs 
and SAEs will be collected 
from signing of informed 
consent and clarified that 
SAEs will be reported within 
24 hours of the Investigator 
becoming aware of the SAE, 
to align with Appendix 4 
(previously it stated ‘from 
randomization’). Deleted 
second paragraph. 
Internal document consistency. 
Section 8.3.6 Disease-
Related Events and/or 
Disease-Related 
Outcomes Not 
Qualifying as AEs or 
SAEs 
Loss of sense of taste and 
smell added to the list of 
common DREs in participants 
with COVID-19. 
Updated in line with updated 
World Health Guidelines. 
Section 9.2 Sample Size 
Determination, 
Section 9.5 Interim 
Analyses, and 
Appendix 5, 
Section 10.5.1 Some 
General Design 
Considerations 
The timing of the interim 
analysis was changed from 
when 60 participants have 
completed the Day 7 
assessment to when 
60 participants have 
completed the Day 10 
assessment to make it 
consistent with the planned 
treatment duration and the 
SoA. 
Internal document consistency. 
Section 9.4.5.2 Clinical 
Laboratory Evaluation 
The following sentence was 
added:  
Participants who had urine 
pregnancy test at screening 
and the results will be listed. 
Updated to include pregnancy 
test data collection. 


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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 1, 
Section 10.1.3 Informed 
Consent Process, and 
Section 10.1.4 Data 
Protection 
Text added clarifying that a 
separate optional ICF will be 
provided for US participants 
who agree to tokenization. 
Added clarification that 
tokenization is for US 
participants only. 
Appendix 4, 
Section 10.4.3 
Recording of follow-up 
of AE and SAE, 
Section 10.4.4 Reporting 
of SAE 
Alignment of reporting details 
to state ‘Parexel Safety 
Services’ throughout 
appendix. Text was added to 
include paper SAE data 
collection tool. 
Internal document consistency 
and inclusion of paper SAE 
reporting data collection tool. 
Appendix 7, 
Abbreviations 
Heading number updated to 
reflect deletion of Appendix 6. 
Updated to reflect changes to 
abbreviations used in the 
document. 
Consistency. 
Section 11 References 
Five new references were 
added to support the above 
updates (Basu et al, Benz et al, 
Brannen et al, Colosanti et al, 
and Saura et al). Two 
references were deleted as 
they are no longer cited. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Whole document 
Minor language and format 
changes. 
For improved clarity and 
readability. 
 


Thirty Respiratory Limited 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
Final Amendment 2 (Version 3.0) 
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11 References 
ACRO, 2020 
Association of clinical research organizations (ACRO). Considerations to Support Clinical Trial 
Monitoring Oversight During COVID-19, 13 March 2020. 
Akerström S et al, 2005 
Akerström S, Mousavi-Jazi M, Klingstr J, Leijon M, Lundkvist and Mirazimi A. Nitric oxide 
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. 
ATS/ACCP, 2003 
American Thoracic Society, American College of Chest Physicians. ATS/ACCP Statement on 
cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003; 167(2):211-77. 
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. 
Bialek et al, 2020 
Bialek S, Boundy E, Bowen V, Chow N, Cohn A, Dowling N, et al. Severe Outcomes Among 
Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 
2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-346. 
doi:10.15585/mmwr.mm6912e2 
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. doi:10.1186/1465-9921-6-144. 
Cao et al, 2020 
Cao B, Wang Y, Wen D, Liu W, Jingli Wang, Fan G et al. A Trial of Lopinavir–Ritonavir in 
Adults Hospitalized with Severe Covid-19. N Engl J Med 2020 March 18: doi: 
10.1056/NEJMoa2001282. [Epub ahead of print] 


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Colosanti et al, 1999 
Colasanti M, Persichini T, Venturini G, Ascenzi P: S-nitrosylation of viral proteins: molecular 
bases for antiviral effect of nitric oxide. Iubmb Life. 1999; 48:25-31. 
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 
Folkerts G, Busse WW, Nijkamp FP, Sorkness R, & Gern JE. Virus-induced airway 
hyperresponsiveness and asthma. Am J Respiratory Critical Care Medicine. 1998; 157:1708-29. 
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. 
HRS, 2020 
Health Research Authority (HRS) (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. 
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(2):532-9. 
Longo et al, 2011 
Longo DL, Fauci AS, Kasper DL, Hauser, et al. Harrison's Principles of Internal Medicine. 18th 
ed. McGraw-Hill: 2011. 
Matos et al, 2020 
Matos, R., Chung, K., et al. US Department of Defense COVID-19 Practice Management Guide 
- Clinical Management of COVID-19 To Consolidate Resources and Optimize the Management 
for Patients Requiring Clinical Care During the Global COVID-19 Pandemic. US Department of 
Defense. 2020; accessed from https://www.health.mil/Reference-Center/Technical-
Documents/2020/03/24/DoD-COVID-19-Practice-Management-Guide 


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Final Amendment 2 (Version 3.0) 
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Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020 
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The 
Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases 
(COVID-19) — China, 2020. China CDC Weekly 2020; 2:113–22. 
NOXIVENT™ FDA Prescribing Information 
NOXIVENT Food and Drug Association Prescribing Information. Accessible via Website at 
https://www.praxair.com/-/media/corporate/praxairus/documents/specification-sheets-and-
brochures/industries/healthcare/rr2-full-noxivent-prescribing-
information.pdf?la=en&rev=caa0194a173a45edaeff44695b229ff9 (last accessed 16 April 2020) 
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 
nebulizer device. Nitroc Oxide. 2013; 31(Suppl 1):S41-42. 
Regev-Shoshani et al, 2013 
Regev-Shoshani G, Vimalanathan S, McMullin B, Road J, Av-Gay Y, Miller C. Gaseous 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(10):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; 54:261–72. 
Rong-Hui et al, 2020 
Rong-Hui Du, Li-Rong Liang, Cheng-Qing Yang, Wen Wang, Tan-Ze Cao Predictors of 
Mortality for Patients with COVID-19 Pneumonia Caused by SARS-CoV-2: A Prospective 
Cohort Study, Eur Respir J 2020; DOI: 10.1183/13993003.00524-2020 
RCP, 2012 
Royal College of Physicians. National Early Warning Score (NEWS): standardising the 
assessment of acute-illness severity in the NHS. Report of a working party. London: RCP, 2012. 
RCP, 2017 
Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the 
assessment of acute-illness severity in the NHS. Updated report of a working party. London: 
RCP, 2017. 


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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(2): 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. 
Simon et al, 2016 
Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, et al. Acute 
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Tucker et al, 2007 
Tucker AT, Barnes NC, Johnston A, Elston WJ, Watson D, Wilks M et al. Formulation and 
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Tucker et al, 1999 
Tucker AT, Pearson RM, Cooke ED, Benjamin N. Effect of nitric-oxide-generating system on 
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Xu et al, 2006 
Xu W, Zheng S, Dweik RA, & Erzurum SP. Role of epithelial nitric oxide in airway viral 
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Yu et al, 2019 
Yu B, Ichinose F, Bloch DB, Zapol WM. Inhaled nitric oxide. Br J Pharmacol. 2019; 
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Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of 
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395:1054–62. 
 
 




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Thirty Respiratory Limited 
Clinical Study Protocol 
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CONFIDENTIAL 
 
Final Amendment 3 (Version 4.0) 
3 of 10316 September 2020Error! Reference source not found. 
 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Amendment 3.0 
Version 4.0 
16-Sep-2020 
Amendment 2.0 
Version 3.0 
10-Jun-2020 
Amendment 1.0 
Version 2.0 
05-Jun-2020 
Original Protocol 
Version 1.0 
01-May-2020 
 
Amendment 3.0 (16-Sep-2020)  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment: 
Three protocol changes are proposed in this substantial amendment to (a) expand the inclusion 
criteria to allow enrolment also of patients in hospital with COVID-19 but not yet requiring 
supplemental oxygen, and (b) allow a minor temporary temperature excursion in the storage 
conditions of the IMP to facilitate transport from the manufacturer to the clinical site or from the 
clinical site pharmacy to the bedside, and (c) to raise the exclusionary level for methaemoglobin 
to >2%. 
During the peak of the first wave of COVID-19, there was a sharp influx of patients to hospitals 
and the vast majority of admissions were at WHO grade 4 and above – i.e. those in need of 
supplemental oxygen, or intensive care.   More recently however, as the hospital numbers have 
fallen, less severely ill patients have been admitted to hospital, with a significant proportion now 
being at WHO grade 3.  This amendment is proposed to allow the recruitment of grade 3 as well 
as grade 4 patients, reflective of the changing hospital admissions pattern.  Treating patients 
earlier in the onset of the disease should help patients and reduce the burden on Intensive 
Therapy Units and respiratory wards. 
The storage conditions for the IMP as outlined in the IMPD state that RESP301 must be stored 
below 25ºC (range 15-25ºC).  On two occasions during transport of the IMP there has been a 
slight temperature excursion; the first occasion was during transport of the IMP from the 
manufacturer to the hospital pharmacy when the temperature rose to 25.4ºC. The second 


Thirty Respiratory Limited 
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Final Amendment 3 (Version 4.0) 
4 of 10316 September 2020Error! Reference source not found. 
 
occasion was during transport from the hospital pharmacy to the ward and the temperature rose 
to 25.0ºC. On both occasions the protocol conditions were followed and the manufacturer was 
contacted and permission given to proceed. However, on the second occasion the delay resulted 
in the patient not receiving the scheduled dose. The IMP has been on stability testing at 40ºC and 
75% relative humidity and has remained completely stable for 3 months under these conditions. 
We do not wish to amend the overall storage conditions but request an amendment to allow for 
short-term temperature excursions up to 30ºC for less than 1 hour while the IMP is in transit.  
Whereas the normal range for methaemoglobin (mHb) is <1%, this does not take account of the 
role of comorbidities that might affect the mHb level. Comorbid disorders that impair oxygen 
transport, such as cardiac and respiratory conditions, can exacerbate a low level mHb (Groeper K 
et a.l South Med J 2003;96:504-509). Symptomatic low-grade methaemoglobinaemia is 
associated with certain treatments for pneumonia, chronic obstructive pulmonary disease and 
heart disease (Dunford LM et al. Biol Blood Marrow Transplant 2006;12:241-242, Skold A et al. 
South Med J 2011;104:757-761). Since many of the patients admitted to hospital with COVID-
19 may also have comorbidities that could affect the mHb level it is proposed that the exclusion 
level for mHb be raised to >2%. 
A number of non-substantial amendments were also made and are included in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial Amendment 1 
Title; 1.1; 4.1 
Change of Title to include ‘WHO 
grade 3 & 4; 
See above 
1.1 Primary Endpoint 
Also Section 3. 
9.4.2 
Previously measured progression of 
level 4 patients to > 4 ; now considers 
progression “by at least one level 
higher”. 
To handle grade 3 
entrants, as well as grade 
4, to the study.   
See above 
1.1 Secondary Endpoint 
Also Section 3 
9.4.3 
Amend secondary endpoints to 
measure time to change in WHO grade 
for those in level 3, as well as those in 
level 4. 
See above 
Throughout 
Change of wording to refer to use of 
supplmental oxygen ‘if applicable’. 
WHO grade 3 do not 
require supplemental 
oxygen, so not all study 
patients will be using 
supplemental oxygen. 


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Section # and Name 
Description of Change 
Brief Rationale 
9.1 , 9.2,  
 
Previous target was level 5 from level 
4; now amended to ‘at least one level’ 
to handle the participants who enter at 
level 3. 
 
Substantial Amendment 2 
6.2.2 
Addition of text to permit temperature 
excursions no longer than 1 hour. 
See above 
Substantial Amendment 3 
2.2.1  
5.3, 13 
Amendment of Methb threshold from 
1% to 2% 
See above 
Non-substantial amendments 
1.3 Schedule of 
Activities 
Changed description of oxygen 
measurements pre/post treatment to 
make clearer and remove repetition. 
Instructions were 
repetitive and 
unnecessarily confusing 
1.3 Schedule of 
Activities.  Footnote 6f 
Correction of 5 to 20, to match text 
elsewhere in document. 
Correcting typo error 
5.3 Point 2 
Amend requirement to receive 
nebulization from 4 minutes to 8 
minutes 
4 minutes was an error; 
8 mins is expected 
length of treatment. 
6.2.1 et alia 
6.4, 8.1.2 
Change of ‘medical supervision’ to 
‘clinical supervision’, and ;a physician’ 
to ‘the clinical team’. 
As monitoring does not 
require a doctor. 
6.2.2 
Addition of text to permit temperature 
excursions no longer than 1 hour. 
See above 
7.1 
Remove reference to direct bilirubin, 
since this is no longer to be measured. 
 
