Clinical Trial Results:
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 World Health Organization (WHO) grade 3 & 4 (NOCoV2)
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Summary
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EudraCT number |
2020-002120-37 |
Trial protocol |
GB |
Global end of trial date |
21 May 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
26 May 2022
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First version publication date |
26 May 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RESP301-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Thirty Respiratory Limited
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Sponsor organisation address |
1 Red Place, London, United Kingdom, W1K 6PL
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Public contact |
Clinical department, Thirty Respiratory Limited, +44 (0)1235 431 201, contact@30.technology
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Scientific contact |
Clinical department, Thirty Respiratory Limited, +44 (0)1235 431 201, contact@30.technology
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Nov 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
21 May 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate efficacy of RESP301 in preventing progression of hospitalized COVID-19 participants at level 3 or 4 in the modified WHO ordinal scale into higher levels.
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Protection of trial subjects |
The protocol, protocol amendments, informed consent form (ICF), Investigator’s Brochure (IB), and other relevant documents (e.g. advertisements) were submitted to an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) by the Investigator and reviewed and approved by the IRB/IEC before the study was initiated.
This study was conducted in accordance with the protocol and with consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines; Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines; Applicable laws and regulations. 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.
The Investigator or his/her representative explained the nature of the study to the participant or his/her legally authorized representative and answered all questions regarding the study.
Participants were informed that their participation was voluntary. Participants or their legally authorized representative were 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 requirements, where applicable, and the IRB/IEC or study center.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Jul 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 19
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Worldwide total number of subjects |
19
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
15
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From 65 to 84 years |
3
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85 years and over |
1
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Recruitment
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Recruitment details |
This study was conducted at 2 centers in the United Kingdom (UK) that enrolled 19 participants from29-Jul-2020 (first subject first visit) to 21-May-2021 (last subject's last visit). | ||||||||||||||||||
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Pre-assignment
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Screening details |
The screening period was 2 days. All the study assessments were performed as per the schedule of assessment. Participants were randomized in the ratio 2:1 to the investigational arm or the control arm either inhaled RESP301 in addition to the standard of care (SoC) or SoC alone. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Blinding implementation details |
This is open-label study.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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RESP301+SoC | ||||||||||||||||||
Arm description |
Participants received inhaled RESP301 administered using a nebulizer three times a day (TID) for up to 10 days in addition to the standard of care (SoC). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
RESP301
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Participants received inhaled RESP301 administered using a nebulizer (6 mL; Delivered dose (62 mg) sodium nitrite (NaNO2)) TID (every 8 hours) with at least 6 hours between 2 consecutive doses for up to 10 days.
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Investigational medicinal product name |
Standard of Care (SoC)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Participants received institutional SOC alone for the treatment of COVID-19.
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Arm title
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Standard of Care (SoC) | ||||||||||||||||||
Arm description |
Participants received institutional SOC alone for the treatment of COVID-19. | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Standard of care (SoC)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Participants received institutional SoC for the treatment of COVID 19.
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Baseline characteristics reporting groups
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Reporting group title |
RESP301+SoC
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Reporting group description |
Participants received inhaled RESP301 administered using a nebulizer three times a day (TID) for up to 10 days in addition to the standard of care (SoC). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard of Care (SoC)
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Reporting group description |
Participants received institutional SOC alone for the treatment of COVID-19. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
RESP301+SoC
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Reporting group description |
Participants received inhaled RESP301 administered using a nebulizer three times a day (TID) for up to 10 days in addition to the standard of care (SoC). | ||
Reporting group title |
Standard of Care (SoC)
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Reporting group description |
Participants received institutional SOC alone for the treatment of COVID-19. | ||
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End point title |
Proportion of Participants Who Progress by at Least One Level Higher on the Modified WHO Ordinal Scale [1] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
A modified WHO ordinal scale was used for consistency with the recent study in adults hospitalized with severe COVID-19, to record the participant's status at the time of assessment. The modified WHO ordinal scale included 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 extracorporeal membrane oxygenation (ECMO); 7= Death. Higher scores mean worse outcomes. The proportion of participants who progress by at least one level higher on the modified WHO ordinal scale was assessed.
