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Clinical Trial Results:
A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of MSTT1041A or UTTR1147A in Patients with Severe COVID-19 Pneumonia

Summary
EudraCT number	2020-002713-17
Trial protocol	ES
Global end of trial date	12 Feb 2021

Results information
Results version number	v1(current)
This version publication date	11 Jan 2022
First version publication date	11 Jan 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GA42469

ISRCTN number

US NCT number

NCT04386616

WHO universal trial number (UTN)

Other trial identifiers

BARDA: OT number: HHSO100201800036C

Sponsor organisation name

Genentech, Inc. c/o F. Hoffmann-La Roche Ltd.

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche Ltd., 41 616878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche Ltd., 41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

12 Feb 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Jan 2021

Global end of trial reached?

Yes

Global end of trial date

12 Feb 2021

Was the trial ended prematurely?

Main objective of the trial

The primary efficacy objective for this study is to evaluate the efficacy of MSTT1041A compared with placebo and of UTTR1147A compared with placebo, in combination with standard of care, on the basis of the following endpoint: Time to recovery, defined as time to score of 1 or 2 on the 7-category ordinal scale (whichever occurs first).

Protection of trial subjects

This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Jun 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 59

Country: Number of subjects enrolled

Mexico: 54

Country: Number of subjects enrolled

Spain: 44

Country: Number of subjects enrolled

United States: 239

Worldwide total number of subjects

396

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

276

From 65 to 84 years

116

85 years and over

Subject disposition

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Recruitment details

Screening details

410 patients were randomized, but 14 of those patients were not enrolled (i.e., did not participate in the study) and did not receive a dose of any study drug; they were therefore excluded from the analysis.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Are arms mutually exclusive

Yes

All Placebo

Arm description

Participants randomized to this arm received one intravenous (IV) infusion of either MSTT1041A-matched placebo or UTTR1147A-matched placebo on Day 1. A second IV infusion of either MSTT1041A-matched placebo or UTTR1147A-matched placebo (same placebo as the first infusion) was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Arm type

Placebo

Investigational medicinal product name

Placebo (matched to UTTR1147A)

Investigational medicinal product code

N/A

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received one intravenous (IV) infusion of UTTR1147A-matched Placebo on Day 1, delivered over 60 (+/-10) minutes. A second IV infusion of UTTR1147A-matched Placebo was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen.

Investigational medicinal product name

Placebo (matched to MSTT1014A)

Investigational medicinal product code

N/A

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received one intravenous (IV) infusion of MSTT1041A-matched Placebo on Day 1, delivered over 60 (+/-10) minutes. A second IV infusion of MSTT1041A-matched Placebo was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen.

MSTT1041A

Arm description

Participants randomized to this arm received one intravenous (IV) infusion of MSTT1041A 700 milligrams (mg) on Day 1. A second IV dose of MSTT1041A 350 mg was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Arm type

Experimental

Investigational medicinal product name

MSTT1041A

Investigational medicinal product code

RO7187807/F01

Other name

Astegolimab

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received one intravenous (IV) infusion of MSTT1041A 700 milligrams (mg) on Day 1, delivered over 60 (+/-10) minutes. A second IV dose of MSTT1041A 350 mg was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen.

UTTR1147A

Arm description

Participants randomized to this arm received one intravenous (IV) infusion of UTTR1147A 90 micrograms/kilogram body weight (μg/kg) on Day 1. A second IV dose of UTTR1147A 90 μg/kg was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Arm type

Experimental

Investigational medicinal product name

UTTR1147A

Investigational medicinal product code

RO7021610/F01

Other name

Efmarodocokin alfa

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received one intravenous (IV) infusion of UTTR1147A 90 micrograms/kilogram body weight (μg/kg) on Day 1, delivered over 60 (+/-10) minutes. A second IV dose of UTTR1147A 90 μg/kg was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen. Weight-based infusions of UTTR1147A have a maximum dose given based on 100 kg total body weight.

Number of subjects in period 1	All Placebo	MSTT1041A	UTTR1147A
Started	134	130	132
Received at Least 1 Dose of Study Drug	134	130	132
Completed 2 Doses of Study Drug, Day 15	31 ^[1]	27 ^[2]	25 ^[3]
Completed	104	95	104
Not completed	30	35	28
Consent withdrawn by subject	2	4	1
Adverse event, non-fatal	1	1	-
Death	22	22	21
Lost to follow-up	5	8	6

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all participants received a second dose of study treatment according to the protocol. Only those that remained hospitalized with a requirement for supplemental oxygen received a second dose.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all participants received a second dose of study treatment according to the protocol. Only those that remained hospitalized with a requirement for supplemental oxygen received a second dose.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not all participants received a second dose of study treatment according to the protocol. Only those that remained hospitalized with a requirement for supplemental oxygen received a second dose.

Baseline characteristics

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Reporting group title

All Placebo

Reporting group description

Reporting group title

MSTT1041A

Reporting group description

Reporting group title

UTTR1147A

Reporting group description

Reporting group values	All Placebo	MSTT1041A	UTTR1147A	Total
Number of subjects	134	130	132	396
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	97	88	91	276
From 65-84 years	35	41	40	116
85 years and over	2	1	1	4
Age Continuous
Units: Years
arithmetic mean (standard deviation)	56.0 ( 13.5 )	57.3 ( 13.4 )	57.8 ( 12.6 )	-
Sex: Female, Male
Units: Participants
Female	45	56	52	153
Male	89	74	80	243
Ethnicity
Units: Subjects
Hispanic or Latino	77	72	70	219
Not Hispanic or Latino	53	53	58	164
Unknown or Not Reported	4	5	4	13
Race
Units: Subjects
American Indian or Alaska Native	2	4	0	6
Asian	6	4	5	15
Native Hawaiian or Other Pacific Islander	0	4	1	5
Black or African American	10	7	10	27
White	92	87	89	268
Unknown	24	24	27	75
Region of Enrollment
Regional enrollment sites included the following countries: North America = Mexico and United States; South America = Brazil; and Western Europe = Spain. This was one of the two stratification factors at randomization.
Units: Subjects
North America	99	97	97	293
South America	19	20	20	59
Western Europe	16	13	15	44
Baseline Mechanical Ventilation Required (Yes/No)
This was one of the two stratification factors at randomization.
Units: Subjects
Yes, Baseline Mechanical Ventilation	12	13	11	36
No Baseline Mechanical Ventilation	122	117	121	360
Clinical Status Score at Baseline
The 7 categories of the clinical status ordinal scale are defined as follows: 1. Discharged (or “ready for discharge”); 2. Non-Intensive Care Unit (ICU) hospital ward (or “ready for hospital ward”) not requiring supplemental oxygen; 3. Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen; 4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen; 5. ICU, requiring intubation and mechanical ventilation; 6. ICU, requiring ECMO or mechanical ventilation and additional organ support; 7. Death
Units: Subjects
Clinical Status Score of 1	0	0	0	0
Clinical Status Score of 2	3	4	1	8
Clinical Status Score of 3	47	49	57	153
Clinical Status Score of 4	71	64	63	198
Clinical Status Score of 5	10	8	8	26
Clinical Status Score of 6	3	4	2	9
Clinical Status Score of 7	0	0	0	0
Clinical Status Score Not Available	0	1	1	2

