Sars-CoV2
Conditions
Keywords
COVID-19, Pneumonia, Severe, Cytokine storm
Brief summary
Study Objectives: Primary * To assess the efficacy (survival without organ failure on Day 14) of three doses of rhu-pGSN administered intravenously (IV) plus standard of care (SOC) to hospitalized subjects with a primary diagnosis of COVID-19 pneumonia and a severity score of 4, 5 or 6 on the World Health Organization (WHO) 9-point severity scale * To evaluate the safety and tolerability of three IV doses of rhu-pGSN administered to hospitalized subjects with a primary diagnosis of COVID-19 pneumonia and a severity score of 4, 5, or 6 on the WHO 9-point severity scale Secondary * To further assess the efficacy of IV administered rhu-pGSN * To assess changes in WHO 9-point severity score for SOC with or without rhu-pGSN * To evaluate the effect of administered rhu-pGSN on survival rates * To assess the relationship of pGSN levels (and other biomarkers) at baseline with clinical outcomes * \[OPTIONAL\] To follow the pharmacokinetics (PK) of administered rhu-pGSN Immunogenicity • To investigate the development of antibodies against rhu-pGSN post-treatment
Detailed description
Efficacy and safety of IV rhu-pGSN on top of SOC will be evaluated initially in 60 participants representative of the drug target population: high-risk subjects with acute severe pneumonia due to COVID-19. The rhu-pGSN dose will be based on actual body weight given at 12 mg/kg. Three doses will be given at 0, 12 and 24 hours intervals promptly after enrollment by IV infusion through a 0.2 µm filter. Participants will be randomized 1:1 rhu-pGSN or placebo. Interim safety analyses will be conducted after enrollment of 12, 24, 36, and 48 patients. The primary efficacy outcome will be the proportion of patients surviving on Day 14 without mechanical ventilation, vasopressors or dialysis. Secondary efficacy outcomes will include: daily change in 9-point WHO severity score through at least Day 14; all-cause mortality at Days 28 and 90; time to death (Kaplan-Meier survival analysis); proportion of subjects alive on Days 7, 28, 60, and 90 without: ongoing use of vasopressors, ongoing intubation/mechanical ventilation, ongoing residence in an intensive care unit (ICU), new ongoing need for dialysis/renal replacement therapy; proportion of subjects discharged to home or immediate prior residence by Day 28; days on the ventilator; length of stay in hospital and in ICU and re-admission to an acute-care hospital up to Day 90. Safety of administration of rhu-pGSN at the indicated dosage will also be evaluated. Baseline and sequential levels of pGSN and inflammatory biomarkers will be measured. On days 1, 28, and 90, immunogenicity due to the formation of anti-pGSN antibodies will be assessed.
Interventions
DRUGRecombinant human plasma gelsolin (Rhu-pGSN)
Intravenous administration of rhu-pGSN at 12 mg/kg, 3 doses
OTHERPlacebo
Normal saline in matched volume to treatment arm. Undistinguishable in syringe.