7.1 
Remove wording ‘non invasive or’ 
Study intervention to be 
discontinued only if 
invasive ventilation is 
required. 
8 
Maximum amount of blood updated to 
reflect volume and number of tests 
 
8.2.2 
Sentence regarding vital signs removed 
as duplicate of previous text in the 
section 
 


Thirty Respiratory Limited 
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Section # and Name 
Description of Change 
Brief Rationale 
10.3 
Remove unnecessary bloodtests: 
Bicarbonate/CO2; Serum Glutamic-
Oxaloacetic Transaminase ; Serum 
Glutamic-Pyruvic Transaminase ; 
direct bilirubin 
 
 
Amendment 2.0 (10-Jun-2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment: 
The protocol was updated to clarify that staggered dosing is required for all participants treated 
before completion of the first Independent Data Monitoring Committee (IDMC) review, and to 
clarify exclusionary criteria and monitoring of methemoglobin (mHb). Information was added to 
ensure that investigators are aware of the potential risk of interaction between nitric oxide (NO) 
and other NO donor agents. Other changes, with brief rationale, are summarized in the following 
table. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA) 
Footnote 4 updated to include mHb 
assessment at the same time points as 
hematology and clinical chemistry 
assessments. 
For monitoring and 
assessment of mHb 
against the 
discontinuation criteria. 
Section 2.2.1 Risk 
Assessment 
Section 5.3 Exclusion 
criteria 
Table 2-1 updated to include 
exclusionary mHb >1%. 
Exclusion criterion 13 updated to 
specify that mHb >1% is exclusionary. 
The normal reference 
range for mHb is 0-1% 
(Longo et al, 2011).  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1 Overall 
Design 
Section 6.1 Study 
Intervention 
Administered 
Section 9.6 Data 
Monitoring Committee 
(DMC) 
Due to the urgency of the pandemic, if 
participants become eligible for the 
study during the IDMC review of the 
first 10 participants then they may be 
recruited. However, their 
administration of RESP301 will be 
staggered in the same way as for the 
first 10 participants.  
Once the IDMC review has been 
completed, and provided there are no 
safety concerns, further recruitment 
will continue as per protocol. The 
Sponsor and contract research 
organization (CRO) confirm that the 
report from the IDMC will be sent in a 
timely manner to all participating sites 
and investigators. 
The staggered dosing 
approach will be used 
for all participants 
enrolled up to 
completion of the first 
IDMC safety review, to 
ensure appropriate safety 
procedures are in place 
for the first participants 
recruited into the study. 
Section 6.5.1 Potential 
Drug Interactions 
A new section was added to describe 
NO donor agents that may increase the 
risk of developing 
methemoglobinemia.  
To ensure that 
investigators are aware 
of the potential risk of 
interaction between NO 
and other NO donor 
agents. 
Section 7.1 Permanent 
Discontinuation of 
Study Intervention 
Addition of Hy’s law discontinuation 
criteria to the first bullet. 
To ensure consistency 
with Appendix 10.3. 
Whole document 
Minor language and format changes. 
For improved clarity and 
readability. 


Thirty Respiratory Limited 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
Final Amendment 3 (Version 4.0) 
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Table of Contents 
Contents 
Clinical Study Protocol ................................................................................................................... 1 
Protocol Amendment Summary of Changes Table ......................................................................... 3 
Table of Contents ............................................................................................................................ 8 
1 
Protocol Summary .................................................................................................................. 12 
1.1 
Synopsis .............................................................................................................................. 12 
1.2 
Schema ............................................................................................................................... 15 
1.3 
Schedule of Activities (SoA) .............................................................................................. 16 
2 
Introduction............................................................................................................................. 21 
2.1 
Background......................................................................................................................... 21 
2.2 
Benefit/Risk Assessment .................................................................................................... 24 
2.2.1 
Risk Assessment ............................................................................................................. 24 
2.2.2 
Benefit Assessment ......................................................................................................... 27 
2.2.3 
Overall Benefit: Risk Conclusion ................................................................................... 29 
3 
Objectives and Endpoints ....................................................................................................... 29 
4 
Study Design ........................................................................................................................... 30 
4.1 
Overall Design .................................................................................................................... 30 
4.2 
Scientific Rationale for Study Design ................................................................................ 32 
4.3 
Justification for Dose .......................................................................................................... 33 
4.4 
End of Study Definition...................................................................................................... 33 
5 
Study Population ..................................................................................................................... 33 
5.1 
Study Rationale .................................................................................................................. 34 
5.2 
Inclusion Criteria ................................................................................................................ 34 
5.3 
Exclusion Criteria ............................................................................................................... 35 
5.4 
Lifestyle Considerations ..................................................................................................... 36 
5.5 
Screen Failures ................................................................................................................... 36 
5.5.1 
Screening and Enrollment Log and Participant Identification Numbers ........................ 36 
6 
Study Intervention .................................................................................................................. 37 
6.1 
Study Intervention Administered ........................................................................................ 37 
6.1.1 
Medical Devices ............................................................................................................. 38 


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Clinical Study Protocol 
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6.1.2 
Device Training .............................................................................................................. 39 
6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 39 
6.2.1 
Preparation of Study Intervention Product ..................................................................... 39 
6.2.2 
Storage and Accountability of Study Intervention ......................................................... 40 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 41 
6.4 
Study Intervention Compliance .......................................................................................... 41 
6.5 
Concomitant Therapy ......................................................................................................... 41 
6.5.1 
Potential Drug Interactions ............................................................................................. 42 
6.5.2 
Rescue Medication ......................................................................................................... 42 
6.6 
Intervention After the End of the Study ............................................................................. 42 
7 
Discontinuation of Study Intervention and Participant Discontinuation ................................ 43 
7.1 
Permanent Discontinuation of Study Intervention ............................................................. 43 
7.2 
Temporary Discontinuation of Study Intervention ............................................................. 44 
7.3 
Participant Discontinuation/Withdrawal from the Study ................................................... 45 
7.4 
Loss of Participants to Follow-Up ...................................................................................... 45 
8 
Study Assessments and Procedures ........................................................................................ 46 
8.1 
Efficacy Assessments ......................................................................................................... 47 
8.1.1 
Modified WHO Ordinal Scale ........................................................................................ 47 
8.1.2 
Pulse Oximetry ............................................................................................................... 48 
8.1.3 
National Early Warning Score (NEWS) 2 ...................................................................... 48 
8.2 
Safety Assessments ............................................................................................................. 49 
8.2.1 
Physical Examinations .................................................................................................... 49 
8.2.2 
Vital Signs ...................................................................................................................... 50 
8.2.3 
Electrocardiograms ......................................................................................................... 50 
8.2.4 
Clinical Safety Laboratory Assessments ........................................................................ 50 
8.3 
Adverse Events and Serious Adverse Events ..................................................................... 51 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 51 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 51 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 52 
8.3.4 
Regulatory Reporting Requirements for SAE ................................................................ 52 
8.3.5 
Pregnancy ....................................................................................................................... 52 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs ............................................................................................................................... 53 
8.3.7 
Adverse Events of Special Interest (Not Applicable) ..................................................... 54 
8.3.8 
Medical Device Deficiencies (Not Applicable) .............................................................. 54 


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8.4 
Tokenization (Optional) ...................................................................................................... 54 
8.5 
Treatment of Overdose (Not Applicable) ........................................................................... 54 
8.6 
Pharmacokinetics (Not Applicable) .................................................................................... 54 
8.7 
Pharmacodynamics (Not Applicable) ................................................................................. 55 
8.8 
Genetics (Not Applicable) .................................................................................................. 55 
8.9 
Biomarkers (Not Applicable) ............................................................................................. 55 
8.10 Medical Resource Utilization and Health Economics (Not Applicable) ............................ 55 
9 
Statistical Considerations........................................................................................................ 55 
9.1 
Statistical Hypothesis ......................................................................................................... 55 
9.2 
Sample Size Determination ................................................................................................ 55 
9.3 
Populations for Analyses .................................................................................................... 56 
9.4 
Statistical Analyses ............................................................................................................. 57 
9.4.1 
General Considerations .................................................................................................. 57 
9.4.2 
Primary Endpoint ............................................................................................................ 58 
9.4.3 
Secondary Endpoint(s) ................................................................................................... 58 
9.4.4 
Tertiary/Exploratory Endpoint(s) ................................................................................... 58 
9.4.5 
Other Safety Analyses .................................................................................................... 58 
9.4.6 
Other Analyses ................................................................................................................ 60 
9.5 
Interim Analyses ................................................................................................................. 60 
9.6 
Data Monitoring Committee (DMC) .................................................................................. 61 
10 Supporting Documentation and Operational Considerations ................................................. 63 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 63 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 63 
10.1.2 
Financial Disclosure ....................................................................................................... 63 
10.1.3 
Informed Consent Process .............................................................................................. 63 
10.1.4 
Data Protection ............................................................................................................... 64 
10.1.5 
Committees Structure ..................................................................................................... 65 
10.1.6 
Data Quality Assurance .................................................................................................. 65 
10.1.7 
Source Documents .......................................................................................................... 66 
10.1.8 
Study and Site Start and Closure .................................................................................... 66 
10.1.9 
Publication Policy ........................................................................................................... 67 
10.1.10 Protocol Approval and Amendment ............................................................................... 67 
10.1.11 Liability and Insurance ................................................................................................... 68 
10.2 Appendix 2: The NEWS 2 Scoring System ....................................................................... 69 
10.3 Appendix 3: Clinical Laboratory Tests ............................................................................... 70 


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10.4 Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 72 
10.4.1 
Definition of AE ............................................................................................................. 72 
10.4.2 
Definition of SAE ........................................................................................................... 73 
10.4.3 
Recording and Follow-up of AE and SAE ..................................................................... 75 
10.4.4 
Reporting of SAE ........................................................................................................... 77 
10.5 Appendix 5: Statistical Design Considerations .................................................................. 80 
10.5.1 
Some General Design Considerations ............................................................................ 80 
10.5.2 
General Design Characteristics ...................................................................................... 83 
10.5.3 
Adaptive Sample Size Re-Estimation ............................................................................ 84 
10.5.4 
Overall Adaptive Design Performance ........................................................................... 86 
10.6 Appendix 6: Abbreviations ................................................................................................. 87 
10.7 Appendix 7: Protocol Amendment History ........................................................................ 89 
10.7.1 
Protocol Amendment 1.0, 05 Jun 2020 .......................................................................... 89 
11 References............................................................................................................................... 98 
Investigator Agreement Page ...................................................................................................... 102 
List of Figures 
Figure 1–1: 
Study Design ......................................................................................................... 15 
Figure 2–1: 
Mode of Action of RESP301 Against SARS-CoV-2 ............................................ 23 
Figure 6-1: 
Staggered Dosing Approach for the First 10 Participants ..................................... 38 
List of Tables 
Table 1-1 
Schedule of Activities (SoA) ................................................................................ 16 
Table 2-1 
Risk Assessment.................................................................................................... 24 
Table 3-1 
Objectives and Endpoints ..................................................................................... 29 
Table 6-1 
Study Intervention(s) Administered ...................................................................... 37 
Table 6-2 
Composition of Drug Product, Diluent and Admixture ........................................ 40 
Table 7-1 
Differences in Signs and Symptoms for Acute Bronchospasm and COVID-19 
Progression ............................................................................................................ 44 
Table 9-1 
Populations for Analysis ....................................................................................... 56 
Table 10-1 
Protocol-Required Laboratory Assessments ......................................................... 70 
 


Thirty Respiratory Limited 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: An 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 (NOCoV2) 
Sponsor Protocol No.: RESP301-002 
Study Phase: Phase 2/Phase 3 
Sponsor: Thirty Respiratory Limited 
Rationale: 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design. Participants will be consented and randomized 2:1 to the 
Investigational arm or the Control arm. Participants randomized to the Investigational arm will 
receive inhaled RESP301 (6 mL) administered using a nebulizer 3 times a day (TID) for up to 
10 days in addition to the standard of care (SOC) while participants in the Control arm will 
receive SOC alone. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 3 or 4 in 
the modified World Health Organization 
(WHO) ordinal scale into higher levels 
 Proportion of participants who progress 
by at least one level higher on the 
modified WHO ordinal scale by Day 14 
Key Secondary 
 To assess the effect of RESP301 as 
measured by room air SpO2 
 Change in room air SpO2 from baseline 
over time 
 To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
 Change in NEWS 2 symptom score from 
baseline over time 


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Thirty Respiratory Limited 
Clinical Study Protocol 
RESP301-002 
CONFIDENTIAL 
 
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Overall Design: 
 Open-label, randomized, multicenter, parallel group, concurrent, controlled study using a 
sequential adaptive design to evaluate the efficacy and safety of RESP301 added to 
standard of care (SOC) in hospitalized patients with COVID-19 WHO ordinal scale grade 
3 & 4. 
 Participants will be stratified by country and presence of risk factors for severe outcomes 
of COVID-19, based on comorbidities and age as detailed in Section 6.3. 
 The study treatment will be permanently discontinued prior to 10 days if the participant: 
o Improves to level 1 or 2 of the modified WHO ordinal scale; 
o Progresses to a level > 4 of the modified WHO ordinal scale; 
o Experiences an event that requires permanent discontinuation as described in 
Section 7.1. 
 An Independent Data Monitoring Committee (IDMC) will be responsible for closely 
reviewing the safety and efficacy data from interim analyses and for providing their 
recommendations on continuation of the study. The IDMC will meet after 10, 20, 60 and 
150 participants have completed the study (see Sections 9.5 and 9.6). 
 A staggered dosing approach will be used for the first 10 participants (up to the first 
IDMC safety review). Each RESP301 dose will be administered by intermittent 
inhalation to monitor the tolerability and response to RESP301 (see Sections 6.1 and 9.6). 
Disclosure Statement: This is a parallel group treatment study with two arms that are 
open-label. 
Number of Participants: 
Approximately 300 adult (male or female) participants will be randomly assigned to study 
intervention (200 to the Investigational arm and 100 to the Control arm). 
Intervention Groups and Duration: 
The total study duration for a participant from screening to last follow up will be up to 30 days 
(±2 days). The study will be divided into the following periods: 




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1.3 Schedule of Activities (SoA) 
Table 1-1 
Schedule of Activities (SoA) 
Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Informed consent 
X 
 
 
 
 
 
 
Optional tokenization 
ICF to be provided for 
a subset of 
participants in the 
United States (see 
Section 8.4) 
Confirmation of COVID-19 
infection by nasopharyngeal 
RT-PCR 3 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Recheck clinical 
status before 1st dose 
of study intervention 
Demographics 
X 
 
 
 
 
 
 
 
Physical examination including 
height and weight 
X 
 
 
X 
X 
 
X 2 
Full physical exam 
and height only at 
screening 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Pregnancy test (urine) 
X 
 
 
 
 
 
 
All women, including 
women of 
childbearing potential 
and pregnant women, 
may be enrolled in the 
study. Pregnancy 
status should be 
recorded (see 
Section 8.3.5). Note: 
Only females of child 
bearing potential and 
pregnant females need 
to undergo a screening 
pregnancy test. 
Medical history (includes 
substance usage) 
X 
 