End points

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Reporting group title

All Placebo

Reporting group description

Reporting group title

MSTT1041A

Reporting group description

Reporting group title

UTTR1147A

Reporting group description

Subject analysis set title

MSTT1041A-Matched Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in this analysis group received treatment with MSTT1041A-matched placebo. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Subject analysis set title

UTTR1147A-Matched Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in this analysis group received treatment with UTTR1147A-matched placebo. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Subject analysis set title

UTTR1147A - PK Participants who Only Received First Dose

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants in this analysis group only received one intravenous (IV) infusion of UTTR1147A 90 micrograms/kilogram body weight (μg/kg) on Day 1. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Subject analysis set title

UTTR1147A - PK Participants who Received Both Doses

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants in this analysis group received one intravenous (IV) infusion of UTTR1147A 90 micrograms/kilogram body weight (μg/kg) on Day 1 and a second IV dose of UTTR1147A 90 μg/kg on Day 15 because they remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Subject analysis set title

UTTR1147A - All PK Participants, Days 1 to 15

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in this analysis group either received only the first dose or both doses of UTTR1147A. One intravenous (IV) infusion of UTTR1147A 90 micrograms/kilogram body weight (μg/kg) was given on Day 1, and a second IV dose of UTTR1147A 90 μg/kg was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Subject analysis set title

MSTT1041A - PK Participants who Only Received First Dose

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants in this analysis group only received one intravenous (IV) infusion of MSTT1041A 700 milligrams (mg) on Day 1. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Subject analysis set title

MSTT1041A - PK Participants who Received Both Doses

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants in this analysis group received one intravenous (IV) infusion of MSTT1041A 700 milligrams (mg) on Day 1 and a second IV dose of MSTT1041A 350 mg was given on Day 15 because they remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Subject analysis set title

MSTT1041A - All PK Participants, Days 1 to 15

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in this analysis group either received only the first dose or both doses of MSTT1041A. One intravenous (IV) infusion of MSTT1041A 700 milligrams (mg) on Day 1, and a second IV dose of MSTT1041A 350 mg was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Primary: Time to Recovery, Defined as the Time to a Clinical Status Score of 1 or 2 on the 7-Category Ordinal Scale (Whichever Occurs First) by Day 28

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End point title

Time to Recovery, Defined as the Time to a Clinical Status Score of 1 or 2 on the 7-Category Ordinal Scale (Whichever Occurs First) by Day 28

End point description

The time to recovery was defined as the time from baseline to a clinical status score of 1 or 2 on the 7-category ordinal scale (whichever occurs first); clinical status scores are defined as follows: 1. Discharged (or “ready for discharge” as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤2 Litres supplemental oxygen); 2. Non-Intensive Care Unit (ICU) hospital ward (or “ready for hospital ward”) not requiring supplemental oxygen; 3. Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen; 4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen; 5. ICU, requiring intubation and mechanical ventilation; 6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy); 7. Death.

End point type

Primary

End point timeframe

From Baseline up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (confidence interval 95%)	10.0 (8.0 to 14.0)	11.0 (9.0 to 14.0)	10.0 (8.0 to 13.0)

Hazard Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9266 ^[1]

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.36

Notes
[1] - p<0.05 threshold for statistical significance

Hazard Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.357 ^[2]

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.54

Notes
[2] - p<0.05 threshold for statistical significance

Hazard Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9812 ^[3]

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.36

Notes
[3] - p<0.05 threshold for statistical significance

Hazard Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5151 ^[4]

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

1.49

Notes
[4] - p<0.05 threshold for statistical significance

Secondary: Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status by Day 28

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End point title

Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status by Day 28

End point description

The 7 categories of the clinical status ordinal scale are defined as follows: 1. Discharged (or “ready for discharge” as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤2 Litres supplemental oxygen); 2. Non-Intensive Care Unit (ICU) hospital ward (or “ready for hospital ward”) not requiring supplemental oxygen; 3. Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen; 4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen; 5. ICU, requiring intubation and mechanical ventilation; 6. ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy); 7. Death

End point type

Secondary

End point timeframe

From Baseline up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (confidence interval 95%)	10.0 (8.0 to 14.0)	11.0 (9.0 to 13.0)	10.0 (8.0 to 12.0)

Hazard Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8373

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.39

Hazard Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3396

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.55

Hazard Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8619

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.39

Hazard Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4913

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

1.5

Secondary: Time to Hospital Discharge or “Ready for Discharge” by Day 28

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End point title

Time to Hospital Discharge or “Ready for Discharge” by Day 28

End point description

Hospital discharge is category number 1 out of the 7 categories of the clinical status ordinal scale, and it is defined as follows: 1. Discharged (or “ready for discharge” as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤2 Litres supplemental oxygen).

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (confidence interval 95%)	10.0 (8.0 to 14.0)	11.0 (9.0 to 13.0)	10.0 (8.0 to 13.0)

Hazard Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4711

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.49

Hazard Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3135

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.56

Hazard Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5735

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.48

Hazard Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5973

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.46

Secondary: Duration of Supplemental Oxygen by Day 28

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End point title

Duration of Supplemental Oxygen by Day 28

End point description

Duration of supplemental oxygen was defined as the number of days during the 28-day treatment period when the participant is alive and receives “Supplemental Oxygen or other forms of ventilation”, as recorded in the Vital Signs and Oxygen Saturation form. For each participant, the duration of multiple non-consecutive periods during which the participant received supplemental oxygen was summed. For any days prior to Day 28 where status of supplemental oxygen use was missing, the last known status was to be carried forward.

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (confidence interval 95%)	18.00 (13.00 to 27.00)	17.00 (11.00 to 27.00)	13.50 (10.00 to 21.00)

No statistical analyses for this end point

Secondary: Percentage of Participants Alive and Free of Respiratory Failure by Day 28

Top of page

End point title

Percentage of Participants Alive and Free of Respiratory Failure by Day 28

End point description

Respiratory failure was defined as requiring non-invasive ventilation, high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]).

