Study of Efficacy and Safety of MAS825 in Patients With COVID-19

Phase 2

Completed

Conditions: COVID-19 Pneumonia, Impaired Respiratory Function

Interventions: Drug: MAS825
Other: Placebo
Drug: Standard of Care (SoC)

Registration Number: NCT04382651

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This clinical study was designed to assess the efficacy and safety of MAS825 for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infected patients with coronavirus disease 2019 (COVID-19) pneumonia and impaired respiratory function.

Detailed Description: This was a Phase 2, randomized, placebo -controlled, participant and investigator blinded, multi-center study to assess efficacy and safety of MAS825 for the treatment of SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired respiratory function.

The study consisted of five study periods:

Screening / Baseline / Treatment visit (Day -1 to 1): Lasted up to a maximum of 24 hours and comprised a screening / baseline assessment. This visit was used to confirm that the study inclusion and exclusion criteria were met and served as baseline assessment prior to randomization. Participants were randomized as soon as possible, but within a maximum of 24 hours after screening in a 1:1 ratio receiving a single intravenous infusion of MAS825 or placebo in addition to standard of care (SoC) on Day -1 to 1.

Treatment period (Day 2-15): Study assessments were conducted every 2 days for hospitalized participants. If participants were discharged from the hospital prior to Day 15, assessments on the day of discharge were performed according to the schedule listed under Day 15 and those participants returned to the site for the Day 15 assessment (all other visits between discharge and Day 15 were omitted).

Follow-up (Day 16-29): After completion of the treatment period, participants were observed until Day 29 or discharged from hospital, whichever was sooner. Study assessments were conducted every 2 days for domiciled participants. If participants were discharged from hospital prior to Day 29, a study visit conducted by telephone was performed on Day 29 (all other visits between discharge and Day 29 were omitted).

Safety follow-up visit assessment (Day 45): A follow-up visit for safety was conducted at Day 45 if the participant was hospitalized. If participants were discharged from the hospital prior to Day 45, a study visit was conducted by telephone on Day 45.

End of Study/Safety follow-up visit assessment (Day 127): A follow-up visit for safety was conducted at Day 127 if the participant was hospitalized. If participants were discharged from the hospital prior to Day 127, a study visit was conducted by telephone on Day 127.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 140

Inclusion Criteria

Male and female patients aged ≥18 years at screening
Signed Informed Consent Form (ICF) by patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representative (if allowed according to local requirements)
Clinically diagnosed with the SARS-CoV-2 virus by polymerase chain reaction (PCR) or by other approved diagnostic methodology within 7 days prior to randomization
Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray, computed tomography scan (CT scan) or magnetic resonance scan (MR scan) (taken within 5 days prior to randomization)
Impaired respiratory function, defined as peripheral oxygen saturation (SpO2) ≤93% on room air or partial pressure of oxygen (PaO2) / fraction of inspired oxygen (FiO2) <300 millimeter of mercury (mmHg) at time of screening For cities located at altitudes greater than 2500 m above sea level, these will be substituted with SpO2 <90% and PaO2/FiO2 <250 mmHg
Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score of ≥10 at time of screening
CRP ≥20 mg/L or ferritin level ≥600 μg/L at screening
Body weight between 45 kg and 145 kg, inclusive, at screening
Ability to comply with the study protocol, in the investigator's judgment

Exclusion Criteria

History of hypersensitivity to the investigational treatment or their excipients or to drugs of similar chemical classes
Suspected active or chronic bacterial (including Mycobacterium tuberculosis), fungal, viral, or other infection with the exception of SARS-CoV-2
In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatment
Intubated prior to randomization
Patients who have explicitly expressed the wish not to receive intensive care support when this would be indicated based on their condition
Previous treatment with anti-rejection and immunomodulatory drugs within the past 2 weeks, or within the past 30 days or 5 half-lives (whichever is the longer) for immunomodulatory therapeutic antibodies or prohibited drugs, with the exception of anti-viral therapies or corticosteroids
- For COVID-19 infection, ongoing corticosteroid treatment is permitted at doses as per local SoC
- For non-COVID-19 disorders, ongoing corticosteroid treatment is permitted at doses up to and including prednisolone 10 mg daily or equivalent.
Serum alanine transaminase (ALT) or aspartate transaminase (AST) >5 times upper limit of normal detected within 24 hours at screening/baseline (according to local laboratory reference ranges) or other evidence of severe hepatic impairment.
Absolute peripheral blood neutrophil count of ≤1000/mm^3
Estimated GFR (eGFR) ≤30 mL/min/1.73m^2 (based on CKD-EPI formula)
Pregnant or breastfeeding, or positive urine or serum pregnancy test in a pre-dose examination
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
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to abstain from any sexual intercourse for a total of 29 days after randomization (the 14-day treatment period plus a 14-day follow-up period).
Current participation in any other investigational trials, with the exception of (not yet) approved COVID-19 therapies that are considered (local) standard of care.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MAS825 + SoC	MAS825	Single dose of MAS825 10 mg/kg by intravenous infusion in addition to SoC
MAS825 + SoC	Standard of Care (SoC)	Single dose of MAS825 10 mg/kg by intravenous infusion in addition to SoC
Placebo + SoC	Placebo	Single dose of matching Placebo by intravenous infusion in addition to SoC
Placebo + SoC	Standard of Care (SoC)	Single dose of matching Placebo by intravenous infusion in addition to SoC