 
 
 
 
 
History of substance 
usage or abuse to be 
recorded but is not 
exclusionary 
Medication history 
X 
 
 
 
 
 
 
In the prior 3 months 
Laboratory assessments 
(including liver chemistries) 4 
X 4 
X 4 
X  
(Days 3 and 
7 only) 4 
X 4 
X 4 
 
X 2,4 
 
12-lead ECG  
X 
 
 
 
 
 
 
After resting supine 
for approximately 
5 minutes.  
QRS, QT, QTcF, PR, 
RR, rate 
Vital signs 5 
X 
X 
X 5 
X 
X 
 
X 
Within 15 minutes 
prior to study 
intervention 
administration 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Randomization 
 
X 
 
 
 
 
 
 
Study intervention, TID 6 
 
X 
X 
X 
 
 
 
A staggered dosing 
approach will be used 
for the first 
10 participants (up to 
the first IDMC safety 
review). Each 
RESP301 dose will be 
administered by 
intermittent inhalation 
to monitor the 
tolerability and 
response to RESP301 
(see Sections 6.1 and 
9.6). Where possible 
study intervention 
should be 
administered at 
approximately the 
same times each day 
At least 6 hours 
between 2 consecutive 
doses 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
 
Pre Treatment oxygen / 
respiratory assessment 7 
X 
X 
X 
X 
 
 
 
 
SpO2 on room air (after at least 
1 minute) prior to study 
intervention administration and 
immediately at the end of 
nebulization 6 
 
X 
X 
X 
 
 
 
See Section 8.1.2 


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Procedure 
Screening 
(up to 
48 hours 
before 
Day 1 1) 
Intervention Period  
Early 
withdrawal 
Efficacy 
follow-up 
(Day 14) 2 
(± 2 days) 
EoS efficacy 
and safety 
follow-up 
(Day 28) 2  
(± 2 days) 
Notes 
Day 1 1 
Daily while 
hospitalized 
Day 10 / 
hospital 
discharge 
Modified WHO ordinal scale 
X 
X 
X 
X 
 
X 
X 
See Section 8.1.1 
NEWS 2 assessment 7 
 
X 
X 
X 
 
 
 
Prior to study 
intervention in the 
morning. See 
Section 8.1.3 


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Abbreviations: AE=adverse event; aPTT= activated partial thromboplastin time; CBC=complete blood count; Chem 7=blood chemistry panel (sodium, 
potassium, chloride, bicarbonate/CO2, blood urea nitrogen, creatinine, glucose); CV=cardiovascular; ECG=electrocardiogram; IDMC=Independent Data 
Monitoring Committee; LFTs=liver function tests; mHb=methemoglobin; PT/INR=prothrombin time/international normalized ratio; RT-PCR=reverse 
transcription-polymerase chain reaction; SAE=serious adverse event; TID=three times daily. 
1. Screening and randomization may be on the same day, providing all eligibility criteria are met.  
2. For participants who are already discharged at either the Day 14 or Day 28 (EoS) follow-up, there will be a phone call to check AEs/SAEs, 
concomitant medications, and modified WHO ordinal scale. At EoS, safety laboratory tests (nitrite and mHb only) and weight will be collected for 
participants in hospital only. 
3. COVID-19 infection must be confirmed and documented in chart with a positive result on a validated test. 
4. At Screening: CBC, chem 7, mHb, LFTs, and coagulation (PT/INR, aPTT). 
On Day 1, Day 3, Day 7 and Day 10, or early withdrawal: CBC, chem 7 (per SOC), and mHb. 
On Day 28: nitrite and mHb (participants in hospital at EoS only). 
5. Vital signs: temperature, heart rate, blood pressure, respiratory rate. Vital signs to be repeated as per SOC during treatment period. 
6. Study intervention comprises the following procedures which are to be done in order and as quickly as possible: 
a. 
Discontinuation of supplemental oxygen administration where applicable * 
b. Close participant oversight by trained health care professional until SpO2 is stable on ambient air after one minute at least * 
c. 
Recording of SpO2 * pre-nebulization on ambient air 
d. Preparation of the admixture of RESP301 (to be done no longer than 5 minutes before administration)* 
e. 
Administration of the nebulization via a vibrating mesh nebulizer while monitoring SpO2 and heart rate (alarms set to 89% and 120 beats / min, 
or as indicated by the Investigator, for stopping study intervention administration and resuming supplemental oxygen where applicable) * If the 
participant is unable to tolerate nebulization without supplemental oxygen, nasal oxygen may be administered during nebulization. 
f. 
Discontinuation of nebulization 20 minutes after preparation of admixture, or no product left in the device, whichever comes first * 
g. Recording of SpO2 * post nebulization on ambient air 
h. Resuming supplemental oxygen where applicable* 
i. 
Participant oversight until SpO2 is stable * 
j. 
Recording of SpO2 * 
* for participants on active treatment arm only 
7. Participant remains on supplemental oxygen if applicable,and measurements made of respiratory rate, heart rate and SpO2 and a record of of oxygen 
flow level including mode (nasal cannula, mask) 


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2 Introduction 
2.1 Background 
Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by a novel coronavirus 
(SARS-CoV-2). COVID-19 was first described in Wuhan, China, in December 2019 and is now 
a global pandemic (Matos et al, 2020). Most of those affected have milder illness (80%), 15% 
will be severely ill (require oxygen) and 5% will require intensive care unit care (Novel 
Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020). Of those who are 
critically ill, most require early intubation and mechanical ventilation. Other complications 
include septic shock and multi-organ failure, including acute kidney injury and cardiac injury 
(Yang et al, 2020). Older age and comorbid diseases, such as chronic obstructive pulmonary 
disease (COPD), hypertension, and diabetes, increase risk of death (Huang et al, 2020; Zhou et 
al, 2020). The virus is highly contagious and spread via respiratory droplets, direct contact and, if 
aerosolized, airborne routes. The most common symptoms include fever, fatigue, dry cough, and 
shortness of breath.  
A critical early component of innate host defense 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 nebulizer, 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. 


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RESP301 is a NO-generating liquid designed to release NO in situ in the upper airways and deep 
in the alveolar spaces. RESP301 is an admixture solution of two precursor solutions mixed 
together at point of care for immediate inhaled administration via a CE-marked handheld 
nebulizer and has specific advantages (see below) over inhaled NO gas in treating patients with 
COVID-19 during the current pandemic. It has 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 nebulizer; 
 
The formulation is nebulized 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 Sponsor has conducted a number of supportive in vitro studies to assess the activity of NO-
generating solutions against major respiratory viruses responsible for infections in humans. 
These studies include the following: 
 
In vitro studies to demonstrate the effects of RESP301 on SARS-CoV-2 replication 
 
In vitro study of RESP301 against influenza A (H1N1) and human rhinovirus 
 
Determination of the anti-viral efficacy of NO-releasing formulations against two 
strains of virus (influenza A virus [H1N1] and human rhinovirus 16) 
 
Anti-microbial activity of acidified nitrite solutions against intracellular drug sensitive 
and drug resistant Mycobacterium tuberculosis and M. abscessus infections 
 
Anti-microbial activity of RESP301 when used alone and in combination with 
antibiotics 
Recent data from experiments at two independent laboratories using two different isolates of 
SARS-CoV-2 suggest that incubation with RESP301 for 36 to 48 hours reduced viral load to 
levels below the limit of detection of the assay at concentrations which were not associated with 
cytotoxicity. The limiting factor of the experiments was the slow growth rate of the viral 
controls; reduction in viral load was 2.2 and 4 Log10 median tissue culture infectious dose 
(TCID50).  
Studies of inhaled nebulized sodium nitrite (AIR001) in healthy subjects and in patients showed 
that inhaled acidified nitrite produces dose proportional plasma pharmacokinetics without 
accumulation following repeated administration, with low systemic blood levels of nitrite and 


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methemoglobin (<3%) (Rix et al, 2015). Inhaled nitrite (AIR001) at doses up to 90 mg three 
times daily (TID) displayed a good safety profile and is well tolerated (Parsley et al, 2013; 
Simon et al, 2016), thus supporting the investigation of RESP301 in the clinical setting. 
RESP301 delivers NO in a specifically focused way and with a unique mode of administration. 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. Whereas inhaled NO 
gas has been used to treat patients with virus-induced acute respiratory distress syndrome and is 
being tested currently in COVID-19 patients, it focuses on increasing vascular permeability and 
is not sufficiently targeted at the infection, it is rapidly dispelled with exhalation and is oxidized 
in air to toxic NO2. By comparison, RESP301 generates NO in a liquid environment that comes 
in direct contact with the virus and the virus-infected cells. As a result, RESP301 has a better 
targeted approach, and lower concentrations of NO are required, with a much more portable 
delivery system. An important environmental safety factor is that RESP301 produces negligible 
levels of NO2 generated and exhaled NO. 
In generating NO, RESP301 has at least three 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 (Figure 2–1). 
Figure 2–1: 
Mode of Action of RESP301 Against SARS-CoV-2 
 


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1. Nitric oxide 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), vital for the life-cycle of the virus, are targets for NO nitrosylation (Benz et al, 
2002; Colosanti et al, 1999). 
2. In coronaviruses like SARS-CoV-2, NO 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 receptor on the host cell. 
3. Nitric oxide can attack 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. Nitric oxide 
suppresses the virus-induced hyperactivity in the host cell and thereby deprives the virus 
of its crucial supply chain.  
RESP301 efficiently delivers with all three modes of action and is therefore considered an ideal 
candidate for clinical trials in COVID-19. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of RESP301 is 
provided in the Investigator’s Brochure. 
2.2 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. 
2.2.1 
Risk Assessment 
Table 2-1 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention RESP301 
Participants may need to be 
discontinued from 
supplemental oxygen for 
Study treatment is to be 
administered via a vibrating 
mesh nebulizer which is 
designed for oral inhalation. 
Participants unable to be 
safely discontinued from 
supplemental oxygen will be 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
several minutes to receive 
nebulized study treatment 
excluded (Exclusion 
criterion 2) 
Treatment administration is to 
be performed as quickly as 
possible (Section 1.3) 
Oxygen saturation (SpO2) 
and heart rate will be 
monitored throughout the 
study intervention 
administration (Section 1.3) 
In case of decrease in SpO2 or 
clinical signs of intolerance to 
nebulization, RESP301 
treatment may be paused 
temporarily and supplemental 
O2 resumed or the study 
treatment may be 
discontinued permanently 
(see Section 7.1) per 
Investigator assessment. 
Risk of methemoglobinemia 
Very low levels are produced 
but as methemoglobinemia 
has been reported with 
continuous NO gas 
administration, the risk 
cannot be firmly ruled out 
Participants with a history of 
methemoglobinemia will be 
excluded (Exclusion 
criterion 4), methemoglobin 
(mHb) level >2% is 
exclusionary (exclusion 
criterion 13), and mHb is 
included in safety laboratory 
tests (Section 1.3) 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Risk of clinical bronchial 
hyper-responsiveness related 
to nebulization 
Excipients in the nebulized 
RESP301 include mannitol 
which is a known bronchial 
irritant at the average dose of 
a positive mannitol test 
(239.0 ± 185.0 mg, Brannan 
et al, 2005). While the dose 
used in this study (54.66 mg) 
is lower than the average dose 
for a positive mannitol test, it 
has not yet been tested in 
COVID-19 patients and may 
potentially cause or 
exacerbate cough or 
bronchospasm in susceptible 
individuals in this specific 
population 
Participants with a known 
history of moderate or severe 
bronchial hyperreactivity 
(such as in asthma) or 
presence of signs of 
significant bronchospasm on 
examination will be excluded 
from study participation 
(Exclusion criterion 5) 
For the first 10 participants 
treated before the first 
Independent Data Monitoring 
Committee (IDMC) safety 
review (Section 9.6), 
RESP301 will be 
administered by intermittent 
inhalation until the intended 
dose is delivered 
(Section 6.1), so that the 
treatment can be quickly 
adjusted and rescue 
bronchodilator initiated if 
needed (Section 6.5.2) 
After reviewing safety data, 
the IDMC will decide 
whether the intermittent 
inhalation of RESP301 can be 
replaced by continuous 
inhalation. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Procedures 
Nebulization 
The delivered dose of 
RESP301, estimated to be 
~40% of the masses listed in 
Table 6-2, can be affected by 
patient technique and 
inspiratory capacity leading 
to inter- and intra-patient 
variation in actual doses of 
these ingredients, given the 
acute nature and high disease 
burden in this proposed 
clinical setting 
Training will be provided to 
study staff to minimize 
variation in dose 
Other 
Risk of spreading SARS-
CoV-2 
SARS-CoV-2 is known to be 
transmissible via respiratory 
droplets and any interventions 
that may potentially increase 
cough or aerosolization of 
respiratory secretions of an 
infected patient may increase 
risk of spread of disease  
Proper personal protective 
equipment including 
appropriate mask, face shield, 
gown and gloves should be 
used at all times. When 
possible, the site staff should 
not remain in the room during 
study intervention 
administration (providing that 
continuous O2 monitoring can 
be conducted remotely and 
study intervention can be 
administered correctly) 
2.2.2 Benefit Assessment 
To date, no treatment of COVID-19 has demonstrated clinical efficacy. Patients and their 
physicians are critically in need for treatments that decrease the risk of severe levels of disease, 


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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. 
Nitric Oxide is already marketed (e.g., INOmax®, NOXIVENT™, etc) in the United States (US) 
and other countries as a gas for continuous use in preterm and near-term (>34 weeks gestation) 
neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence 
of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents. 
It is well tolerated, although under continuous use, a small number of cases of 
methemoglobinemia have been reported (NOXIVENT™ FDA Prescribing Information). 
Nitric oxide has been shown in vitro to inhibit the replication cycle of severe acute respiratory 
syndrome coronavirus (Akerström S et al, 2005). In addition, NO is a naturally occurring and 
potent antimicrobial agent in the human body, which is active against viruses, bacteria, fungus, 
and yeasts (Fang, 1997). In particular, NO inhibits replication in vitro in a number of respiratory 
viruses including influenza A and B (Rimmelzwaan et al, 1999, Regev-Shoshani et al, 2013), 
human rhinovirus (Sanders et al, 1998), and respiratory syncytial virus (Ali-Ahmad D et al, 
2003). 
The ability of RESP301 to have a marked antibacterial action is highly relevant in the context of 
treating patients with SARS-CoV-2 infection since superimposed bacterial infection is a critical 
factor and a major cause of morbidity and mortality. RESP301 would restore and replenish the 
NO deficiency in patients who have succumbed to SARS-CoV-2 infection. RESP301 also has 
key advantages over inhaled NO gas, as discussed in Section 2.1. 
A vibrating mesh nebulizer is advised for administration of RESP301. Amongst the suitable 
nebulizers, the device chosen for the study is a commercially available, CE-marked vibrating 
mesh device that delivers a mist of fine droplets in the size range required for pulmonary 
deposition (Mass Median Aerodynamic Diameter < 5 µm). This has been shown to be ideally 
suited for penetration deep into the alveolar spaces of the lung. As with all nebulizers in clinical 
use, there is a residual amount of drug that remains in the nebulizer so that not the full amount of 
drug is administered. The device operates continuously once initiated and automatically switch 
off once the medication has been delivered. The device may be used in pediatric and adult 
populations, as permitted by the prescribed medication, and is suitable for use in home 
environments or hospital/clinic settings. 
As testing inefficient product would distract sites from participating in other research efforts, two 
interim analysis for futility purpose have been planned. 