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Percentage of participants
number (confidence interval 95%)	38.1 (29.47 to 46.65)	39.2 (30.45 to 48.01)	40.2 (31.41 to 48.89)

Odds Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8451

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.72

Odds Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7267

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.79

Odds Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8458

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

1.79

Odds Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7907

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.81

Secondary: Clinical Status Score at Day 14, Assessed Using a 7-Category Ordinal Scale

Top of page

End point title

Clinical Status Score at Day 14, Assessed Using a 7-Category Ordinal Scale

End point description

The clinical status scores of the 7 category ordinal scale are defined as follows: 1. Discharged (or “ready for discharge” as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤2 Litres supplemental oxygen); 2. Non-Intensive Care Unit (ICU) hospital ward (or “ready for hospital ward”) not requiring supplemental oxygen; 3. Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen; 4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen; 5. ICU, requiring intubation and mechanical ventilation; 6. ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy); 7. Death

End point type

Secondary

End point timeframe

Day 14

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Score on a scale
median (inter-quartile range (Q1-Q3))	1.0 (1.0 to 4.0)	1.0 (1.0 to 3.0)	1.0 (1.0 to 4.0)

Odds Ratio - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5652

Method

Proportional Odds Model

Parameter type

Odds ratio (OR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.89

Odds Ratio - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5475

Method

Proportional Odds Model

Parameter type

Odds ratio (OR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.91

Secondary: Clinical Status Score at Day 28, Assessed Using a 7-Category Ordinal Scale

Top of page

End point title

Clinical Status Score at Day 28, Assessed Using a 7-Category Ordinal Scale

End point description

End point type

Secondary

End point timeframe

Day 28

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Score on a scale
median (inter-quartile range (Q1-Q3))	1.0 (1.0 to 4.0)	1.0 (1.0 to 1.0)	1.0 (1.0 to 1.0)

Odds Ratio - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3408

Method

Proportional Odds Model

Parameter type

Odds ratio (OR)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

2.29

Odds Ratio - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

P-value

= 0.332

Method

Proportional Odds Model

Parameter type

Odds ratio (OR)

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

2.29

Secondary: Percentage of Participants Needing Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Day 28

Top of page

End point title

Percentage of Participants Needing Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Day 28

End point description

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Percentage of participants
number (confidence interval 95%)	24.6 (16.96 to 32.29)	28.5 (20.32 to 36.60)	24.2 (16.55 to 31.93)

Difference in Event Rate - MSTT1041A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of participants

Point estimate

3.83

Confidence interval

level

95%

sides

2-sided

lower limit

-7.57

upper limit

15.24

Difference in Event Rate - UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of participants

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-11.46

upper limit

10.7

Odds Ratio (Unstratified) - MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4804

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

2.1

Odds Ratio (Unstratified) - UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9418

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.71

Odds Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4988

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

2.44

Odds Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9043

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.96

Secondary: Number of Ventilator-Free Days by Day 28

Top of page

End point title

Number of Ventilator-Free Days by Day 28

End point description

The number of ventilator-free days was defined as the number of days during the 28-day treatment period when the participant is alive and without need for invasive mechanical ventilation. For any day during Day 1 and Day 28, if invasive mechanical ventilation or ECMO was recorded for any part of the day ( >= 12 hours during mechanical invasive ventilation for patients with tracheostomy), the day was not to be counted as a ventilator-free day; otherwise, the day was to be counted. For any days prior to Day 28 where status of mechanical ventilator was missing, the last known status was to be carried forward. The total number of days was the sum of all ventilator-free days, regardless of whether the days occurred consecutively or in nonconsecutive intervals.

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (inter-quartile range (Q1-Q3))	28.0 (20.00 to 28.00)	28.0 (20.00 to 28.00)	28.0 (23.50 to 28.00)

No statistical analyses for this end point

Secondary: Percentage of Participants with an Intensive Care Unit (ICU) Stay by Day 28

Top of page

End point title

Percentage of Participants with an Intensive Care Unit (ICU) Stay by Day 28

End point description

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Percentage of participants
number (confidence interval 95%)	58.2 (49.48 to 66.93)	54.6 (45.67 to 63.56)	46.2 (37.33 to 55.10)

Difference in Event Rate - MSTT1041A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of participants

Point estimate

-3.59

Confidence interval

level

95%

sides

2-sided

lower limit

-16.31

upper limit

9.12

Difference in Event Rate - UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of participants

Point estimate

-12

Confidence interval

level

95%

sides

2-sided

lower limit

-24.67

upper limit

0.67

Odds Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.556

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.41

Odds Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0502

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

Odds Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7002

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.6

Odds Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0448

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

0.99

Secondary: Duration of Intensive Care Unit (ICU) Stay by Day 28

Top of page

End point title

Duration of Intensive Care Unit (ICU) Stay by Day 28

End point description

Duration of ICU stay was calculated as the total number of hours (expressed in days) spent in ICU up to and inclusive of 28 days. ICU duration was derived from the ICU Stay Information Log using the difference between ICU discharge date/time and ICU admission date/time. If ICU admission occurred before randomization, the ICU duration was to be counted from the date of dosing. Partial admission and discharge date/time were to be imputed following a conservative approach. For each participant, durations of multiple ICU stays were to be summed.

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (confidence interval 95%)	3.10 (0.00 to 5.23)	2.62 (0.00 to 6.02)	0.00 (0.00 to 2.14)

No statistical analyses for this end point

Secondary: Time to Clinical Failure by Day 28, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal of Care (Whichever Occurs First)

Top of page

End point title

Time to Clinical Failure by Day 28, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal of Care (Whichever Occurs First)

End point description

The value '999999' indicates that the median and interquartile range limit(s) could not be estimated because an insufficient number of clinical failure events had occurred.

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (inter-quartile range (Q1-Q3))	999999 (13.0 to 999999)	999999 (9.0 to 999999)	999999 (999999 to 999999)

Hazard Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4456

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.88

Hazard Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7213

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.48

Hazard Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3963

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.96

Hazard Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9174

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.58

Secondary: Percentage of Participants who Died by Day 14

Top of page

End point title

Percentage of Participants who Died by Day 14

End point description

End point type

Secondary

End point timeframe

Up to Day 14

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Percentage of participants
number (confidence interval 95%)	6.0 (1.59 to 10.35)	8.5 (3.29 to 13.63)	8.3 (3.24 to 13.43)

Difference in Event Rate - MSTT1041A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Mortality Rates

Point estimate

2.49

Confidence interval

level

95%

sides

2-sided

lower limit

-4.51

upper limit

9.49

Difference in Event Rate - UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Mortality Rates

Point estimate

2.36

Confidence interval

level

95%

sides

2-sided

lower limit

-4.58

upper limit

9.31

Odds Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4336

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

3.74

Odds Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4543

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.43

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

3.68

Odds Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.49

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

3.97

Odds Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3595

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

4.28

Secondary: Percentage of Participants who Died by Day 28

Top of page

End point title

Percentage of Participants who Died by Day 28

End point description

End point type

Secondary

End point timeframe

Up to Day 28

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Percentage of participants
number (confidence interval 95%)	11.2 (5.48 to 16.91)	14.6 (8.16 to 21.07)	12.9 (6.79 to 18.97)

Difference in Event Rate - MSTT1041A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Mortality Rates

Point estimate

3.42

Confidence interval

level

95%

sides

2-sided

lower limit

-5.42

upper limit

12.26

Difference in Event Rate - UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Mortality Rates