Primary Outcome Measures

Name	Time	Method
APACHE II Severity of Disease Score on Day 15 or on the Day of Discharge (Whichever is Earlier)	up to Day 15	The APACHE II ("Acute Physiology And Chronic Health Evaluation II") is a severity-of-disease classification system. An integer score from 0 to 71 is computed based on several measurements; higher scores correspond to more severe disease and a higher risk of death. In practice, it is rare for any participant to accumulate more than 55 points. APACHE II score was measured on Day 15 or on the day of discharge (whichever was earlier). Participants who died on Day 15 or earlier were assigned the highest observed APACHE II score of any of the participants at any time during the trial (worst case imputation for deaths). Missing data values of the parameters required for the derivation of the APACHE II score were replaced by the last available assessment.

Secondary Outcome Measures

Name	Time	Method
Serum C-reactive Protein (CRP) Levels	Baseline, days 2, 4, 6, 8, 10, 12, 14 and 15	C-reactive protein (CRP) is a blood test marker for inflammation in the body. It was analyzed on a log-scale fitting a repeated measures mixed model: treatment, visit, stratification factors, visit \* treatment and visit \* stratification factors as fixed effects and log-transformed baseline score and visit \* log-transformed baseline score as continuous covariate. Values reported were back-transformed to original scale.
Ferritin Levels	Baseline, days 2, 4, 6, 8, 10, 12, 14 and 15	Ferritin is a blood test marker for inflammation in the body. For a standard ferritin test, a normal reading is less than 300 micrograms per liter (μg/L). It was analyzed on a log-scale fitting a repeated measures mixed model: treatment, visit, stratification factors, visit \* treatment and visit \* stratification factors as fixed effects and log-transformed baseline score and visit \* log-transformed baseline score as continuous covariate. Values reported were back-transformed to original scale.
Number of Participants Not Requiring Mechanical Ventilation for Survival	Until Day 15 (Assessments on Days 2, 4, 6, 8, 10, 12, 14 and 15) and until Day 29 (Additional assessments on Days 17, 19, 21, 23, 25, 27 and 29)	Number of participants not requiring mechanical ventilation for survival until Day 15 and Day 29: defined by WHO 9-point ordinal scale score of \< 6 points at all time points assessments. The scoring is - Uninfected patients have a score 0. - Ambulatory patients can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support). - Patients who die have a score 8. Missing data values were handled as follows: For participants who died prior to Day 29, the score for death was imputed for all following visits up to and including Day 29. For all the other participants, last observation carried forward was applied up to and including Day 29.
Number of Participants With at Least One-point Improvement From Baseline in Clinical Status	Baseline, Day 15 and Day 29	Number of participants with at least one-point improvement from baseline in clinical status, which was measured with WHO 9-point ordinal scale. The scoring is - Uninfected patients have a score 0. - Ambulatory patients can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support). - Patients who die have a score 8. Missing data values were handled as follows: For participants who died prior to Day 29, the score for death was imputed for all following visits up to and including Day 29. For all the other participants, last observation carried forward was applied up to and including Day 29.
Clinical Status Over Time	Baseline, days 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 45 and 127	Clinical status was measured with World Health Organization (WHO) 9-point ordinal scale. The scoring is - Uninfected patients have a score 0. - Ambulatory patients can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support - pressors, renal replacement therapy, extracorporeal membrane oxygenation). - Patients who die have a score 8. Missing data values were handled as follows: For participants who died prior to Day 127, the score for death was imputed for all following visits up to and including Day 127. For all the other participants, last observation carried forward was applied up to and including Day 127.