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2.2.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this first-in-man 
study, the potential risks identified in association with RESP301 are justified by the anticipated 
benefits that may be afforded to participants with COVID-19. 
3 Objectives and Endpoints 
Table 3-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 To evaluate efficacy of RESP301 in 
preventing progression of hospitalized 
COVID-19 participants at level 3 or 4 in 
the modified World Health Organization 
(WHO) ordinal scale into higher levels.  
 Proportion of participants who progress 
by at least one level higher on the 
modified WHO ordinal scale by Day 14 
Key Secondary 
 To assess the effect of RESP301 as 
measured by room air SpO2 
 Change in room air SpO2 from baseline 
over time 
 To assess the effect of RESP301 as 
measured by the National Early Warning 
Score (NEWS) 2 symptom score 
 Change in NEWS 2 symptom score from 
baseline over time 
 To assess the treatment response on 
clinical status 
 Change from baseline on the modified 
WHO ordinal scale at each visit up to 
Day 28 
 Time to improvement of at least one level 
lower on the modified WHO ordinal scale 
 Time to progression of at least one level 
higher on the modified WHO ordinal 
scale 
Additional Secondary 
 To assess the treatment response on 
clinical status 
 Time to hospital discharge 
 Incidence of mortality by Day 28 
Safety 
 To assess the overall safety profile of 
RESP301 in COVID-19 participants 
 Clinical safety laboratory measurements 
 Physical examinations 


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 
Intervention period: up to 10 days; Day 1 to Day 10 
 
Efficacy follow-up: Day 14 and Day 28 (±2 days) 
 
Safety follow-up: 28 days after treatment initiation; with the participant being contacted 
by phone call, if not still hospitalized, on Day 28 (±2 days) 
After screening, eligible participants will be randomized to either RESP301+SOC or SOC alone 
on Day 1, and the study treatment will be initiated as applicable (Table 1-1). Screening and 
randomization may happen on the same day (Day 1).  
An individual administration of study intervention will be stopped, and supplemental oxygen 
resumed if applicable, if threshold limits of SpO2 89% or heart rate 120 beats/min (or as 
indicated by the Investigator) are exceeded (see Section 4.2 and Section 8.1.2). However, the 
participant may continue with subsequent doses if the Investigator judges that the benefit / risk 
ratio remains positive. In this case, the instruction to continue should be duly recorded in the 
participant’s hospital file and the subsequent nebulization should be closely monitored. 
Inhalation of study intervention should be completed within 20 minutes. A staggered dosing 
approach will be used for the first 10 participants (and enrolment up to completion of the first 
IDMC safety review) to monitor tolerability and response to RESP301 (see Sections 6.1 and 
9.6). 
The study treatment will be permanently discontinued prior to 10 days if the participant: 
 Improves to level 1 or 2 of the modified WHO ordinal scale; 
 Progresses to a level > 4 of the modified WHO ordinal scale; 
 Experiences an event that requires permanent discontinuation as described in Section 7.1. 
In the above cases, participants will be considered as ongoing in the study until the final Safety 
follow-up phone call (Day 28). Participants will be withdrawn from the study prior to Day 10 
(Early withdrawal) only if they withdraw consent.  
The total study duration for a participant from screening to last follow up will be up to 30 days 
(±2 days). 
Participants will be stratified by country and presence of risk factor(s) for severe outcomes of 
COVID-19, based on comorbidities and age, as detailed in Section 6.3. 
Two interim analyses are planned (see Section 9.5 for details). 


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An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study. The IDMC will 
meet after 10, 20, 60 and 150 participants have completed the study (see Sections 9.5 and 9.6). 
4.2 Scientific Rationale for Study Design 
NO is a naturally occurring and potent antimicrobial agent in the human body which has been 
shown in vitro to inhibit replication of severe acute respiratory syndrome coronavirus 
(Akerström S et al, 2005), including SARS-CoV2, and other respiratory viruses. NO as an 
inhaled gas is already marketed in the US and other countries (see Section 2.2.2) but has 
disadvantages over NO produced locally in the oropharynx or lung airways (lengthy treatment 
requiring NO canisters, the inhaled NO is expelled in exhalation, the NO gas oxidizes in air to 
form toxic NO2 which is a potential lung irritant and a contaminant in the patient’s environment, 
and the half-life of NO in air is short).  
RESP301 has potential advantages over inhaled NO gas: 
 
RESP301 demonstrates powerful evidence in vitro as a broad-spectrum anti-microbial; 
 
Treatment is quick, easy and portable using a standard handheld nebulizer; 
 
The formulation is nebulized 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. 
In this study, the effect of RESP301 as an add on treatment to SOC will be evaluated for its 
efficacy in reducing rate of progression to a more severe level of COVID-19 and for safety by 
comparison with SOC alone in hospitalized COVID-19 patients. A sequential adaptive design 
was chosen in order to assess futility and sample size after interim analyses (see Section 9.5). 
The study design was developed in accordance with the latest WHO and regional regulatory 
agencies guidelines.  
Several risks factors for severe or fatal outcomes have been reported (Bialek et al, 2020; Huang 
et al, 2020; Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020; 
Rong-Hui et al, 2020; Zhou et al, 2020). To minimize bias, the results will be stratified according 
to the known risk factors as described in Section 6.3. 
In this study, measures will be in place to trigger discontinuation of study intervention at a SpO2 
limit pre-agreed at the site (see Section 8.1.2). There is no critical level of oxygen saturation 
below which tissue hypoxia occurs due to the large number of variables that contribute to 


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hypoxia at the tissue and cellular level (temperature, pH, tissue blood flow). As a result, there is 
no consensus about what constitutes normal and abnormal oximetry (ATS/ACCP, 2003). To 
support and guide the team in charge of study intervention administration, a default value of 
SpO2=89% and heart rate (120 beats/min) has been proposed as a suitable limit of tolerance. 
However, for the reason stated above, this limit can be overruled by the Investigator in either 
direction. 
Newly released guidelines for ongoing clinical trials during the COVID-19 pandemic have 
emphasized the need to reduce the burden on sites and clinical trial personnel/investigators 
whether they be administrative, site visit, or other burdens (ACRO, 2020; EMA, 2020; HRS, 
2020). Thus, without blinding and a placebo, along with minimal procedures, the additional 
burden on clinical staff has been reduced as much as possible. 
4.3 Justification for Dose 
Studies with nebulized sodium nitrite (AIR001) in healthy subjects and in patients have shown 
that inhaled nitrite produces dose proportional plasma pharmacokinetic without accumulation 
following repeated administration, with low systemic blood levels of nitrite and methemoglobin 
(<3%). Inhaled nitrite at doses up to 90 mg TID displayed a good safety profile and is well 
tolerated (Rix et al, 2015; Parsley et al, 2013; Simon et al, 2016).  
In this study, 6.0 mL RESP301 (delivered dose 62 mg) will be administered via a vibrating mesh 
nebulizer, TID with at least 6 hours between each dose. Each 6.0 mL dose for nebulization 
contains the masses described in Table 6-2. 
4.4 End of Study Definition 
A participant is considered to have completed the study if he/she has completed the Treatment 
Period and the Follow-up Period (through the Day 28 EoS Follow-up). End of the study is 
defined as the last participant’s last visit or follow up call. 
5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of male and female COVID-19 patients, including pregnant 
women and women of child bearing potential. Participants must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 


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5.1 Study Rationale 
This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using 
a sequential adaptive design to evaluate the efficacy and safety of RESP301 plus SOC versus 
SOC alone in hospitalized patients with COVID-19 (WHO level 3 & 4). 
Each constituent (see Section 6.2) of RESP301 is used as SOC for various conditions. Product 
application is straightforward, requiring a few minutes of inhalation using a standard nebulizer. 
RESP301 is likely to be beneficial in treating patients with COVID-19 who are not receiving 
ventilation but may be using supplementary oxygen in order to maintain a safe level of SpO2. 
Considering the well-established and global use of NO and the device, and the current public 
health emergency resulting from the COVID-19 pandemic, a Phase2/3 study of RESP301 is 
considered reasonable in order to generate efficacy data in patients infected with COVID-19. 
5.2 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is ≥18 years of age, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participant has laboratory-confirmed SARS-CoV-2 infection as determined by reverse 
transcriptase polymerase chain reaction (RT-PCR) or other approved clinical testing prior 
to randomization. 
3. Participant is hospitalized in relation to COVID-19 (WHO level 3 & 4). 
Sex 
4. Participant is male or female. All females of childbearing potential, including pregnant 
females, must consent to urine pregnancy testing at screening to be eligible for the study. 
(Females who are not of childbearing potential do not need to undergo a pregnancy test at 
screening). 
Informed Consent 
5. Participant is capable of giving signed informed consent as described in Appendix 1 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 


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5.3 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Rapidly deteriorating or likely to require escalation to high flow oxygen, invasive or 
non-invasive ventilatory support within 24 hours according to Investigator’s opinion. 
2. Unable to safely receive a nebulized treatment for approximately 8 minutes according to 
Investigator’s opinion. 
3. Unable to receive or considered ineligible for invasive or non-invasive ventilatory 
support. 
4. History of methemoglobinemia. 
5. Uncontrolled asthma or history of severe bronchospasm. 
6. Severe (requiring baseline oxygen therapy > 12 h/day prehospitalization) chronic 
respiratory disease (e.g., known COPD, pulmonary arterial hypertension, idiopathic 
pulmonary fibrosis, interstitial lung disease). 
7. Suspected or confirmed untreated, active tuberculosis. 
8. Severely immune-compromised participants in Investigator’s opinion. 
9. Recent (within 3 months) active coronary artery disease or decompensated heart failure 
(New York Heart Association class 3-4). 
10. Presence of tracheostomy. 
Prior/Concomitant Therapy 
11. Chronic (≥4 weeks) use of corticosteroids >10 mg/day of prednisone or equivalent within 
4 weeks of randomization. 
Prior/Concurrent Clinical Study Experience 
12. Participation in other clinical investigations utilizing investigational treatment or within 
30 days / 5 half-lives whichever is longer. 


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Diagnostic Assessments 
13. Clinically significant abnormalities in clinical chemistry or hematology at screening, 
defined as: 
 
Methemoglobin level >2%  
 
Platelet count <50,000 mm3 
 
Alanine aminotransferase or aspartate aminotransferase >5 × upper limit of normal 
(ULN). 
 
Estimated glomerular filtration rate <30 mL/min/1.73 m2 (modification of diet in renal 
disease formula) or requiring hemofiltration or dialysis. 
Other Exclusions 
14. Anticipated transfer to another hospital which is not a study site during the treatment 
period. 
15. Allergy to any of the components of the study intervention. 
5.4 Lifestyle Considerations 
No restrictions are required. 
5.5 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography and reason for screen 
failure (e.g., eligibility requirements failed). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
5.5.1 
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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6 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. 
6.1 Study Intervention Administered 
Table 6-1 
Study Intervention(s) Administered 
Study Treatment 
RESP301 + SOC 
Intervention Name: 
RESP301 
Type: 
Drug 
Dosage Formulation: 
Admixture for inhalation 
Unit Dose 
Strength(s): 
Delivered dose (62 mg) sodium nitrite (NaNO2) 
(6 mL of NO-generating admixture of 150 mM NaNO2, 50 mM mannitol and 100 mM 
citric acid) 
Dosage Level(s): 
One 6 mL-inhalation TID (every 8 hours) with at least 6 hours between 2 consecutive 
doses. 
Route of 
Administration: 
Inhalation 
IMP and NIMP: 
IMP 
Sourcing: 
RESP301 provided centrally by the Sponsor. 
Dosing Instructions: 
A vibrating mesh nebulizer will be used to administer the RESP301, under the 
direction of the study physician. 
Treatment is to commence within 5 minutes of RESP301 preparation.  
For the first 10 participants (and enrolment up to completion of the first IDMC safety 
review) RESP301 will be administered by intermittent inhalation to monitor 
tolerability and response to RESP301. After reviewing safety data, the IDMC will 
decide whether the intermittent inhalation of RESP301 can be replaced by a continuous 
inhalation. 
Before initiating each RESP301 inhalation, supplemental oxygen, if being used,  will 
be interrupted for a few minutes until SpO2 levels are stable. Depending on the extent 
of SpO2 decrease, the RESP301 inhalation may be initiated or supplemental oxygen 
may be resumed at the discretion of the investigator. After treatment initiation, in case 
of SpO2 decrease, RESP301 inhalation may be paused and supplemental oxygen 
resumed.  
If the participant is unable to tolerate nebulization without supplemental oxygen, nasal 
oxygen may be administered during nebulization. 
Packaging and 
Labeling: 
Study intervention will be provided as two separate vials: NaNO2/mannitol (3 mL) and 
citric acid buffered to pH 5.4 (3 mL), which will be labeled as required per country 
requirement.  
 