Point estimate

1.68

Confidence interval

level

95%

sides

2-sided

lower limit

-6.89

upper limit

10.26

Odds Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4067

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

2.8

Odds Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6728

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

2.46

Odds Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5495

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

2.87

Odds Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5551

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.24

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

2.71

Secondary: Time to Clinical Improvement, Defined as a National Early Warning Score 2 (NEWS2) Aggregate Score of ≤2 Maintained for 24 Hours

Top of page

End point title

Time to Clinical Improvement, Defined as a National Early Warning Score 2 (NEWS2) Aggregate Score of ≤2 Maintained for 24 Hours

End point description

The National Early Warning Score 2 (NEWS2) is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. Its purpose is to identify acutely ill patients. The NEWS2 scoring system measures 7 physiological parameters: respiration rate, peripheral capillary oxygen saturation, breathing air or supplementary oxygen, systolic blood pressure, pulse rate, level of consciousness or new-onset confusion, and body temperature. A score of 0, 1, 2, or 3 is allocated to each parameter (except for air or oxygen, with respective scores of 0 and 2). A higher score means the parameter is further from the normal range. The score is then aggregated, and a higher score indicates a worse clinical condition of the patient, thus indicating the need for a more urgent clinical response.

End point type

Secondary

End point timeframe

Up to 28 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Days
median (confidence interval 95%)	5.5 (4.0 to 7.0)	6.0 (4.0 to 8.0)	6.0 (3.0 to 9.0)

Hazard Ratio (Unstratified)- MSTT1014A vs. Placebo

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3831

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

2.4

Hazard Ratio (Unstratified)- UTTR1147A vs. Placebo

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5925

Method

Unstratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

2.15

Hazard Ratio (Stratified) - MSTT1014A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v MSTT1041A

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7487

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

2.05

Hazard Ratio (Stratified) - UTTR1147A vs. Placebo

Statistical analysis description

The analysis was adjusted for the baseline characteristics of region of enrollment and need for mechanical ventilation.

Comparison groups

All Placebo v UTTR1147A

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6092

Method

Stratified Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

2.21

Secondary: Safety Summary of the Number of Participants with at Least One Adverse Event, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Top of page

End point title

Safety Summary of the Number of Participants with at Least One Adverse Event, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

End point description

The terms “severe” and “serious” are not synonymous with respect to an adverse event (AE). Severity refers to the intensity of an AE (rated according to NCI-CTCAE v5.0 criteria or, if not listed, the following scale: Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria), such as a life-threatening or fatal AE or an AE that prolongs inpatient hospitalization. Severity and seriousness were independently assessed by the investigator for each AE that was recorded. The investigator also assessed each AE for whether the event was considered to be related to the study drug.

End point type

Secondary

End point timeframe

Up to 60 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Participants
Any Adverse Event (AE)	87	85	95
AE with Fatal Outcome	23	23	21
Serious AE (SAE)	38	38	34
SAE Leading to Withdrawal from Treatment	2	2	1
SAE Leading to Dose Mod./Interruption	0	0	0
Related SAE	0	2	3
AE Leading to Withdrawal from Treatment	4	3	3
AE Leading to Dose Mod./Interruption	0	0	0
Related AE	15	12	25
Related AE Leading to Withdrawal from Treatment	0	0	1
Related AE Leading to Dose Mod./Interruption	0	0	0
Grade 3-5 AE	43	46	41

No statistical analyses for this end point

Secondary: Number of Participants with Clinical Laboratory Test Abnormalities by Highest NCI-CTCAE Grade Post-Baseline

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End point title

Number of Participants with Clinical Laboratory Test Abnormalities by Highest NCI-CTCAE Grade Post-Baseline

End point description

Clinical laboratory tests were performed over the course of the study and the grading of any abnormal values outside of the normal range (High or Low) was based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0); the higher the grade, the greater the lab parameter deviates from the normal range. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Abs. = absolute count; SGPT/ALT = alanine aminotransferase; SGOT/AST = aspartate aminotransferase; INR = international normalized ratio; aPTT = activated partial thromboplastin time