The intent-to-treat (ITT) population included all randomized participants.
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End point type |
Primary
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End point timeframe |
Baseline, Day 2 and Day 3
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis is available for the primary endpoint. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change Time in Room Air Oxygen Saturation (SpO2) From Baseline Over Time | |||||||||||||||||||||||||||||||||
End point description |
Pulse oximetry measurements were performed to evaluate SpO2. The effect of RESP301 as measured by room air SpO2 was assessed.
The intent-to-treat (ITT) population included all randomized participants.
Justification: 9999.9999 is an arbitrary number that refers to 0 participant being present in the arm for specific timepoints; data was not available.
99.99 is an arbitrary number that refers to Post-dose nebulization that did not occur in the SOC arm on Day 1. Soc arm data is not applicable.
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End point type |
Secondary
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End point timeframe |
Day 1 (Baseline), Day 2, 3, 4, 5, 6, and 7
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title |
Change in National Early Warning Score (NEWS) 2 Symptom Score From Baseline Over Time | ||||||||||||||||||||||||||||||
End point description |
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. 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.
Each score is 0–3 and individual scores are added together for an overall score. An additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from 0 to 20. The higher the score the greater the clinical risk. Higher scores indicate the need for escalation, medical review and possible clinical intervention, and more intensive monitoring.
Justification: 9999.9999 is an arbitrary number that refers to 0 participant being present in the arm for specific timepoints; data was not available.
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End point type |
Secondary
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End point timeframe |
Day 1 (Baseline), Day 2, 3, 4, 5, 6, and 7
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline for Number of Participants on the Modified WHO Ordinal Scale at Each Visit | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
A modified WHO ordinal scale was used for consistency with the recent study in adults hospitalized with severe COVID-19, to record the participant's status at the time of assessment. The modified WHO ordinal scale included 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. Higher scores mean worse outcome. Change from baseline for Number of participants on the modified WHO ordinal scale was assesed.
The intent-to-treat (ITT) population included all randomized participants.
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End point type |
Secondary
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End point timeframe |
Day 1 (Baseline), Day 2, 3, 4, 5, 6, and 7
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Time to Improvement of at Least One Level Lower on the Modified WHO Ordinal Scale | ||||||||||||
End point description |
Time to improvement is the time in which the participant sees a decrease after first study treatment in the WHO 7-point ordinal scale from baseline to a value at least one level lower in days (date of decrease in WHO scale - first dose date + 1). In the case that a patient has not decreased in the WHO scale at time of analysis or withdraws from the study before leaving the hospital, they would be censored at their date of last assessment in the data cut or early discontinuation date, respectively.
The intent-to-treat (ITT) population included all randomized participants.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 28
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to Progression of at Least One Level Higher on the Modified WHO Ordinal Scale | ||||||||||||
End point description |
Time to progression is the time in which the patient sees an increase after first study treatment in the WHO 7-point ordinal scale from baseline to a value at least one level higher in days (date of increase in WHO scale - first dose date + 1). In the case that a patient has not increased in the WHO scale at time of analysis or withdraws from the study before leaving the hospital, they would be censored at their date of last assessment in the data cut or early discontinuation date, respectively.
The intent-to-treat (ITT) population included all randomized participants.
Justification: 999.99 is an arbitrary number that refers to only 1 participant was evaluable, hence Median and Full range is not calculable.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 28
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| Notes [2] - Data is not available. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With Adverse Events | |||||||||||||||||||||||||||||||||
End point description |
AEs (non-serious) as variables of safety and tolerability of RESP301 were assessed.
The safety analysis set included the safety population (SP) would include all randomized participants who inhale any amount of study intervention or were randomized to the control arm. The SP would be analyzed according to the actual treatment received. This set will be used for the safety analyses.
