A Study to Evaluate the Safety and Efficacy of MSTT1041A (Astegolimab) or UTTR1147A in Patients With Severe COVID-19 Pneumonia

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.

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

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).

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.

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

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

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

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.

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.

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 scores for each parameter are then summed (with an aggregate score ranging from 0 to 20), and a higher aggregate score indicates a worse clinical condition of the patient, thus indicating the need for a more urgent clinical response.

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 SAE 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.

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 deviated 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. SGPT/ALT = alanine aminotransferase; SGOT/AST = aspartate aminotransferase; INR = international normalized ratio; aPTT = activated partial thromboplastin time

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.

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.

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. Participants who received placebo treatment were only assessed for the presence of ADAs at baseline. The percentage of ADA-positive participants at baseline (baseline prevalence) and after drug administration (postbaseline incidence) 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 ADA response), 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 ADA response).