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Staggered dosing approach for the first 10 participants: 
For the first 10 participants treated, and enrolment up to completion of the first IDMC safety 
review (Section 9.6), RESP301 dose will be administered in a staggered approach: after 2 
minutes of inhalation, treatment is briefly paused to assess the participant. Provided there is no 
evidence of bronchospasm, treatment is continued for a further 2 minutes, after which treatment 
is again briefly paused for participant assessment. Thereafter, provided there is no evidence of 
bronchospasm and the participant is able to continue, the dose is completed (Figure 6-1), so that 
treatment can be quickly adjusted and rescue bronchodilator initiated if needed (Section 6.5.2). 
After reviewing safety data, the IDMC will decide whether the intermittent inhalation of 
RESP301 can be replaced by a continuous inhalation (see also Section 9.6). Due to the urgency 
of the pandemic, if participants become eligible for the study during the IDMC review of the first 
10 participants then they may be recruited; however, their administration of RESP301 will be 
staggered in the same way as for the first 10 participants.  
Figure 6-1: 
Staggered Dosing Approach for the First 10 Participants 
 
  
6.1.1 
Medical Devices 
1. Medical device (not manufactured by or for Thirty Respiratory Limited) provided for use 
in this study will be an FDA-approved and CE-marked vibrating mesh nebulizer.  
2. Instructions for medical device use will be provided in the User Manual. 


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6.1.2 
Device Training 
Training will be provided to ensure all study staff are familiar with the device, including mixing 
the solutions, adding the admixture to the device and cleaning the device. 
6.2 Preparation, Handling, Storage, and Accountability 
6.2.1 
Preparation of Study Intervention Product 
RESP301 is prepared at bedside by mixing two sterile 3 mL solutions (one of NaNO2/mannitol 
and one of citric acid buffered to pH 5.4). The solution is to be nebulized immediately or within 
5 minutes post mixing as per the instructions given in the SoA (Table 1-1) and, for the first 
10 participants, as in Section 6.1 above (staggered dosing). The first administration of study 
intervention should be provided under clinical supervision. 
RESP301 is mixed in the nebulizer chamber before use following the steps below (see Table 6-2 
for details of composition): 
1. First the vial marked A (NaNO2 and mannitol) is opened and its contents are poured into 
the nebulizer chamber. 
2.  Next, the vial marked B (citric acid) is opened and its contents are poured into the 
nebulizer chamber. 
3. The nebulizer lid should be closed, and the nebulizer should be swirled gently for a few 
seconds to mix the two solutions. The nebulizer should not be inverted. 
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. 
This combined mildly acidified nitrite solution (6 mL) is inhaled through the mouth using a 
vibrating mesh nebulizer under the direction of the clinical team. The purpose of the acidified 
nitrite aerosol is to deliver NO to the participant. The delivered dose of RESP301, assessed via 
simulated tidal breathing is estimated to be ~40% of the masses listed below; it should be noted 
that delivered dose can be further affected by participant’s breathing pattern and inspiratory 
capacity and so inter- and intra-participant variation in actual doses of these ingredients may 
vary, given the acute nature and high disease burden in this proposed clinical setting. 


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Table 6-2 
Composition of Drug Product, Diluent and Admixture 
 
Material 
Function 
Quantity per vial 
Drug Product 
Sodium Nitrite 
Drug Substance 
62.10 mg 
Mannitol 
Excipient  
54.66 mg  
Sterile water for injection 
Diluent 
 
Total Volume 
 
3.0 mL 
Diluent 
Citric Acid  
Diluent 
115.28 mg 
Sterile water for injection 
Diluent 
 
Total Volume 
 
3.0 mL 
Acidified Drug 
Product Mixture 
(RESP301) 
Sodium Nitrite 
Drug Substance 
62.10 mg 
Mannitol 
Excipient  
54.66 mg  
Citric Acid  
Diluent 
115.28 mg 
Sterile water for injection 
Diluent 
 
Total Volume 
 
6.0 mL 
 
6.2.2 
Storage and Accountability of Study Intervention 
The Investigator or designee must document whether appropriate temperature conditions 
(<25°C) have been maintained during storage for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. Temperature 
excursions are permitted up to 30ºC for no longer than 1 hour. Such a temperature excursion 
must be recorded, however the study intervention can be safely administered to participants. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study interventions 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 authorized 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). 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Investigator Manual. 


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6.3 Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; however, the specific intervention to be taken by a participant will be 
assigned using an interactive voice response system (IVRS)/interactive web response system 
(IWRS). The site will contact the IVRS/IWRS prior to the start of study intervention 
administration for each participant. The site will record the intervention assignment on the 
applicable case report form (CRF), if required.  
Potential bias will be reduced using a central stratified randomization to assign participants into 
one of the study treatment arms, RESP301+SOC or SOC (control), with a randomization ratio of 
2:1. Participants will be stratified by country and presence of risk factors for severe outcomes of 
COVID-19, based on comorbidities and age as follows: 
1. Age >65 years 
2. Ongoing or currently treated diabetes mellitus 
3. Ongoing or currently treated hypertension 
4. Ongoing or currently treated cardiovascular disease 
5. Ongoing or currently treated chronic lung disease 
6. Cancer history of less than 3 years, basal cell skin carcinoma excluded 
7. Ongoing or currently treated chronic kidney disease 
Participants will be stratified as no risk factor (none of the above criteria), one risk factor (one 
single of the above) or high-risk factor (2 or more of the above). 
6.4 Study Intervention Compliance 
Participants will receive study intervention directly from the Investigator or designee, under 
clinical supervision. The date and time of each inhalation will be recorded in the source 
documents and recorded in the CRF. The study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the study 
intervention. 
6.5 Concomitant Therapy 
During the study, participants will receive institutional SOC for the treatment of COVID-19. 


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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency and route 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 
Potential Drug Interactions 
Investigators should be aware of the potential interaction between NO generated by RESP301 
and that generated from NO donor agents, such as prilocaine, sodium nitroprusside, and 
nitroglycerine, that may increase the risk of developing methemoglobinemia. 
6.5.2 
Rescue Medication 
For participants treated before completion of the first safety review by the IDMC (Section 9.6), 
at the time of RESP301 treatment, a ready-to-use nebulization of a bronchodilator (short acting 
beta agonist such as salbutamol/albuterol according to investigational site standard practice for 
acute bronchospasm) may be administered to participants in case of bronchospasm. 
After reviewing safety data, the IDMC will decide whether the availability of rescue 
bronchodilator at the time of RESP301 treatment is still required. 
Although the use of rescue medications is allowable for the first 10 participants, the use of rescue 
medication should be delayed, if possible, for at least 2 minutes following each administration of 
study intervention. The date and time of rescue medication administration as well as the name of 
the rescue medication must be recorded. 
6.6 Intervention After the End of the Study 
After the end of the study, participants may continue their SOC (if any). Study intervention for 
COVID-19 will not continue beyond this study. 


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7 Discontinuation of Study Intervention and Participant Discontinuation 
7.1 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 the Day 14 and Day 28 safety follow-ups. See the SoA 
(Table 1-1) for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
Study intervention will be permanently discontinued prior to 10 days if the participant: 
 Improves to level 1 or 2 of the modified WHO ordinal scale; 
 Progresses to a level > 4 of the modified WHO ordinal scale. 
Additionally, study intervention should be permanently discontinued in the following 
circumstances: 
1. Discontinuation of study intervention for abnormal liver tests should be considered if the 
Investigator believes that it is in best interest of the participant. The development of 
alanine aminotransferase (ALT) ≥3 × ULN and bilirubin ≥2 × ULN  or ALT ≥3 × ULN 
and international normalized ratio (INR) >1.5, if INR is measured, which may indicate 
severe liver injury (according to Hy’s Law), must be reported as an SAE and the study 
intervention discontinued. 
2. If, as part of normal clinical follow-up, a clinically significant change in ECG is 
identified, the Investigators should exercise their clinical judgement to decide whether 
continuing study intervention administration is in the best interest of safety of the 
participant. 
3. AE/SAE if the Investigator believes that it is in best interest of the participant, including 
the following: 
 Development of significant bronchospasm * or worsening of cough that is not tolerated 
by the participant and leads to immediate discontinuation of the nebulization. 
 Progressive COVID-19 requiring initiation of  invasive ventilation or high flow oxygen. 
 Development of mHb level above 3%. 


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 Inability to safely continue receiving study intervention due to compromised respiratory 
status while off supplemental oxygen and receiving nebulized therapy (manifest by drop 
in SpO2, increased respiratory rate or clinical other findings). 
Refer to the SoA (Table 1-1) for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
* Inhaled citric acid and inhaled mannitol provoke bronchospasm in patients with bronchial 
hyperresponsiveness in a dose dependent pattern. Although the concentrations of mannitol and 
citric acid are below the provocative dose and concentration inducing bronchospasm, there is a 
theoretical risk that a participant may develop acute bronchospasm during the use of RESP301. 
Participants should therefore be monitored during RESP301 administration. In case of clinical 
intolerance or saturation decrease, nebulization should be immediately discontinued (see 
Section 7.2). Further clarification of the differences in signs and symptoms for acute 
bronchospasm and COVID-19 progression are provided in Table 7-1. 
Table 7-1 
Differences in Signs and Symptoms for Acute Bronchospasm and 
COVID-19 Progression 
 
Acute bronchospasm related to 
inhaled bronchial irritant  
Progression of COVID-19 lung 
disease to acute respiratory 
failure  
Mechanism 
Acute contraction of bronchial muscles 
resulting in bronchial obstruction 
resulting in increased ventilatory load 
Cytokine storm resulting in alveolar 
damage resulting in gas transfer 
impairment 
Onset 
Within minutes (<15 minutes) 
following inhalation (no late phase 
since it is not an allergic IgE mediated 
reaction) 
Within hours or days and not related to 
nebulization  
Clinical auscultatory signs 
Wheezing (almost all cases) 
Bilateral rales (inconstant) 
Patient history 
Asthma or respiratory allergy  
Age > 65 years, increased BMI, high 
blood pressure, cardiac diseases, etc. 
Reversibility with inhaled 
beta mimetics 
Within minutes 
No 
Abbreviations: BMI=body mass index; IgE=immunoglobulin E. 
 
7.2 Temporary Discontinuation of Study Intervention 
Brief temporary discontinuation of study intervention is permitted during the study, providing 
inhalation of study intervention is completed within 20 minutes.  


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Study intervention should be temporarily discontinued in the following circumstance: 
1. Clinical intolerance to nebulization. 
An individual administration of study treatment will be stopped, and supplemental 
oxygen if applicable resumed, if threshold limits of SpO2 89% or heart rate 120 beats/min 
(or as indicated by the Investigator) are exceeded (see Sections 4.2 and 8.1.2).  
The participant may continue with subsequent doses if the Investigator judges that the benefit / 
risk ratio remains positive. In this case, the instruction to continue should be duly recorded in the 
participant’s hospital file and the subsequent nebulization should be closely monitored.  
Refer to Section 6.1 for information on staggered dosing in the first 10 participants. 
7.3 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, behavioral, 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. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
At the time of discontinuing from the study, if possible, an early discontinuation assessment 
should be conducted, as shown in the SoA (Table 1-1). 
7.4 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. The following actions must be taken if a participant cannot be contacted at Day 14 or 
Day 28: 
 
The site must attempt to contact the participant and counsel the participant on the 
importance of maintaining the assigned schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
 
In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant (where possible, 


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three telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record/CRF. 
 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
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 utilized 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 1-1). 
The maximum amount of blood collected from each participant, should be approximately 20 mL 
per occasion (Screen, Day 1 , Day 3, Day 7, Day 10 and Day 28). 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Informed Consent 
Informed consent must be documented according to Appendix 1, Section 10.1.3.  
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or designee to ensure 
that the participant qualifies for the study. 