Sponsors
BioAegis Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Treatment blinded to all but unblinded pharmacist
Intervention model description
Randomized, blinded, placebo controlled interventional
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Hospitalized with laboratory-confirmed (RT-PCR+) or highly suspected (compatible with at least bilobar lung involvement without another plausible diagnosis) COVID-19 * Weight ≤100 kg * Within 24 hours of reaching a WHO severity score of 4-6 either: * At admission * While already hospitalized * Informed consent obtained from subject/next of kin/legal proxy * Primary admitting diagnosis of pneumonia supported by a compatible clinical presentation with a documented infiltrate consistent with pneumonia on chest radiograph or CT as assessed by the admitting emergency-department (ED), clinic, or ward physician or equivalent caregiver * Recommended (not mandatory) guidance/discretionary criteria defining patients with pneumonia satisfying all 4 categories below: * At least 2 symptoms: difficulty breathing, cough, production of purulent sputum, or chest pain * At least 2 vital sign abnormalities: fever, tachycardia, or tachypnea (thresholds -- fever: oral or core temperature \>100.4 °F \[38 °C\]; heart rate \>100 beats/min; respiratory rate \>24/min) * At least one finding of other clinical signs and laboratory abnormalities: hypoxemia (O2 saturation \<90%), clinical evidence of pulmonary consolidation, or leukocytosis or leukopenia * Chest imaging or CT showing new (or presumed new or worsening) pulmonary infiltrates * Principal investigator to note radiologic findings in the electronic case report form (eCRF) * Radiology report to be placed in the eCRF * A copy of the radiograph attached to be saved for review * A hyperinflammatory status (defined by increased ferritin ≥500 µg/L, D-dimer ≥1000 ng/mL, or C-reactive protein (CRP) ≥75 mg/L) * During the course of the study starting at screening and for at least 6 months after their final study treatment: * Female subjects of childbearing potential must agree to use 2 medically accepted birth control methods * Male subjects with a partner who might become pregnant must agree to use reliable forms of contraception (i.e., vasectomy, abstinence), or an acceptable method of birth control must be used by the partner * All subjects must agree not to donate sperm or eggs (ovocytes)
Exclusion criteria
* A negative RT-PCR test for COVID-19 during the evaluation of the present illness * Extracorporeal membrane oxygenation (ECMO) * Pregnant or lactating women * Active underlying cancer treated with systemic chemotherapy or radiation therapy during the last 30 days * Transplantation of hematopoietic or solid organs * Chronic mechanical ventilation or dialysis * Otherwise unsuitable for study participation because of chronic, severe, end-stage, and life-limiting underlying disease unrelated to COVID-19 likely to interfere with management and assessment of acute pneumonia, only comfort or limited (non-aggressive) care is to be given, or life expectancy \<6 months unrelated to acute COVID infection in the opinion of the Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Proportion of Subjects Alive Not on Vasopressors, Mechanical Ventilator, or Dialysis | Day 14 | Number and percentage of subjects alive on Day 14 without ongoing use of vasopressors, ongoing intubation/mechanical ventilation, or new/ongoing need for dialysis/RRT. Subjects who discontinued from the study early or whose survival status was inconclusive on Day 14 were considered as a failure (Not Alive). |
| Safety: Number of Subjects With SAEs | Day 1 through Day 90 | Number of subjects with SAEs during the study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity: Subjects With Rhu-pGSN Antibodies | Day 28 | Number of subjects with rhu-pGSN antibodies at Day 28 |
| Efficacy: Alive Without Support at Day 90 | Day 90 | Number of subjects Alive without organ support at Day 90 |
| Efficacy: All Cause Mortality Rate at Day 90 | Day 90 | All cause mortality rate using Kaplan-Meier survival analysis |
| Number of Subjects Alive Without Organ Support at Day 90 | Through Day 90 | number of subjects alive and without organ support at the Day 90 visit |
| Safety and Tolerability: Proportion of Subjects With Drug-related Adverse Events (AEs) | Continuous through Day 14 | Proportion of subjects with drug-related adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |
| Safety and Tolerability: Proportion of Subjects With Adverse Events (AEs) | Continuous through Day 28 | Proportion of subjects with adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |
Countries
Romania, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Normal saline in matched volume to treatment arm. Undistinguishable in syringe.
Placebo: Normal saline in matched volume to treatment arm. Undistinguishable in syringe. | 31 |
| Rhu-pGSN Recombinant human plasma gelsolin reconstituted for slow bolus injection.
Recombinant human plasma gelsolin (Rhu-pGSN): Intravenous administration of rhu-pGSN at 12 mg/kg, 3 doses | 30 |
| Total | 61 |
Baseline characteristics
| Characteristic | Placebo | Total | Rhu-pGSN |
|---|---|---|---|
| Age, Continuous | 64 years | 64 years | 64 years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 55 Participants | 27 Participants |
| Region of Enrollment Romania | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Spain | 29 Participants | 58 Participants | 29 Participants |
| Sex: Female, Male Female | 12 Participants | 26 Participants | 14 Participants |
| Sex: Female, Male Male | 19 Participants | 35 Participants | 16 Participants |
| World Health Organization (WHO) Severity Scale WHO Severity 4: Oxygen by Mask or Nasal Cannula; Less severe than WHO 5. | 27 Participants | 54 Participants | 27 Participants |
| World Health Organization (WHO) Severity Scale WHO Severity 5: Noninvasive ventilation (CPAP or BiPAP) or high-flow oxygen; More severe than WHO 4 | 4 Participants | 7 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 31 | 2 / 30 |
| other Total, other adverse events | 16 / 31 | 16 / 30 |
| serious Total, serious adverse events | 8 / 31 | 5 / 30 |
Outcome results
Primary
Efficacy: Proportion of Subjects Alive Not on Vasopressors, Mechanical Ventilator, or Dialysis
Number and percentage of subjects alive on Day 14 without ongoing use of vasopressors, ongoing intubation/mechanical ventilation, or new/ongoing need for dialysis/RRT. Subjects who discontinued from the study early or whose survival status was inconclusive on Day 14 were considered as a failure (Not Alive).