End point type

Secondary

End point timeframe

From Baseline up to 60 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Participants
Albumin, Low - Any Grade (Gr.)(n=133,129,131)	103	105	118
Albumin, Low - Gr. 1 (n=133,129,131)	32	36	40
Albumin, Low - Gr. 2 (n=133,129,131)	56	58	66
Albumin, Low - Gr. 3 (n=133,129,131)	15	11	12
Alkaline Phosphatase, High -Any Gr.(n=133,130,132)	20	23	24
Alkaline Phosphatase, High -Gr. 1 (n=133,130,132)	14	22	22
Alkaline Phosphatase, High -Gr. 2 (n=133,130,132)	5	1	1
Alkaline Phosphatase, High -Gr. 3 (n=133,130,132)	1	0	1
SGPT/ALT, High - Any Gr. (n=132,129,132)	60	48	60
SGPT/ALT, High - Gr. 1 (n=132,129,132)	48	37	47
SGPT/ALT, High - Gr. 2 (n=132,129,132)	5	7	7
SGPT/ALT, High - Gr. 3 (n=132,129,132)	5	3	5
SGPT/ALT, High - Gr. 4 (n=132,129,132)	2	1	1
SGOT/AST, High - Any Gr. (n=133,129,131)	47	38	44
SGOT/AST, High - Gr. 1 (n=133,129,131)	40	30	36
SGOT/AST, High - Gr. 2 (n=133,129,131)	4	5	4
SGOT/AST, High - Gr. 3 (n=133,129,131)	0	2	2
SGOT/AST, High - Gr. 4 (n=133,129,131)	3	1	2
Calcium, Low - Any Gr. (n=133,130,132)	73	82	84
Calcium, Low - Gr. 1 (n=133,130,132)	34	47	48
Calcium, Low - Gr. 2 (n=133,130,132)	31	26	29
Calcium, Low - Gr. 3 (n=133,130,132)	5	7	4
Calcium, Low - Gr. 4 (n=133,130,132)	3	2	3
Calcium, High - Any Gr. (n=133,130,132)	5	2	4
Calcium, High - Gr. 1 (n=133,130,132)	5	2	4
Creatinine, High - Any Gr. (n=133,130,132)	24	39	29
Creatinine, High - Gr. 1 (n=133,130,132)	6	11	8
Creatinine, High - Gr. 2 (n=133,130,132)	11	24	15
Creatinine, High - Gr. 3 (n=133,130,132)	7	3	5
Creatinine, High - Gr. 4 (n=133,130,132)	0	1	1
Fibrinogen, Low - Any Gr. (n=125,122,130)	7	3	1
Fibrinogen, Low - Gr. 1 (n=125,122,130)	1	1	0
Fibrinogen, Low - Gr. 2 (n=125,122,130)	3	2	0
Fibrinogen, Low - Gr. 3 (n=125,122,130)	2	0	0
Fibrinogen, Low - Gr. 4 (n=125,122,130)	1	0	1
Glucose, Low - Any Gr. (n=133,130,132)	8	11	12
Glucose, Low - Gr. 1 (n=133,130,132)	6	6	9
Glucose, Low - Gr. 2 (n=133,130,132)	1	5	0
Glucose, Low - Gr. 3 (n=133,130,132)	1	0	2
Glucose, Low - Gr. 4 (n=133,130,132)	0	0	1
Hemoglobin, Low - Any Gr. (n=133,130,132)	77	72	78
Hemoglobin, Low - Gr. 1 (n=133,130,132)	43	47	46
Hemoglobin, Low - Gr. 2 (n=133,130,132)	17	17	21
Hemoglobin, Low - Gr. 3 (n=133,130,132)	17	8	11
Hemoglobin, High - Any Gr. (n=133,130,132)	9	7	5
Hemoglobin, High - Gr. 1 (n=133,130,132)	9	6	5
Hemoglobin, High - Gr. 3 (n=133,130,132)	0	1	0
Lymphocytes, Abs, Low - Any Gr.(n=100,91,93)	61	45	48
Lymphocytes, Abs, Low - Gr. 1 (n=100,91,93)	14	9	11
Lymphocytes, Abs, Low - Gr. 2 (n=100,91,93)	23	17	23
Lymphocytes, Abs, Low - Gr. 3 (n=100,91,93)	23	18	11
Lymphocytes, Abs, Low - Gr. 4 (n=100,91,93)	1	1	3
Lymphocytes, Abs, High - Any Gr. (n=100,91,93)	4	4	1
Lymphocytes, Abs, High - Gr. 2 (n=100,91,93)	4	4	1
Neutrophils, Total(Abs), Low -Any Gr.(n=100,91,93)	5	3	1
Neutrophils, Total (Abs), Low -Gr. 1 (n=100,91,93)	4	3	0
Neutrophils, Total (Abs), Low -Gr. 2 (n=100,91,93)	1	0	1
Platelets, Low - Any Gr. (n=133,130,132)	17	17	12
Platelets, Low - Gr. 1 (n=133,130,132)	14	15	9
Platelets, Low - Gr. 2 (n=133,130,132)	2	0	2
Platelets, Low - Gr. 3 (n=133,130,132)	1	1	0
Platelets, Low - Gr. 4 (n=133,130,132)	0	1	1
Potassium, Low - Any Gr. (n=133,130,132)	29	19	25
Potassium, Low - Gr. 2 (n=133,130,132)	25	18	23
Potassium, Low - Gr. 3 (n=133,130,132)	4	1	2
Potassium, High - Any Gr. (n=133,130,132)	15	25	16
Potassium, High - Gr. 1 (n=133,130,132)	7	19	12
Potassium, High - Gr. 2 (n=133,130,132)	5	3	3
Potassium, High - Gr. 3 (n=133,130,132)	2	3	1
Potassium, High - Gr. 4 (n=133,130,132)	1	0	0
INR, High - Any Gr. (n=126,125,130)	71	69	75
INR, High - Gr. 1 (n=126,125,130)	60	61	67
INR, High - Gr. 2 (n=126,125,130)	9	8	6
INR, High - Gr. 3 (n=126,125,130)	2	0	2
aPTT, High - Any Gr. (n=121,126,128)	47	42	42
aPTT, High - Gr. 1 (n=121,126,128)	38	35	36
aPTT, High - Gr. 2 (n=121,126,128)	6	5	3
aPTT, High - Gr. 3 (n=121,126,128)	3	2	3
Sodium, Low - Any Gr. (n=133,130,132)	67	58	58
Sodium, Low - Gr. 1 (n=133,130,132)	60	50	51
Sodium, Low - Gr. 2 (n=133,130,132)	6	6	7
Sodium, Low - Gr. 3 (n=133,130,132)	1	1	0
Sodium, Low - Gr. 4 (n=133,130,132)	0	1	0
Sodium, High - Any Gr. (n=133,130,132)	17	16	23
Sodium, High - Gr. 1 (n=133,130,132)	11	10	21
Sodium, High - Gr. 2 (n=133,130,132)	5	5	1
Sodium, High - Gr. 3 (n=133,130,132)	0	1	0
Sodium, High - Gr. 4 (n=133,130,132)	1	0	1
Bilirubin, High - Any Gr. (n=133,130,132)	16	14	11
Bilirubin, High - Gr. 1 (n=133,130,132)	12	9	8
Bilirubin, High - Gr. 2 (n=133,130,132)	2	5	2
Bilirubin, High - Gr. 3 (n=133,130,132)	2	0	1
Uric Acid, High - Any Gr. (n=114,112,114)	33	24	22
Uric Acid, High - Gr. 3 (n=114,112,114)	33	24	22
Total Leukocyte Count, Low -Any Gr.(n=133,130,132)	12	6	10
Total Leukocyte Count, Low - Gr. 1 (n=133,130,132)	10	6	10
Total Leukocyte Count, Low - Gr. 2 (n=133,130,132)	2	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Vital Sign Abnormalities at Anytime Post-Baseline

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End point title

Number of Participants with Vital Sign Abnormalities at Anytime Post-Baseline

End point description

The number of participants with vital sign abnormalities outside of the normal upper (i.e., High) and lower limits (i.e., Low) were summarized for each parameter. The normal reference range used for each vital sign parameter was as follows: Diastolic Blood Pressure, 50-90 millimetres of mercury (mmHg); Oxygen Saturation, ≥94%; Pulse Rate, 60-100 beats per minute; Respiratory Rate, 8-20 breaths per minute; Systolic Blood Pressure, 90-140 mmHg; Temperature, 36.5-38 degrees Celsius (C). Not every vital sign abnormality qualified as an adverse event. A vital sign result was to be reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgement.

End point type

Secondary

End point timeframe

From Baseline up to 60 days

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	133	130	132
Units: Participants
Diastolic Blood Pressure - Low	23	23	21
Diastolic Blood Pressure - High	39	43	39
Oxygen Saturation - Low	112	107	105
Pulse Rate - Low	66	66	61
Pulse Rate - High	75	62	57
Respiratory Rate - Low	1	0	2
Respiratory Rate - High	108	104	103
Systolic Blood Pressure - Low	20	11	17
Systolic Blood Pressure - High	77	81	70
Temperature - Low	116	113	113
Temperature - High	13	10	14

No statistical analyses for this end point

Secondary: Number of Participants by the Investigator's Interpretations of Electrocardiogram Recordings at Specified Timepoints

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End point title

Number of Participants by the Investigator's Interpretations of Electrocardiogram Recordings at Specified Timepoints

End point description

Electrocardiogram (ECG) recordings were to be performed after the participant had been resting in a supine position for at least 10 minutes if possible. The investigator's interpretation of the ECG (e.g., normal or abnormal) was recorded.

