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

Study Overview
=================
Brief Summary
-----------------
This is a Phase II, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of MSTT1041A (astegolimab) compared with placebo and of UTTR1147A compared with placebo, in combination with standard of care (SOC), in patients hospitalized with severe coronavirus disease 2019 (COVID-19) pneumonia.

Official Title
-----------------
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

Conditions
-----------------
COVID-19 Pneumonia

Intervention / Treatment
-----------------
* Drug: MSTT1041A
* Drug: MSTT1041A-matched Placebo
* Drug: UTTR1147A
* Drug: UTTR1147A-matched Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan Peripheral capillary oxygen saturation (SpO2) ≤93% (on room air or supplemental oxygen) or partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≤300 millimetres of mercury (mmHg) or requiring supplemental oxygen to maintain SpO2 >93% or requirement for supplemental oxygen to maintain SpO2 at an acceptable level per local standard of care Exclusion Criteria: Pregnant or breastfeeding, or positive pregnancy test at screening Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Participating in another clinical drug trial Treatment with investigational therapy (other than for COVID-19) within 5 half-lives or 30 days (whichever is longer) prior to initiation of study drug Use of Janus kinase (JAK) inhibitor within 30 days or 5 drug elimination half-lives (whichever is longer) prior to screening Have received high-dose systemic corticosteroids (≥1 mg/kg/day methylprednisolone or equivalent) within 72 hours prior to Day 1 Known HIV infection with CD4 <200 cells/microlitre (uL) or <14% of all lymphocytes ALT or AST >10 times the upper limit of normal (ULN) detected at screening History of anaplastic large-cell lymphoma or mantle-cell lymphoma History of cancer within the previous 5 years unless it has been adequately treated and considered cured or remission-free in the investigator's judgment Clinical evidence of active or unstable cardiovascular disease (e.g., acute myocardial ischemia or decompensated heart failure), as determined by investigator assessment, ECG, laboratory assessment, or echocardiographic data History of moderate or severe allergic, anaphylactic, or anaphylactoid reactions or hypersensitivity to any component of study treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: All Placebo<br>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. | Drug: MSTT1041A-matched Placebo<br>* Participants received up to 2 intravenous infusions of MSTT1041A-matched placebo.<br>Drug: UTTR1147A-matched Placebo<br>* Participants received up to 2 intravenous infusions of UTTR1147A-matched placebo.<br>|
| Experimental: MSTT1041A<br>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. | Drug: MSTT1041A<br>* Participants 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.<br>* Other names: RO7187807;|
| Experimental: UTTR1147A<br>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. | Drug: UTTR1147A<br>* Participants 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.<br>* Other names: IL-22Fc;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | From Baseline up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status by Day 28 | 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 | From Baseline up to 28 days | 
| Time to Hospital Discharge or Ready for Discharge by Day 28 | 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). | Up to 28 days | 
| Duration of Supplemental Oxygen by Day 28 | 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. | Up to 28 days | 
| Percentage of Participants Alive and Free of Respiratory Failure by Day 28 | Respiratory failure was defined as requiring non-invasive ventilation, high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]). | Up to 28 days | 
| Clinical Status Score at Day 14, Assessed Using a 7-Category Ordinal Scale | 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 | Day 14 | 
| Clinical Status Score at Day 28, Assessed Using a 7-Category Ordinal Scale | 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 | Day 28 | 
| Percentage of Participants Needing Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Day 28 |  | Up to 28 days | 
| Number of Ventilator-Free Days by Day 28 | 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. | Up to 28 days | 
| Percentage of Participants With an Intensive Care Unit (ICU) Stay by Day 28 |  | Up to 28 days | 
| Duration of Intensive Care Unit (ICU) Stay by Day 28 | 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. | Up to 28 days | 
| Time to Clinical Failure by Day 28, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal of Care (Whichever Occurs First) |  | Up to 28 days | 
| Percentage of Participants Who Died by Day 14 |  | Up to Day 14 | 
| Percentage of Participants Who Died by Day 28 |  | Up to Day 28 | 
| Time to Clinical Improvement, Defined as a National Early Warning Score 2 (NEWS2) Aggregate Score of ≤2 Maintained for 24 Hours | 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. | Up to 28 days | 
| 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) | 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. | From Baseline until study completion/discontinuation (up to 60 days) | 
| Number of Participants With Clinical Laboratory Test Abnormalities by Highest NCI-CTCAE Grade Post-Baseline | 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 | From Baseline up to 60 days | 
| Number of Participants With Vital Sign Abnormalities at Anytime Post-Baseline | 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. | From Baseline up to 60 days | 
| Number of Participants by the Investigator's Interpretations of Electrocardiogram Recordings at Specified Timepoints | 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. | Baseline, Days 14 and 28, Discharge Day (up to Day 28), and Study Completion Visit (up to Day 60) | 
| Percentage of Participants Who Tested Positive for Anti-Drug Antibodies (ADAs) to MSTT1041A and UTTR1147A at Baseline and at Anytime Post-Baseline | 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). | At Baseline (pre-dose on Day 1) and post-baseline (Days 15 and 28; and discharge day and study completion [up to 60 days]) | 
| Serum Concentration of UTTR1147A at Specified Timepoints |  | 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 | 
| Serum Concentration of MSTT1041A at Specified Timepoints |  | 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 |