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Participant Identification Card 
All participants will be given a participant identification card identifying them as participants in 
a research study. The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency. The Investigator or qualified designee will 
provide the participant with a participant identification card immediately after the participant 
provides written informed consent. At the time of intervention allocation/randomization, site 
personnel will add the intervention/randomization number to the participant identification card. 
Medical History 
A medical history will be obtained by the Investigator or qualified designee. The medical history 
will collect all active conditions and any condition diagnosed that the Investigator considers to be 
clinically relevant. Details regarding the disease for which the participant has enrolled in this 
study will be recorded separately and not listed as medical history. 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 3 months prior to screening. This should include a 
history of hypertension medication, in particular angiotensin-converting enzyme inhibitors and 
angiotensin receptor blockers. 
The Investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the last assessment. Concomitant medications will be recorded on an 
ongoing basis during the study (or longer if related to an SAE). 
8.1 Efficacy Assessments 
8.1.1 
Modified WHO Ordinal Scale 
A modified WHO ordinal scale will be used for consistency with the recent study of 
lopinavir-ritonavir in adults hospitalized with severe COVID-19 (Cao et al, 2020), to record the 
participant’s status at the time of assessment. The modified WHO ordinal scale includes the 
following levels: 
1. Not hospitalized, no limitations on activities; 
2. Not hospitalized, limitation on activities; 
3. Hospitalized, not requiring supplemental oxygen; 


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4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 
6. Hospitalized, on invasive mechanical ventilation or extra corporeal membrane 
oxygenation (ECMO); 
7. Death. 
8.1.2 
Pulse Oximetry 
Pulse oximetry measurements will be performed to evaluate SpO2 as outlined in the SoA 
(Table 1-1) and in accordance with the site standard operating procedures, on a medical-grade 
medical device. Measurements will be taken with a probe on fingertip, toe or earlobe and 
recorded as percent oxygenated hemoglobin. Supplemental oxygen used at the time of 
assessment and method of oxygen delivery will be collected and documented along with the 
SpO2. 
Prior to administration of study intervention, supplemental oxygen will be held for at least a 
minute and SpO2 checked in order to ensure participant may safely receive the study 
intervention. For safety reasons, since due to the current pandemic it cannot be guaranteed that 
study intervention will be consistently administered under direct clinical supervision, the study 
Investigators should provide study personnel who are able to monitor the participant and their 
SpO2 and ensure that should it decrease to a threshold, this would trigger immediate 
discontinuation. By default, unless overruled by the study Investigator, this SpO2 threshold is set 
to 89%. This threshold should be entered into the saturation monitoring device to trigger an 
alarm during nebulization. 
FiO2 will be measured per site standard practice and recorded in the eCRF. The device used to 
administer oxygen should also be recorded. 
8.1.3 
National Early Warning Score (NEWS) 2 
The NEWS 2 will be measured prior to study intervention in the morning according to the SoA 
in Table 1-1. 
The NEWS is based on a simple aggregate scoring system in which a score is allocated to 
physiological measurements, already recorded in routine practice, when patients present to, or 
are being monitored in hospital (RCP, 2012). Six simple physiological parameters form the basis 
of the scoring system: 
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2. Oxygen saturation 
3. Systolic blood pressure 
4. Pulse rate 
5. Level of consciousness or new confusion* 
6. Temperature 
*The patient has new-onset confusion, disorientation and/or agitation, where previously their 
mental state was normal – this may be subtle. The patient may respond to questions coherently, 
but there is some confusion, disorientation and/or agitation. This would score 3 or 4 on the 
Glasgow Coma Scale (rather than the normal 5 for verbal response), and scores 3 on the NEWS 
system. 
A score is allocated to each parameter as they are measured, with the magnitude of the score 
reflecting how extremely the parameter varies from the norm (zero for ‘normal’; maximum 
score 3). The score is then aggregated. The score is increased by 2 points for people requiring 
supplemental oxygen to maintain their recommended oxygen saturation. This is a pragmatic 
approach, with a key emphasis on system-wide standardization and the use of physiological 
parameters that are already routinely measured in National Health Service (NHS) hospitals and 
in prehospital care, recorded on a standardized clinical chart – the NEWS 2 chart (Refer to 
Appendix 2: The NEWS 2 Scoring System). 
Reproduced from: Royal College of Physicians. National Early Warning Score (NEWS) 2: 
Standardising the assessment of acute-illness severity in the NHS. Updated report of a working 
party. London: RCP, 2017 (RCP, 2017). 
8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1-1). 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
head/ear/eyes/nose/throat, cardiovascular, respiratory, gastrointestinal, lymphatic, skin and 
neurological systems. Height (screening only) and weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 


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8.2.2 
Vital Signs 
Vital signs to be collected as outlined in the SoA (Table 1-1) and include body temperature, heart 
rate, blood pressure, and respiratory rate. 
Body temperature will be assessed per the local practice (temporal or otic are preferred sites), 
and site will be recorded. Pulse rate, respiratory rate, and blood pressure will also be assessed per 
site SOC. Where possible the same methods should be used throughout the study for an 
individual participant. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). During study 
intervention administration, an alarm threshold should be set for heart rate at 120 beats/min (or 
as indicated by the Investigator), as outlined in the SoA (Table 1-1). 
8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (Table 1-1) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals for 
local reading.  
8.2.4 
Clinical Safety Laboratory Assessments 
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA 
(Table 1-1) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically relevant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically abnormal during participation in the study 
or within 4 days after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator 
or Medical Monitor.  
 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, where possible, and the 
Sponsor notified. 


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 
All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the Laboratory Manual and the SoA (Table 1-1). 
 
If laboratory values from laboratory assessments not specified in the protocol and 
performed at the institution’s local laboratory result in the need for a change in 
participant management or are considered clinically relevant by the Investigator (e.g., 
are considered to be an SAE or an AE), then the results must be recorded in the CRF. 
8.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 4. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized 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 AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue the study intervention (see Section 7). 
8.3.1 
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 1-1). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
Investigator becoming aware of the SAE, as indicated in Appendix 4. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obliged to actively seek AEs or SAEs after the conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 
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 4. 


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.3.3 
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, stabilization, 
until the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.4). Further information on follow-up procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Appendix 4) 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 IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
All women, including women of childbearing potential are allowed in the study. Urine pregnancy 
test will be performed on female participants of childbearing potential and pregnant females at 
screening. Females who are not of child bearing potential do not need to undergo a screening 
pregnancy test. 
Pregnant females will be followed to determine the outcome of the pregnancy: 


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 The Investigator will collect any follow-up information on the participant and the neonate 
and the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of the pregnancy will be reported, regardless of fetal state (presence or 
absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered to be SAEs. Any post-study 
pregnancy-related SAE considered reasonably related to study intervention by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting. 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
The following disease-related events (DREs) are common in participants with COVID-19 and 
can be serious/life-threatening: 
 
Fever 
 
Cough* 
 
Dyspnea* 
 
Asthenia 
 
Loss of sense of taste and smell 
* A cough or dyspnea episode related to study intervention administration does not meet the 
definition of a DRE and should be reported as an AE. 
Because these events are typically associated with the disease under study, they will not be 
reported as AEs. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an SAE (instead of a DRE): 
 
The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant. 
OR 


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 
The Investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.3.7 
Adverse Events of Special Interest (Not Applicable) 
No AEs of special interest are defined for this study. 
8.3.8 
Medical Device Deficiencies (Not Applicable) 
The medical device to be used in this study is a vibrating mesh nebulizer 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. 
8.4 Tokenization (Optional) 
Tokenization is the process of converting a piece of data into a random string of characters 
known as a token. Tokenization protects sensitive data by substituting non-sensitive data. The 
token serves merely as a reference to the original data, but cannot be utilized to determine those 
values. The advantage of tokens is that there is no mathematical relationship to the real data that 
they represent. The real data values cannot be obtained through reversal, and hence, a breach 
renders the information invaluable. Tokens are being increasingly used to secure varying types of 
sensitive information. In particular, personal identifiable information such as healthcare 
information, email addresses and account numbers are such examples. From a security 
perspective, tokenization significantly reduces risk based on the fact that sensitive data cannot be 
breached if it is not there in the first place. 
Tokenization applies only to US participants who agree and sign the optional ICF. The piece of 
personal data needed to generate the token will be collected to create a unique, de-identified 
token. This token would be instrumental to enrich and aggregate other study participants’ data 
coming from different sources for the purpose of future research. The benefit of linking data in 
general, is that the data set that is created can be used to answer a variety of healthcare- and 
therapy-related questions that could not otherwise be answered through conventional means. 
8.5 Treatment of Overdose (Not Applicable) 
There is no risk of overdose. 
8.6 Pharmacokinetics (Not Applicable) 
Pharmacokinetic parameters are not evaluated in this study. 


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8.7 Pharmacodynamics (Not Applicable) 
Pharmacodynamic parameters are not evaluated in this study. 
8.8 Genetics (Not Applicable) 
Pharmacogenomics are not evaluated in this study. 
8.9 Biomarkers (Not Applicable) 
Biomarkers are not evaluated in this study. 
8.10 Medical Resource Utilization and Health Economics (Not Applicable) 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9 Statistical Considerations 
9.1 Statistical Hypothesis 
RESP301 reduces the rate of progression in the modified WHO ordinal scale in COVID-19 (see 
Section 8.1.1). 
The endpoint of worsening level on the WHO ordinal scale represents a composite endpoint of 
scales above the entry level, being (i) death (level 7), (ii) hospitalized, on invasive mechanical 
ventilation or ECMO (level 6), (iii) hospitalized, on non-invasive ventilation or high-flow 
oxygen devices (level 5) , or, for those patients who were recruited at WHO ordinal scale 3, (iv) 
hospitalized, requiring supplemental oxygen. 
9.2 Sample Size Determination 
A total of 300 hospitalized participants with confirmed COVID-19 will be randomized 2:1 to 
receive RESP301+SOC (200 participants) or SOC alone (100 participants). 
The comparison between the treatment arms for the primary endpoint will have approximately 
80% power and alpha level 0.025 (one-sided) to demonstrate significant reductions (15% versus 
30%) of the primary endpoint between RESP001+SOC and the Control arm (SOC), a 50% 
relative reduction for the proportion of participants who progress by at least one level on the 
WHO ordinal scale (see definition of the primary endpoint). 
Two interim analyses are planned (see Section 9.5 for details): 


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1. The first IDMC interim analysis will take place after the first 60 participants have 
completed Day 10 of the study to evaluate whether the study can be stopped for futility 
based on change from baseline in room air SpO2. For a final decision to stop the study for 
futility the results on other endpoints will be considered as well. 
2. The second interim analysis will take place after 150 participants have completed Day 14 
post-randomization based on event rate for the primary endpoint. The purpose of the 
second interim analysis will be futility as well as a potential sample size re-estimation in 
case the actual results differ from the original assumptions. 
In addition to the review of efficacy data, safety will be assessed at each of the interim analysis 
by the IDMC. Further details are provided in Appendix 5. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Table 9-1 
Populations for Analysis 
Population (Analysis Set) 
Description 
Intent-To-Treat (ITT) 
Population 
The ITT Population will include all randomized participants. The 
ITT participants will be analyzed according to randomized 
treatment, irrespective of the actual treatment received. 
Participants who withdraw from treatment early will be followed 
for the assessment of the Day 14 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 randomized participants who inhale any 
amount of study intervention or are randomized to the control 
arm. The SP will be analyzed according to the actual treatment 
received. This set will be used for the safety analyses. 
 
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 primary efficacy endpoint. 


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9.4 Statistical Analyses 
Below is a description of planned statistical analyses. Further details are presented in the 
Statistical Analysis Plan (SAP). 
9.4.1 
General Considerations 
All statistical analyses will be conducted using SAS, Version 9.4 or later. Baseline characteristics 
will be summarized by treatment arm. For continuous measures the mean and standard deviation 
(SD) will be summarized. Categorical variables will be described by the proportion in each 
category. In addition, 95% confidence intervals (CIs) will be computed as indicated. 
All the categorical variables including the primary endpoint will be summarized by treatment 
with the numbers and percentages of the participants. Treatment difference will be tested using a 
Cochran–Mantel–Haenszel test stratified by 1) country and 2) participant’s clinical status at 
Baseline. For the categorical endpoints, relative risk and its 95% CI will be presented. 
All of the continuous variables, including the changes from Baseline, will be summarized by 
treatment with the means, SD, medians and the ranges. The mixed model with repeated 
measurements /analysis of covariance model with treatment, country, participant’s clinical status 
at Baseline and visit as the model term, and Baseline value as the covariate will be used to test 
for the significance of the treatment difference. Least square means, standard errors, 95% CIs 
and p-values will be presented. 
Time to event endpoints will be analyzed using the Cox Proportional Hazard model with 
treatment, participant’s clinical status at Baseline and country as the model term. The hazard 
ratio of RESP301+SOC versus SOC will be presented along with 95% CI and p-value from the 
model. The Kaplan-Meier curves of the time to events will be presented by treatment for each 
applicable endpoint. 
Handling of missing data 
If participants are discharged from the hospital prior to Day 14 due to improvement of the 
clinical status and their status on Day 14 cannot be obtained, their status on Day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. Depending on the 
reasons for missing data on the primary endpoint up to Day 14, additional sensitivity analyses 
will be performed. Further details on handling on missing data will be provided in the SAP. 


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9.4.5.1 
Adverse Events 
Adverse Events will be coded using the MedDRA coding dictionary. 
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 summarized. The number of deaths due to an AE, hospitalization due to an AE, 
and study discontinuation due to an AE will be summarized. 
The number and percentage of participants with an AE, as well as the total number of AEs, will 
be summarized 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. 
9.4.5.2 
Clinical Laboratory Evaluation 
Baseline is defined as the last non-missing value obtained at the screening visit and prior to the 
first exposure to study drug. Actual values and changes from Baseline clinical laboratory tests 
will be summarized by study day. If more than one laboratory result is reported per study visit 
per parameter, the last non-missing result will be selected for change from Baseline analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the Investigator. The number of participants with a non-missing 
result, the number and percentage of participants with a clinically significant result less than the 
lower limit of normal, non-clinically significant result more than the ULN, and clinically 
significant result more than the ULN will be summarized by study visit. If more than one 
laboratory result is reported per study day per parameter, the result yielding the most severe 
classification will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study day per parameters, the result yielding the 
most severe classification will be selected for analysis.  
Participants who had urine pregnancy test at screening and the results will be listed. 
Participants with clinically significant abnormal laboratory test results will be listed. This listing 
will include all results of the laboratory parameter that was abnormal and determined to be 
clinically significant by the Investigator for a participant across study visit. 


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9.4.5.3 
Vital Signs 
Baseline is defined as the last non‑missing value obtained in screening and prior to the first 
exposure to study drug. Actual values and changes from Baseline in vital signs will be 
summarized by study day and study time point. All vital sign data will be presented in patient 
listings. 
Vital sign values will be classified according to the clinical significance as determined by the 
Investigator. The number of participants with a non-missing result, the number and percentage of 
participants with a non-clinically significant result, and clinically significant result will be 
summarized by study visit and study time point. If more than one vital sign result is reported per 
study day and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis. 
Participants with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the Investigator to be clinically 
significant for a participant across study time points. 
9.4.5.4 
Physical Examination 
Abnormal physical examination findings will be listed. 
9.4.6 
Other Analyses 
Other analyses may be added to the SAP as applicable. 
9.5 Interim Analyses 
Two interim analyses will be performed.  
1. The first analysis will be conducted when about 60 participants (40 participants in the 
RESP301+SOC arm and 20 participants in the SOC arm) have completed the Day 10 
assessment. The purpose of this analysis is to evaluate efficacy of RESP301 with the 
application of a futility criterion based on the results on SpO2 change from baseline on 
Day 10. The following futility criterion will be used for this first interim analysis: 
If the difference in the percentage of participants with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints 
will be considered as well.  