End point type

Secondary

End point timeframe

Baseline, Days 14 and 28, Discharge Day (up to Day 28), and Study Completion Visit (up to Day 60)

End point values	All Placebo	MSTT1041A	UTTR1147A
Number of subjects analysed	134	130	132
Units: Participants
Baseline - Abnormal ECG (n=132,126,130)	56	60	55
Baseline - Normal ECG (n=132,126,130)	76	66	75
Day 14 - Abnormal ECG (n=34,29,24)	20	13	14
Day 14 - Normal ECG (n=34,29,24)	14	16	10
Day 28 - Abnormal ECG (n=15,5,7)	12	3	4
Day 28 - Normal ECG (n=15,5,7)	3	2	3
Discharge Day - Abnormal ECG (n=64,75,76)	27	28	37
Discharge Day - Normal ECG (n=64,75,76)	37	47	39
Study Completion - Abnormal ECG (n=69,65,62)	13	18	21
Study Completion - Normal ECG (n=69,65,62)	56	46	40
Study Completion - Unable to Evaluate (n=69,65,62)	0	1	1

No statistical analyses for this end point

Secondary: Percentage of Participants who Tested Positive for Anti-Drug Antibodies (ADAs) to MSTT1041A and UTTR1147A at Baseline and at Anytime Post-Baseline

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End point title

Percentage of Participants who Tested Positive for Anti-Drug Antibodies (ADAs) to MSTT1041A and UTTR1147A at Baseline and at Anytime Post-Baseline ^[5]

End point description

Serum samples were collected, and participants who received treatment with MSTT1041A or MSTT1041A-matched placebo were assessed for antidrug antibodies (ADAs) to MSTT1041A, while those who received UTTR1147A or UTTR1147A-matched placebo were assessed for ADAs to UTTR1147A. The percentage of ADA-positive participants at baseline (baseline prevalence) and after drug administration (postbaseline incidence; for experimental drugs only, not placebo) are summarized. When determining postbaseline incidence, participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADAs), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (treatment-enhanced ADAs). The value '999999' indicates that no results are available because 0 participants were analyzed.

End point type

Secondary

End point timeframe

At Baseline (pre-dose on Day 1) and post-baseline (Days 15 and 28; and discharge day and study completion [up to 60 days])

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The percentage of participants who test positive for ADAs at Baseline is also presented here for those in the All Placebo Arm, but this arm is split into 2 subgroups according to the type of placebo received (i.e., MSTT1041A-matched or UTTR1147A-matched).

End point values	MSTT1041A	UTTR1147A	MSTT1041A-Matched Placebo	UTTR1147A-Matched Placebo
Number of subjects analysed	130	132	59	59
Units: Percentage of participants
number (not applicable)
ADA Positive at Baseline (n=117,126,59,59)	2.6	1.6	3.4	1.7
ADA Positive Post-Baseline, Total (n=104,107,0,0)	2.9	0.9	999999	999999
Treatment-Induced ADA Positive (n=104,107,0,0)	1.9	0.9	999999	999999
Treatment-Enhanced ADA Positive (n=104,107,0,0)	1.0	0.0	999999	999999

No statistical analyses for this end point

Secondary: Serum Concentration of UTTR1147A at Specified Timepoints

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End point title

Serum Concentration of UTTR1147A at Specified Timepoints

End point description

The Pharmacokinetics (PK) analysis population for UTTR1147A consisted of participants who received at least one dose of UTTR1147A and had at least one evaluable PK concentration data point. The PK analysis population is further divided into three groups: participants who only received the first dose, participants who received both doses, and all participants who received the first dose only or both doses (from Days 1 to 15). The value '999999' indicates that no results are available because 0 participants were analyzed at that timepoint. The value '99999' indicates that the standard deviation could not be calculated with data from 1 participant.

End point type

Secondary

End point timeframe

For the first dose: at 0.5 hours post-dose on Day 1, on Days 2, 3, 7, and 15; and for the second dose: Days 15 (0.5 hours post-dose), 21, and 28

End point values	UTTR1147A - PK Participants who Only Received First Dose	UTTR1147A - PK Participants who Received Both Doses	UTTR1147A - All PK Participants, Days 1 to 15
Number of subjects analysed	105	25	130
Units: nanograms per millilitre (ng/mL)
arithmetic mean (standard deviation)
Day 1, 0.5 hours post-dose (n=98,24,122)	1260 ( 568 )	1600 ( 1820 )	1320 ( 952 )
Day 2 (n = 96, 23, 119)	707 ( 268 )	674 ( 372 )	700 ( 290 )
Day 3 (n = 84, 24, 108)	518 ( 221 )	604 ( 222 )	537 ( 223 )
Day 7 (n = 46, 24, 70)	258 ( 110 )	259 ( 109 )	258 ( 109 )
Day 15, pre-dose (n = 4, 25, 29)	42.3 ( 27.8 )	88.1 ( 40.6 )	81.8 ( 41.9 )
Day 15, 0.5 hours post-dose (n=0,25,0)	999999 ( 999999 )	1410 ( 802 )	999999 ( 999999 )
Day 21 (n = 1, 14, 0)	2.69 ( 99999 )	297 ( 147 )	999999 ( 999999 )
Day 28 (n = 3, 8, 0)	11.3 ( 8.89 )	173 ( 78.4 )	999999 ( 999999 )

No statistical analyses for this end point

Secondary: Serum Concentration of MSTT1041A at Specified Timepoints

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End point title

Serum Concentration of MSTT1041A at Specified Timepoints

End point description

The Pharmacokinetics (PK) analysis population for MSTT1041A consisted of participants who received at least one dose of MSTT1041A and had at least one evaluable PK concentration data point. The PK analysis population is further divided into three groups: participants who only received the first dose, participants who received both doses, and all participants who received the first dose only or both doses (from Days 1 to 15). The value '999999' indicates that no results are available because 0 participants were analyzed at that timepoint.