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End point type |
Secondary
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End point timeframe |
From screening to safety follow up (Day 28)
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title |
Time to Hospital Discharge | ||||||||||||
End point description |
Time to hospital discharge is the time in the hospital after first study treatment in days (date of discharge - first dose date + 1). Patients who die before leaving the hospital would be considered failures (did not achieve hospital discharge) and censored. In the case that a patient is still hospitalized at time of analysis or withdraws from the study before leaving the hospital, they would be censored at their date of last assessment in the data cut or early discontinuation date, respectively.
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End point type |
Secondary
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End point timeframe |
Day 10
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants with Mortality | |||||||||
End point description |
Incidence of mortality by Day 28 is the number of patients who have died by Day 28 and the percentage of patients reaching this endpoint would be summarized by treatment group.
The safety analysis set included the safety population (SP) would include all randomized participants who inhale any amount of study intervention or were randomized to the control arm. The SP would be analyzed according to the actual treatment received. This set will be used for the safety analyses.
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End point type |
Secondary
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End point timeframe |
Day 28
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| No statistical analyses for this end point | ||||||||||
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End point title |
Reduction in Oxygen Saturation (SpO2) to <90% | ||||||||||||||||||||||||||||||
End point description |
Room Air SpO2 for a summary of participants with reduction to < 90%, unless well clinically tolerated according to Investigator's opinion was assessed.
The intent-to-treat (ITT) population included all randomized participants.
Justification: 99.999 is an arbitrary number that refers to Post-dose nebulization that did not occur in the SOC arm on specific timepoints. Soc arm data is not applicable.
999.99 is an arbitrary number that refers to only 1 participant was evaluable, hence SD is not calculable.
9999.9999 is an arbitrary number that refers to 0 participant being present in the arm for specific timepoints; Data not available.
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End point type |
Secondary
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End point timeframe |
Day 1 (Baseline), Day 2, Day 3
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Events of Clinical Bronchial Hyper Responsiveness Related to Nebulization | |||||||||
End point description |
Incidence of clinical bronchial hyper responsiveness related to nebulization was assessed. Oxygen saturation decreased and wheezing was assessed as an incidence of clinical bronchial hyper-responsiveness related to nebulization, requiring temporal increase of supplemental oxygen.
The safety analysis set included the safety population (SP) would include all randomized participants who inhale any amount of study intervention or were randomized to the control arm. The SP was analyzed according to the actual treatment received. This set was used for the safety analyses.
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End point type |
Secondary
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End point timeframe |
From screening to safety follow up (Day 28)
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From screening to safety follow up (30 days)
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Adverse event reporting additional description |
Severe AEs is defined as an event that prevents normal everyday activities. An AE that is assessed as severe should not be confused with an SAE. Severe is a category utilized for rating the intensity of an event; and both AE and SAE can be assessed as severe.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
RESP301+SoC
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Reporting group description |
Participants received inhaled RESP301 administered using a nebulizer three times a day (TID) for up to 10 days in addition to the standard of care (SoC). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard of Care (SoC)
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Reporting group description |
Participants received institutional SOC alone for the treatment of COVID-19. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 Jun 2020 |
The original protocol was updated to include important safety guidelines for RESP301 administration for the first 10 participants (i.e., up to the first IDMC safety review). It was also updated to align with the IB Version 2.0, dated 27 May 2020. |
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10 Jun 2020 |
The protocol was updated to clarify that staggered dosing was required for all participants treated before completion of the first IDMC review, and to clarify exclusionary criteria and monitoring of mHb. Information was added to ensure that Investigators are aware of the potential risk of interaction between NO and other NO donor agents. |
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16 Sep 2020 |
The amendment included changes to (a) expand the inclusion criteria to allow enrolment also of patients in hospital with COVID-19 but not yet requiring supplemental oxygen, (b) to allow a minor temporary temperature excursion in the storage conditions of RESP301 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 mHb to >2%. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