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As no other modification of the study at the time of the first interim analysis is considered, 
no adjustment of the alpha level is required. 
2. The second interim analysis will be conducted after 150 participants (100 participants in 
the RESP301+SOC arm and 50 participants in the SOC arm) have completed the Day 14 
assessment. The purpose of this analysis is the assessment of futility or a sample size 
re-estimation in case the actual results differ from the original assumptions for the power 
calculations of the study, related to the percentage of participants meeting the primary 
endpoint in the control arm and/or the relative treatment benefit achieved in the 
RESP301+SOC arm compared to the SOC arm. 
To account for the multiple testing due to the second interim analysis an adjustment for 
the type I error alpha will be applied using the Haybittle-Peto approach which would 
spend one sided alpha=0.0005 at the second interim analysis and leave one-sided nominal 
alpha of 0.0249 for the final analysis. The futility criterion for the second interim analysis 
will be based on the conditional power (CP) for the final results based on the assumption 
that the remainder of the study will follow the same trend as observed in the interim 
analysis. If CP at the time of the second interim analysis is less than 20% consideration 
will be given to stop the study for futility. At the same time sample size re-estimation will 
be performed to achieve 80% power at the end of the study. The methodology for the 
adjustment and the procedure to maintain the type I error level will be described in greater 
detail in the SAP. 
Detailed information, including the boundaries futility and characteristics for the sample size 
re-estimation at the time of the interim analyses will be provided in the SAP and Data 
Monitoring Committee (DMC) Charter. Further details are also provided in Appendix 5. 
9.6 Data Monitoring Committee (DMC) 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study. The IDMC will 
meet to review after 10 and 20 participants have completed as well as at the time of the interim 
analyses (i.e., after 60 and 150 participants have completed; see Section 9.5). 
Due to the urgency of the pandemic, if participants become eligible for the study during the 
IDMC review of the first 10 participants then they may be recruited. However, their 
administration of RESP301 will be staggered in the same way as for the first 10 participants (see 
also Section 6.1). Once the IDMC review has been completed, and provided there are no safety 
concerns, further recruitment will continue as per protocol. The Sponsor and CRO confirm that 


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the report from the IDMC will be sent in a timely manner to all participating sites and 
investigators. 
The detailed procedures and criteria of the interim analyses will be described in the DMC 
Charter. 


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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 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. 
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. 
10.1.2 Financial Disclosure 
Information on financial disclosure can be found in the Investigator Site File. 
10.1.3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. 


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Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
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 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
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 currently enrolled in 
the study. 
For US participants who agree to tokenization, a separate optional ICF will be provided. 
10.1.4 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 authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Data Protection for Tokenization information is addressed in the separate optional ICF (for US 
participants only). 


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10.1.5 Committees Structure 
An IDMC will be responsible for closely reviewing the safety and efficacy data from the interim 
analyses and for providing their recommendations on continuation of the study (see Sections 9.5 
and 9.6). 
10.1.6 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. 
 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations [CROs]). 
 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized 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. 


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 All data generated by the site personnel will be captured electronically at each study 
center using eCRFs. Data from external sources (such as laboratory data) will be 
imported into the database. Once the eCRF clinical data have been submitted to the 
central server at the independent data center, 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. Once all 
source data verification is complete and all queries are closed, the monitor will freeze the 
eCRF page. 
 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. 
10.1.7 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. 
10.1.8 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 visit 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. 


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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 
10.1.9 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 multicenter 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. 
10.1.10 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). In the US: Following approval, the protocol 


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amendment(s) will be submitted to the Investigational New Drug application under which the 
study is being conducted. 
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. 
10.1.11 Liability and Insurance 
10.1.11.1 Access to Source Data 
Access to source data is described in the Clinical Site contract. 


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10.2 Appendix 2: The NEWS 2 Scoring System 
Chart 1: The NEWS 2 scoring system 
 
Abbreviations: CVPU: C=new onset confusion, disorientation or agitation, V=responds to voice, P=responds to 
pain, U=unresponsive; SpO2=oxygen saturation. 
Source: Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of 
acute-illness severity in the NHS. Updated report of a working party. London: RCP, 2017. 
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2 
 










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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
(Applies only during the safety follow up period for participants who may have 
been discharged during the treatment period, i.e., between Day 1 and Day 10) 
 In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are considered 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
 Hospitalization for elective intervention of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
 Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
 Examples of such events include invasive or malignant cancers, intensive intervention 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 










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However, as far as possible all points on the SAE form should be covered in the initial report, or 
the completed SAE form itself must be emailed or faxed to the Parexel Safety Services. In 
addition, the event must be documented in the electronic CRF/EDC system. 
After receipt of the initial report, Parexel Safety Services will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the event. 
Parexel will be responsible for all information processing and reporting according to local legal 
requirements. Where necessary, Investigators will inform regulatory authorities in their own 
countries. 
 


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10.5 Appendix 5: Statistical Design Considerations 
10.5.1 Some General Design Considerations 
1. Binary primary endpoint: progression to critical stage/death up to Day 14 
 to be analyzed by a Cochran-Mantel-Haenszel (CMH) stratified for the factors used in 
the stratified randomization 
 subjects who withdraw from study treatment will be followed up until their primary 
endpoint outcome is known (i.e., up to Day 14 or progression to critical stage/death, 
whatever is first) 
 it is, therefore, not clear what current protocol synopsis text could mean: If subjects 
are discharged from the hospital prior to day 14 due to improvement of the clinical 
status and their status on day 14 cannot be obtained, their status on day 14 for the 
primary endpoint will be imputed with the status on the day of discharge. and what 
the implications on statistical study characteristics could be. Further discussion is 
needed.  
2. Timing of the two planned interim analyses with stopping options is stated as 
There are 2 interim analyses planned, the first interim analysis after the first 60 participants 
have completed day 10 of the observation period … and a second interim analysis after 150 
participants have completed day 14 of the observation period. 
With the current text for the timing of the first interim analysis, it is not clear how many 
subjects will have been randomized at least 14 days prior to the interim data cut-off date and 
can therefore provide data for the binary primary endpoint (“progression to critical 
stage/death up to Day 14”).  
For such a binary endpoint, Parexel does not recommend including any participant 
randomized less than 14 days prior to the interim data cut-off date (note this would be 
different to a study with a time-to-event endpoint) as 
 for such participants not yet progressed, the outcome up to Day 14 is unknown and 
should not be imputed as “not progressed up to Day 14” 
 for such participants progressed prior to Day 14, the outcome is known but their 
inclusion would bias the estimation of progression probability up to Day 14 in an 
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In order to set up the adaptive group-sequential study design, the following assumptions have 
been used: 
 first interim analysis: a total of ≈ 39 participants randomized at least 14 days prior to 
data cut-off date 
 second interim analysis: a total of ≈ 50% of the initially planned number of 
participants randomized at least 14 days prior to data cut-off date. 
3. Non-binding DMC guidance for stopping the study for futility at the first interim analysis 
is stated as: 
If the difference in the percentage of participants with at least a 2% improvement in SpO2 
between both treatment arms is less than 5%, a benefit of RESP301 treatment is not 
expected. For a final decision to stop the study for futility the results on other endpoints will 
be considered as well. 
As the main futility stopping criterion is based on improvement in SpO2 (and not on the 
primary efficacy endpoint), this first interim analysis will be “ignored” in these statistical 
considerations for an adaptive group-sequential design. We may revisit the first interim 
analysis at a later point in time when more information is available.  
4. Non-binding DMC guidance for stopping the study for futility at the second interim 
analysis stated as:  
The futility criterion for the second interim analysis will be based on the conditional power 
(CP) for the final results based on the assumption that the remainder of the study will follow 
the same trend as observed in the interim analysis. If CP at the time of the second interim 
analysis is less than 20% consideration will be given to stop the study for futility. 
5. Current DMC guidance for stopping the study for superior efficacy at the second interim 
analysis is stated as: 
To account for the multiple testing due to the second interim analysis an adjustment for the 
type-I-error probability will be applied using the Haybittle-Peto approach with one sided 
alpha=0.0005 at the second interim analysis and leave one-sided nominal alpha of 0.0249 
for the final analysis. 
6. For initial sample size calculation, the following additional assumptions / features from 
the protocol have been used 
 progression probability up to Day 14 for Standard of Care (SOC): 30% 


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 progression probability up to Day 14 for RESP301+SOC: 15%  
 desired power assuming the alternative hypothesis stated above: 80% 
 2:1 randomization 
7. Method for adaptation of the sample size based on the second interim analysis data is 
stated as 
A sample size re-estimation will be performed to achieve 80% conditional power at the end 
of the study. The methodology for the adjustment and the procedure to maintain the type-I-
error level will be described in greater detail in an appendix to the protocol.  The maximum 
increase of the sample size will be limited to a total number of 600 randomized subjects.  
Parexel has put a suggestions with some fictitious interim data for illustration in 
Section 10.5.3; that section also illustrates by simulations the Cui/Hung/Wang (CWH) 
approach using a weighted (weights fixed at the design-stage) test for the final analysis 
versus the Chen/DeMets/Lan (CDL) approach without such weights at the final analysis. 
 
 


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10.5.2 General Design Characteristics 
Parexel proposes to base non-binding futility stopping criteria on conditional power criteria. 
Conditional power (CP) is the conditional probability for achieving statistically significant 
superiority of RESP301+SOC over SOC at the final analysis, given the interim results and 
calculated by assuming the interim estimates to be the true distribution parameters for the 
remaining part of the study (an alternative would be predictive power (PP), a Bayesian version of 
CP where prior distributions and observed interim results are combined to obtain the probability 
for achieving statistically significant superiority of gimsilumab over placebo at the final 
analysis).  
Randomization 2:1 
Group-Sequential Design 
1st Interim Analysis (IA) 
N ≈ 39 for D14 
2nd IA 
≈ 50% for D14 
Futility criterion 1st IA 
Based on SpO2 
Futility criterion 2nd IA 
Superior efficacy criterion 2nd IA 
CP < 4% 
p < 0.0005 
Total sample size required for 80% power 
300 
Futility stopping probability at 2nd IA under 
“No effect” 
1st IA: NA 
2nd IA: 70% 
Futility stopping probability at 2nd IA under 
“Planned effect 30% vs 15%” 
1st IA: NA 
2nd IA: 6% 
Superiority stopping probability at 2nd IA 
under “Planned effect 30% vs 15%” 
10% 
Superiority stopping probability at 2nd IA 
under “30% vs 10%” 
28% 
 


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10.5.3 Adaptive Sample Size Re-Estimation 
Another objective of the 2nd interim analysis is to re-estimate the sample size based on the 
unblinded interim results.  
Proposed procedure at 2nd interim analysis (planned to include approximately 150 subjects) 
 unblinded analysis of the primary efficacy endpoint (“Proportion of participants who 
progress by at least one level higher on the modified WHO ordinal scale by Day 14” as a 
binary endpoint)  
 calculation of conditional power (CP) given the interim results and calculated by assuming 
the interim estimates to be the true distribution parameters for the remaining part of the study 
 if CP < 4%: recommend early stop for futility 
 if one-sided p-value < 0.0005: recommend early stop for superior efficacy 
 if 50% < CP < 80% and one-sided p-value ≥ 0.0005:  
o continue the study with an increased total sample size N*, so that CP with a 
total of N* subjects is increased to 80%, same value as the (unconditional) 
desired power in the study design 
o N*, however, is limited to 600 (which is twice the original sample size 300) 
 if 4% ≤ CP ≤ 50%: continue the study without a change in sample size (otherwise, the 
sample size would need to be increased too much or the maximum sample size of 600 
would not be sufficient to come close to a CP of 80%. 
The table on the next page illustrated the proposed procedure for a number of possible results 
observed at the 2nd interim analysis.  
 