Time frame: Day 14
Population: Full Analysis Set: All randomized and treated with at least 1 dose of study therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Efficacy: Proportion of Subjects Alive Not on Vasopressors, Mechanical Ventilator, or Dialysis | 27 participants |
| Rhu-pGSN | Efficacy: Proportion of Subjects Alive Not on Vasopressors, Mechanical Ventilator, or Dialysis | 25 participants |
p-value: >0.05Cochran-Mantel-Haenszel
p-value: >0.1Chi-squared
Primary
Safety: Number of Subjects With SAEs
Number of subjects with SAEs during the study
Time frame: Day 1 through Day 90
Population: Full Analysis Set: All randomized and treated with at least 1 dose of study therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Safety: Number of Subjects With SAEs | 8 participants |
| Rhu-pGSN | Safety: Number of Subjects With SAEs | 5 participants |
Secondary
Efficacy: Alive Without Support at Day 90
Number of subjects Alive without organ support at Day 90
Time frame: Day 90
Population: Full Analysis Set: All randomized and treated with at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Efficacy: Alive Without Support at Day 90 | 28 participants |
| Rhu-pGSN | Efficacy: Alive Without Support at Day 90 | 25 participants |
Secondary
Efficacy: All Cause Mortality Rate at Day 90
All cause mortality rate using Kaplan-Meier survival analysis
Time frame: Day 90
Population: Full Analysis Set: All randomized and treated with at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Efficacy: All Cause Mortality Rate at Day 90 | 2 participants |
| Rhu-pGSN | Efficacy: All Cause Mortality Rate at Day 90 | 2 participants |
Secondary
Immunogenicity: Subjects With Rhu-pGSN Antibodies
Number of subjects with rhu-pGSN antibodies at Day 28
Time frame: Day 28
Population: Full analysis set (not all tested for anti-drug antibodies at all time points on days 1, 28, and 90)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Immunogenicity: Subjects With Rhu-pGSN Antibodies | 7 participants with anti-drug antibodies |
| Rhu-pGSN | Immunogenicity: Subjects With Rhu-pGSN Antibodies | 7 participants with anti-drug antibodies |
Secondary
Number of Subjects Alive Without Organ Support at Day 90
number of subjects alive and without organ support at the Day 90 visit
Time frame: Through Day 90
Population: full analysis set (all treated subjects)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects Alive Without Organ Support at Day 90 | 28 Participants |
| Rhu-pGSN | Number of Subjects Alive Without Organ Support at Day 90 | 25 Participants |
Secondary
Safety and Tolerability: Proportion of Subjects With Adverse Events (AEs)
Proportion of subjects with adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time frame: Continuous through Day 28
Population: Full Analysis Set (all randomized and treated (At least 1 dose) subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety and Tolerability: Proportion of Subjects With Adverse Events (AEs) | 16 Participants |
| Rhu-pGSN | Safety and Tolerability: Proportion of Subjects With Adverse Events (AEs) | 16 Participants |
Secondary
Safety and Tolerability: Proportion of Subjects With Drug-related Adverse Events (AEs)
Proportion of subjects with drug-related adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time frame: Continuous through Day 14
Population: Full Analysis Set (all randomized and treated (At least 1 dose) subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety and Tolerability: Proportion of Subjects With Drug-related Adverse Events (AEs) | 0 Participants |
| Rhu-pGSN | Safety and Tolerability: Proportion of Subjects With Drug-related Adverse Events (AEs) | 1 Participants |