End point type

Secondary

End point timeframe

For the first dose: at 0.5 hours post-dose on Day 1, on Days 2, 3, 7, and 15; and for the second dose: Days 15 (0.5 hours post-dose), 21, and 28

End point values	MSTT1041A - PK Participants who Only Received First Dose	MSTT1041A - PK Participants who Received Both Doses	MSTT1041A - All PK Participants, Days 1 to 15
Number of subjects analysed	96	23	119
Units: micrograms per millilitre (μg/mL)
arithmetic mean (standard deviation)
Day 1, 0.5 hours post-dose (n=90,22,112)	206 ( 71.1 )	227 ( 66.7 )	210 ( 70.4 )
Day 2 (n = 89, 23, 112)	175 ( 49.1 )	178 ( 54.3 )	176 ( 50.0 )
Day 3 (n = 81, 23, 104)	147 ( 40.1 )	135 ( 41.0 )	144 ( 40.4 )
Day 7 (n = 49, 23, 72)	88.6 ( 32.3 )	83.9 ( 28.1 )	87.1 ( 30.9 )
Day 15, pre-dose (n = 4, 22, 26)	32.2 ( 15.2 )	33.8 ( 17.2 )	33.5 ( 16.6 )
Day 15, 0.5 hours post-dose (n=0,21,0)	999999 ( 999999 )	144 ( 48.0 )	999999 ( 999999 )
Day 21 (n = 0, 9, 0)	999999 ( 999999 )	45.4 ( 20.8 )	999999 ( 999999 )
Day 28 (n = 0, 5, 0)	999999 ( 999999 )	22.5 ( 9.17 )	999999 ( 999999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline until study completion/discontinuation (up to 60 days)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

All Placebo

Reporting group description

Reporting group title

MSTT1041A

Reporting group description

Participants randomized to this arm received one intravenous (IV) infusion of MSTT1041A 700 milligrams (mg) on Day 1. A second IV dose of MSTT1041A 700 mg was given on Day 15 if the participant remained hospitalized with a requirement for supplemental oxygen. Study treatment was given in combination with the standard of care for COVID-19 pneumonia.

Reporting group title

UTTR1147A

Reporting group description

Serious adverse events	All Placebo	MSTT1041A	UTTR1147A
Total subjects affected by serious adverse events
subjects affected / exposed	38 / 134 (28.36%)	38 / 130 (29.23%)	34 / 132 (25.76%)
number of deaths (all causes)	23	23	21
number of deaths resulting from adverse events	0	2	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Distributive shock
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 134 (1.49%)	2 / 130 (1.54%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Shock haemorrhagic
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Ill-defined disorder
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 134 (0.75%)	2 / 130 (1.54%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Acute respiratory failure
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	4 / 132 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 3
Dyspnoea
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 134 (0.00%)	2 / 130 (1.54%)	3 / 132 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pleural effusion
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pneumothorax
subjects affected / exposed	5 / 134 (3.73%)	2 / 130 (1.54%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 134 (2.24%)	1 / 130 (0.77%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory distress
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	5 / 134 (3.73%)	4 / 130 (3.08%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 1	0 / 2
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 134 (0.00%)	2 / 130 (1.54%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 134 (1.49%)	3 / 130 (2.31%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 134 (0.75%)	1 / 130 (0.77%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1
Cardiac failure
subjects affected / exposed	1 / 134 (0.75%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	5 / 134 (3.73%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 5	0 / 0	0 / 1
Left ventricular failure
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Right ventricular dysfunction
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal incontinence
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 134 (0.75%)	2 / 130 (1.54%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 2	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Liver injury
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 134 (1.49%)	2 / 130 (1.54%)	3 / 132 (2.27%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Haematuria
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 134 (1.49%)	0 / 130 (0.00%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Renal impairment
subjects affected / exposed	2 / 134 (1.49%)	1 / 130 (0.77%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacillus bacteraemia
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	2 / 134 (1.49%)	3 / 130 (2.31%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
COVID-19 pneumonia
subjects affected / exposed	5 / 134 (3.73%)	7 / 130 (5.38%)	5 / 132 (3.79%)
occurrences causally related to treatment / all	0 / 5	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 5	0 / 7	0 / 5
Candida sepsis
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	1 / 132 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 134 (0.75%)	3 / 130 (2.31%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	1 / 3	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 134 (0.75%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	2 / 134 (1.49%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 134 (0.00%)	0 / 130 (0.00%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	3 / 134 (2.24%)	3 / 130 (2.31%)	4 / 132 (3.03%)
occurrences causally related to treatment / all	0 / 3	0 / 3	1 / 4
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 2
Superinfection bacterial
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	2 / 132 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	1 / 134 (0.75%)	0 / 130 (0.00%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	0 / 134 (0.00%)	1 / 130 (0.77%)	0 / 132 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	All Placebo	MSTT1041A	UTTR1147A
Total subjects affected by non serious adverse events
subjects affected / exposed	29 / 134 (21.64%)	42 / 130 (32.31%)	40 / 132 (30.30%)
Vascular disorders
Hypertension
subjects affected / exposed	4 / 134 (2.99%)	8 / 130 (6.15%)	2 / 132 (1.52%)
occurrences all number	4	8	2
Hypotension
subjects affected / exposed	5 / 134 (3.73%)	7 / 130 (5.38%)	5 / 132 (3.79%)
occurrences all number	6	8	6
Nervous system disorders
Headache
subjects affected / exposed	4 / 134 (2.99%)	7 / 130 (5.38%)	4 / 132 (3.03%)
occurrences all number	4	8	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 134 (4.48%)	9 / 130 (6.92%)	7 / 132 (5.30%)
occurrences all number	6	9	8
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 134 (1.49%)	3 / 130 (2.31%)	7 / 132 (5.30%)
occurrences all number	2	3	7
Constipation
subjects affected / exposed	6 / 134 (4.48%)	10 / 130 (7.69%)	10 / 132 (7.58%)
occurrences all number	6	10	10
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	5 / 134 (3.73%)	4 / 130 (3.08%)	9 / 132 (6.82%)
occurrences all number	5	4	9
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 134 (0.75%)	5 / 130 (3.85%)	8 / 132 (6.06%)
occurrences all number	1	5	8
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	8 / 134 (5.97%)	9 / 130 (6.92%)	8 / 132 (6.06%)
occurrences all number	8	9	10

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Were there any global substantial amendments to the protocol? Yes

27 May 2020

Protocol Version 2: The purpose of this update was to define the time to clinical failure for patients entering the study who were already in the ICU or on mechanical ventilation. A new secondary endpoint, "Proportion of patients alive and free of respiratory failure at Day 28", was added. The protocol was updated to indicate that the re-screening assessments were required at specified durations after the initial screen failure. The peripheral capillary oxygen saturation (SpO2) inclusion criterion was updated, and the protocol was updated to require that the specific form of ventilation required be recorded. The protocol was updated to clarify that all concomitant therapy for COVID-19 should be recorded on the appropriate electronic Case Report Form (eCRF), independently of the start date of such therapy, and to prohibit concomitant therapy with tumor necrosis factor (TNF) inhibitors, anti-IL-1 agents, and investigational agents other than for COVID-19. Details on laboratory abnormalities associated with RO7021610 were added; the protocol was updated to specify reporting of dermatological toxicity on the rash eCRF.MSTT1041A/UTTR1147A—Genentech, Inc. 4/Protocol GA42469, Version 2. Guidelines for managing patients who experienced infusion-related reactions (IRR) was added.