 


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Table with examples for the adaptive sample size procedure described above using the 
Cui/Hung/Wang (CHW) approach using a weighted (fixed weights determined by the stage-wise 
sample sizes planned at the design-stage) test for the final analysis: 
2nd IA results with n=150 
subjects (50 for SOC, 
100 for RESP301+SOC 
CP under 
observed trend 
for planned 300 
Total sample size 
required for CP 80% 
under observed trend
CP under observed 
trend if total sample 
size capped by 600 
15 (30%) 
5 (5%) 
p < 0.0005   early stop for superior efficacy 
15 (30%) 
10 (10%) 
99% 
Not applicable 
Not applicable 
15 (30%) 
15 (15%) 
90% 
Not applicable 
Not applicable 
15 (30%) 
18 (18%) 
66% 
393 
Not applicable 
15 (30%) 
19 (19%) 
55% 
483 
Not applicable 
15 (30%) 
21 (21%) 
34% 
[798] 
[67%] 
15 (30%) 
26 (26%) 
3.99% 
Early stop for futility 
12 (24%) 
10 (10%) 
92% 
Not applicable 
Not applicable 
12 (24%) 
12 (12%) 
77% 
321 
Not applicable 
12 (24%) 
14 (14%) 
54% 
498 
Not applicable 
12 (24%) 
15 (15%) 
42% 
[646] 
[77%] 
12 (24%) 
18 (18%) 
14% 
[1800] 
[31%] 
12 (24%) 
20 (20%) 
2.6% 
Early stop for futility 
10 (20%) 
8 (8%) 
85% 
Not applicable 
Not applicable 
10 (20%) 
10 (10%) 
64% 
412 
Not applicable 
10 (20%) 
11 (11%) 
50.4% 
534 
Not applicable 


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10 (20%) 
13 (13%) 
26% 
[1014] 
[55%] 
10 (20%) 
15 (15%) 
10% 
[2460] 
[23%] 
10 (20%) 
18 (18%) 
1.4% 
Early stop for futility 
Quantities in [ ] indicate theoretical values as sample size would not be increased per the 
currently proposed adaptive design.  
10.5.4 Overall Adaptive Design Performance 
Finally, the Cui/Hung/Wang (CHW) approach is compared to the Chen/DeMets/Lan (CDL) 
approach without pre-defined fixed weights for the final analysis (which is valid as sample size 
may only be increased if CP (obtained under observed trend) at the second interim analysis 
exceeds 50%).  
All the results below are for the group-sequential design with adaptive sample size re-estimation 
procedure as described in previous sections and based on 10.000 simulated trials each. 
Scenario 1: true progression probabilities are 30% (SOC) and 15% (RESP301+SOC) 
Scenario 2: true progression probabilities are 24% (SOC) and 14% (RESP301+SOC) 
Scenario 3: true progression probabilities are 30% (SOC) and 10% (RESP301+SOC) 
Scenario 4: true progression probabilities are 24% (SOC) and 20% (RESP301+SOC) 


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10.6 Appendix 6: Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
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 
CP 
Conditional power 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
CRO 
contract research organization 
CV 
cardiovascular 
DMC 
Data Monitoring Committee 
DRE 
disease-related events 
ECG 
electrocardiogram 
ECMO 
Extra corporeal membrane oxygenation 
EDC 
electronic data capture 
EoS 
End of study 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
interactive voice response system 


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IWRS 
interactive web response system 
LFT 
Liver function test 
mHb 
Methemoglobin 
NEWS 
National Early Warning Score 
NHS 
National Health Service 
NO 
Nitric oxide 
NO2 
Nitrogen dioxide 
NOx 
Oxide of nitrogen 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
PP 
Per protocol 
PT 
Prothrombin time 
QTcF 
QT interval corrected using Fridericia’s formula 
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 
Three times daily 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 
 
 


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10.7 Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.7.1 Protocol Amendment 1.0, 05 Jun 2020 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment: 
The original protocol was updated to include important safety guidelines for study intervention 
administration for the first 10 participants (i.e., up to the first independent data monitoring 
committee [IDMC] safety review). It was also updated to align with the IB Version 2.0, dated 
27 May 2020. Other changes, with brief rationale, are summarized in the following table. 
Section # and Name 
Description of Change 
Brief Rationale 
Global change 
Device name Philips 
InnoSpire Go was replaced 
with generic reference to a 
vibrating mesh nebulizer. 
The decision was made to keep 
the device generic for flexibility. 
Section 1.1 Synopsis 
and Section 4.1 Overall 
Design 
Clarified that participants 
were (male or female) adults. 
Wording of study design also 
clarified to include study 
intervention and minor 
clarification to text for 
screening period. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 1.1 Synopsis, 
Section 4.1 Overall 
Design, Section 7.1, 
Discontinuation of 
Study Intervention 
Bullets specifying reasons for 
permanent discontinuation 
updated to reflect content of 
Section 7.1. 
Correction, for consistency 
across the protocol. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema 
Dose of study intervention 
corrected to 6.0 mL. Minor 
clarifications added in 
footnotes. 
Correction. 
Section 1.2 Schema 
Footnote 2 updated. 
Text added to make it clear that 
participants will be allowed 
sufficient time to consider their 
participation in the study. 
Section 1.1 Synopsis, 
Section 1.3 Schedule of 
Activities (SoA), 
Section 2.2.1 Risk 
Assessment, Section 4.1 
Overall Design, and 
Section 6.1 Study 
Intervention 
Administered 
The following statement was 
added: A staggered dosing 
approach will be used for the 
first 10 participants (up to the 
first IDMC safety review). 
RESP301 will be administered 
by intermittent inhalation to 
monitor the tolerability and 
response to RESP301 (see 
Sections 6.1 and 9.6). 
The time gap between 
consecutive doses in the 
3 times per day (TID) 
schedule was updated to “at 
least 6 hours” from “at least 
4 hours”.  
Updated to align with the 
Investigator Brochure (IB) 
Version 2.0, dated 27 May 2020. 
Section 1.3 SoA, Section 
5.2 Inclusion Criteria, 
Section 8.3.5 Pregnancy, 
Appendix 3, Clinical 
Laboratory Tests 
Addition of urine pregnancy 
test at screening. Requirement 
for all females of childbearing 
potential, including pregnant 
females, to consent to urine 
pregnancy testing at 
screening. Details of 
pregnancy follow-up 
procedures added. 
All women, including women of 
childbearing potential and 
pregnant women, are allowed in 
the study. Therefore, it is 
necessary to determine pregnancy 
status at study entry so that 
pregnant females can be followed 
to determine the outcome of the 
pregnancy. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 SoA,  
Appendix 3, Clinical 
Laboratory Tests 
Deletion of tuberculosis (TB) 
screening test. Nitrite added to 
the protocol-required 
laboratory assessments (End 
of Study [EoS] only). 
Screening TB test is not 
mandatory for this study. Nitrite 
is to be measured for participants 
who are still hospitalized at EoS. 
Section 1.3 SoA and 
Section 7.1 Permanent 
discontinuation of Study 
Intervention 
Deletion of electrocardiogram 
(ECG) testing after screening. 
Clarified that significant 
changes in ECGs would be 
identified only as part of 
normal clinical follow-up. 
Only routine ECG monitoring is 
needed for this study. 
Section 2.1 Background, 
Section 11 References 
Text deleted from end of 
paragraph 12. References no 
longer cited were removed 
from Section 11. 
Removal of text that was specific 
to the Philips InnoSpire Go 
nebulizer. 
Table 2-1, Risk 
Assessment and 
Section 11 References 
The risk assessment table was 
updated to align with the 
above changes and IB. A new 
reference (Brannan et al, 
2005) was added to Section 11 
to support additional text 
around risk of bronchospasm. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 1.1 Synopsis, 
Section 1.3 SoA, 
Section 4.1, Overall 
Design 
Visit window for Day 14 and 
Day 28 follow-up extended to 
(± 2 days). 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 SoA 
Footnote 2 corrected to 
include weight and exclude 
ECG. Clarified that laboratory 
testing at EoS follow up is for 
nitrite and methemoglobin 
only. 
Correction and clarification. 
Section 1.3 SoA 
Footnote 6e corrected from 
‘Recording of SpO2 * pre-
nebulization on ambient air’ to 
‘Recording of SpO2 * on 
ambient air’. 
‘pre-nebulization’ was removed 
as SpO2 measurement on ambient 
air is required for both active and 
control group. 
Section 1.3 SoA 
Footnote 7 amended to clarify 
text that is applicable to 
participants in the active arm 
only. 
Clarification. 
Section 1.3 SoA, 
Section 8.3 Adverse 
Events and Serious 
Adverse Events, 
Section 8.3.8 Medical 
Device Deficiencies, and 
Appendix 5: Medical 
Device Adverse Events 
(AEs) Adverse Device 
Effects (ADEs), Serious 
Adverse Events (SAEs) 
and Device 
Deficiencies: Definition 
and Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting 
Changes related to the 
removal of Appendix 5. 
Table 8-1 deleted. 
Appendix and table were not 
required because the nebulizer 
device used in the study is 
licensed and there is no 
requirement to collect data on the 
device. 


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Error! Reference source not found. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2.1 Background 
Updated to include a 
description of the three 
mechanisms of action of 
RESP301 in fighting virus 
infection, including addition 
of new figure (Figure 2–1). 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 2.2.2 Benefit 
Assessment 
Clarification added regarding 
choice of nebulizer for this 
study. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 3 Objectives and 
Endpoints 
Safety endpoint for AEs 
amended to include both 
counts and cumulative 
incidence. 
Both types of data will be 
summarized. 
Section 3 Objectives and 
Endpoints, Section 9.4.4 
Tertiary/Exploratory 
Endpoint(s) 
Exploratory endpoint: 
timepoint for change from 
baseline measurement of 
fraction of inspired oxygen 
(FiO2) changed from Day 7 to 
Day 10.  
Correction; the endpoint should 
be measured at end of treatment. 
Section 4.4 End of Study 
Definition 
The following clarification 
was added to the definition: 
“End of the study is defined as 
the last participant’s last visit 
or follow up call.” 
Clarification of definition. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 Study 
Intervention(s) 
Administered 
This section (including 
Table 6-1) was updated to 
include dosing instructions for 
the first 10 participants (i.e., 
up to the first IDMC safety 
review). In the event of 
bronchospasm, rescue 
bronchodilator can be initiated 
if needed. A new figure was 
also added to clearly show the 
staggered approach 
(Figure 6-1). The TID dosage 
was also clarified as every 8 
hours with at least 6 hours 
between consecutive doses. 
Dosing Instructions were 
updated to clarify that nasal 
oxygen may be administered 
during nebulization if the 
participant is unable to 
tolerate nebulization without 
supplemental oxygen. 
Specific study drug 
administration guidelines 
(including the use of a rescue 
medication) were provided to 
monitor tolerability and response 
to RESP301 inhalation (as 
described in the risk-benefit table 
in Section 2.2.1) and to align 
with the IB, Version 2.0, dated 
27 May 2020. 
Section 6.2.1 
Preparation of Study 
Intervention Product 
Instructions for mixing the 
two solutions were updated. 
Further clarification on the 
delivered dose was added. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.1 Rescue 
Medication 
A new section was added to 
describe allowed 
bronchodilator rescue 
medication for participants 
treated before the first IDMC 
safety review (short acting 
beta agonist such as 
salbutamol/ albuterol 
according to investigational 
site standard practice for acute 
bronchospasm) 
Allowed rescue medication was 
added to minimize the risk of 
bronchospasm to participants, 
and to align with the IB 
Version 2.0, dated 27 May 2020. 
Section 7.1 
Discontinuation of 
Study Intervention 
Rationale was added for 
additional monitoring and 
discontinuation guidance in 
case of bronchospasm. 
Table 7-1 added to provide 
additional clarification on the 
differences in signs and 
symptoms for acute 
bronchospasm and COVID-19 
progression. 
Safety guidance (including the 
use of a rescue medication) was 
updated to minimize the risk of 
bronchospasm to participants (as 
described in the risk-benefit table 
in Section 2.2.1) and to align 
with the IB Version 2.0, dated 
27 May 2020. 
Section 7.1 
Discontinuation of 
Study Intervention 
Section 7.2, Temporary 
Discontinuation of 
Study Intervention 
Subsequent subsections 
of renumbered to 
account for new 
Section 7.2. 
Heading updated to 
“Permanent” Discontinuation 
of Study Intervention. 
Text relating to temporary 
discontinuation moved to new 
Section 7.2. 
Text describing temporary 
discontinuation now moved into 
separate section for clarity and 
consistency. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Corrected statement that AEs 
and SAEs will be collected 
from signing of informed 
consent and clarified that 
SAEs will be reported within 
24 hours of the Investigator 
becoming aware of the SAE, 
to align with Appendix 4 
(previously it stated ‘from 
randomization’). Deleted 
second paragraph. 
Internal document consistency. 
Section 8.3.6 Disease-
Related Events and/or 
Disease-Related 
Outcomes Not 
Qualifying as AEs or 
SAEs 
Loss of sense of taste and 
smell added to the list of 
common DREs in participants 
with COVID-19. 
Updated in line with updated 
World Health Guidelines. 
Section 9.2 Sample Size 
Determination, 
Section 9.5 Interim 
Analyses, and 
Appendix 5, 
Section 10.5.1 Some 
General Design 
Considerations 
The timing of the interim 
analysis was changed from 
when 60 participants have 
completed the Day 7 
assessment to when 
60 participants have 
completed the Day 10 
assessment to make it 
consistent with the planned 
treatment duration and the 
SoA. 
Internal document consistency. 
Section 9.4.5.2 Clinical 
Laboratory Evaluation 
The following sentence was 
added:  
Participants who had urine 
pregnancy test at screening 
and the results will be listed. 
Updated to include pregnancy 
test data collection. 


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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 1, 
Section 10.1.3 Informed 
Consent Process, and 
Section 10.1.4 Data 
Protection 
Text added clarifying that a 
separate optional ICF will be 
provided for US participants 
who agree to tokenization. 
Added clarification that 
tokenization is for US 
participants only. 
Appendix 4, 
Section 10.4.3 
Recording of follow-up 
of AE and SAE, 
Section 10.4.4 Reporting 
of SAE 
Alignment of reporting details 
to state ‘Parexel Safety 
Services’ throughout 
appendix. Text was added to 
include paper SAE data 
collection tool. 
Internal document consistency 
and inclusion of paper SAE 
reporting data collection tool. 
Appendix 7, 
Abbreviations 
Heading number updated to 
reflect deletion of Appendix 6. 
Updated to reflect changes to 
abbreviations used in the 
document. 
Consistency. 
Section 11 References 
Five new references were 
added to support the above 
updates (Basu et al, Benz et al, 
Brannen et al, Colosanti et al, 
and Saura et al). Two 
references were deleted as 
they are no longer cited. 
Updated to align with the IB 
Version 2.0, dated 27 May 2020. 
Whole document 
Minor language and format 
changes. 
For improved clarity and 
readability. 
 


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Clinical Study Protocol 
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brochures/industries/healthcare/rr2-full-noxivent-prescribing-
information.pdf?la=en&rev=caa0194a173a45edaeff44695b229ff9 (last accessed 16 April 2020) 
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Investigator Agreement Page 
Declaration of the Principal or Global Coordinating Investigator 
Title: An 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 (NOCoV2) 
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 or Global Coordinating Investigator 
 
_____________________________________ 
_____________________ 
Signature  
 
 
 
 
 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 
 



SAP_001.pdf: 
NOCoV2 - An 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 requiring 
supplemental oxygen 
ClinicalTrials.gov Identifier: NCT04460183 
Statistical Analysis Plan: 05 Jan 2022 (Version 2.0) 
                                           16 Jul 2020 (Version 1.0)


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