03 Aug 2020

Protocol Version 3: Amended to allow for use of a conventional troponin assay if a high-sensitivity immunoassay was not available locally. Incidence of ECMO was upgraded from an exploratory to a secondary efficacy endpoint, and duration of hypoxemia was removed from the list of secondary efficacy endpoints. Language was updated to clarify that a stratification factor, the enrollment cap, and certain statistical summaries and analyses would be based on invasive mechanical ventilation. Language was updated to clarify that discharge assessments were applicable to patients transferred to a different care facility upon discharge from the hospital. The inclusion criteria and description of laboratory tests were modified to accommodate sites at an altitude 5000 feet. Language regarding pregnancy testing was updated to account for the fact that either a urine or serum test may be performed and to clarify that women of childbearing potential must have a negative pregnancy test at screening. Exclusion criteria (EC) were modified to allow enrollment of patients with a troponin level equal to the ULN. EC were also modified to clarify that prolonged QT interval was based on QT interval corrected (Fridericia's formula) and to include guidance for patients with a ventricular pacemaker. Language was modified to clarify timing for recording vital signs, oxygen saturation, and NEWS2 specific assessments, and for assessing clinical status. Statistical analysis methods for the primary endpoint was modified to indicate that a non-parametric method that does not assume proportional odds (Van Elteren test) would be used if the proportional odds assumption is violated. Language was modified to clarify the timing of PK samples. The timing of the second dose of study drug was modified to allow for drug administration on Days 14, 16, or 17 for cases when the dose could not be given on Day 15, provided certain assessments were performed prior to administration.

16 Sep 2020

Protocol Version 4: The protocol was amended to change the primary endpoint and increase the sample size. Substantive changes to the protocol, along with a rationale for each change, are summarized below: The primary endpoint was changed to “Time to recovery, defined as time to score of 1 or 2 on the 7-category ordinal scale (whichever occurs first)”. The previous primary endpoint, “Clinical status assessed using a 7-category ordinal scale at Day 28,” was moved to the secondary efficacy endpoints. On the basis of published data from other clinical trials for COVID-19 pneumonia (Beigel et al. 2020; McCreary and Angus 2020), there appeared to be growing consensus that time to recovery reflected a clinically meaningful outcome measurement for the targeted patient population. Additionally, given the variable time course of COVID-19, a fixed time endpoint could miss recognition of clinical benefit and therefore may not be optimal (Dodd et al. 2020). The incidence of mechanical ventilation and extracorporeal membrane oxygenation was combined into a single secondary efficacy endpoint, as both represented a worsening of the clinical status and choice of management could vary between institutions. Clarifications were made to the reporting requirements for possible RO7021610-mediated dermatologic reactions. The sample size was increased from 300 patients to approximately 390 patients with severe COVID-19 pneumonia, which was anticipated provide approximately 80% power to detect a difference between treatment groups for the new primary endpoint, “time to recovery, defined as time to score of 1 or 2 on the 7-category ordinal scale (whichever occurs first)”.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of MSTT1041A or UTTR1147A in Patients with Severe COVID-19 Pneumonia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to Recovery, Defined as the Time to a Clinical Status Score of 1 or 2 on the 7-Category Ordinal Scale (Whichever Occurs First) by Day 28

Primary: Time to Recovery, Defined as the Time to a Clinical Status Score of 1 or 2 on the 7-Category Ordinal Scale (Whichever Occurs First) by Day 28

Secondary: Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status by Day 28

Secondary: Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status by Day 28

Secondary: Time to Hospital Discharge or “Ready for Discharge” by Day 28

Secondary: Time to Hospital Discharge or “Ready for Discharge” by Day 28

Secondary: Duration of Supplemental Oxygen by Day 28

Secondary: Duration of Supplemental Oxygen by Day 28

Secondary: Percentage of Participants Alive and Free of Respiratory Failure by Day 28

Secondary: Percentage of Participants Alive and Free of Respiratory Failure by Day 28

Secondary: Clinical Status Score at Day 14, Assessed Using a 7-Category Ordinal Scale

Secondary: Clinical Status Score at Day 14, Assessed Using a 7-Category Ordinal Scale

Secondary: Clinical Status Score at Day 28, Assessed Using a 7-Category Ordinal Scale

Secondary: Clinical Status Score at Day 28, Assessed Using a 7-Category Ordinal Scale

Secondary: Percentage of Participants Needing Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Day 28

Secondary: Percentage of Participants Needing Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Day 28

Secondary: Number of Ventilator-Free Days by Day 28

Secondary: Number of Ventilator-Free Days by Day 28

Secondary: Percentage of Participants with an Intensive Care Unit (ICU) Stay by Day 28

Secondary: Percentage of Participants with an Intensive Care Unit (ICU) Stay by Day 28

Secondary: Duration of Intensive Care Unit (ICU) Stay by Day 28

Secondary: Duration of Intensive Care Unit (ICU) Stay by Day 28

Secondary: Time to Clinical Failure by Day 28, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal of Care (Whichever Occurs First)

Secondary: Time to Clinical Failure by Day 28, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal of Care (Whichever Occurs First)

Secondary: Percentage of Participants who Died by Day 14

Secondary: Percentage of Participants who Died by Day 14

Secondary: Percentage of Participants who Died by Day 28

Secondary: Percentage of Participants who Died by Day 28

Secondary: Time to Clinical Improvement, Defined as a National Early Warning Score 2 (NEWS2) Aggregate Score of ≤2 Maintained for 24 Hours

Secondary: Time to Clinical Improvement, Defined as a National Early Warning Score 2 (NEWS2) Aggregate Score of ≤2 Maintained for 24 Hours

Secondary: Safety Summary of the Number of Participants with at Least One Adverse Event, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Secondary: Safety Summary of the Number of Participants with at Least One Adverse Event, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Secondary: Number of Participants with Clinical Laboratory Test Abnormalities by Highest NCI-CTCAE Grade Post-Baseline

Secondary: Number of Participants with Clinical Laboratory Test Abnormalities by Highest NCI-CTCAE Grade Post-Baseline

Secondary: Number of Participants with Vital Sign Abnormalities at Anytime Post-Baseline

Secondary: Number of Participants with Vital Sign Abnormalities at Anytime Post-Baseline

Secondary: Number of Participants by the Investigator's Interpretations of Electrocardiogram Recordings at Specified Timepoints

Secondary: Number of Participants by the Investigator's Interpretations of Electrocardiogram Recordings at Specified Timepoints

Secondary: Percentage of Participants who Tested Positive for Anti-Drug Antibodies (ADAs) to MSTT1041A and UTTR1147A at Baseline and at Anytime Post-Baseline

Secondary: Percentage of Participants who Tested Positive for Anti-Drug Antibodies (ADAs) to MSTT1041A and UTTR1147A at Baseline and at Anytime Post-Baseline

Secondary: Serum Concentration of UTTR1147A at Specified Timepoints

Secondary: Serum Concentration of UTTR1147A at Specified Timepoints

Secondary: Serum Concentration of MSTT1041A at Specified Timepoints

Secondary: Serum Concentration of MSTT1041A at Specified Timepoints

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of MSTT1041A or UTTR1147A in Patients with Severe COVID-19 Pneumonia