Confirmed Coronavirus Disease
Conditions
Brief summary
The primary purpose of this study is to evaluate if adding rhC1-INH to standard of care (SOC) in patients admitted for stage II COVID-19 infection may reduce the risk of disease progression, i.e. ALI requiring mechanical ventilation, or increase the chance of a faster clinical improvement compared to SOC alone.
Detailed description
Patients fulfilling all eligibility criteria will be randomized in a 2:1 ratio in an open-label controlled design to treatment with rhC1-INH in addition to SOC or SOC only starting on day 0. The first rhC1-INH treatment will be administered on the same day and continued for a total of 4 days.
Interventions
DRUGRuconest
Patients will be randomized to Ruconest or Standard of Care
Sponsors
Pharming Technologies B.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-85 years, * Admitted to the hospital because of confirmed positive SARS-CoV-2 (COVID-19 infection). * Evidence of pulmonary involvement on CT scan or X-Ray of the chest, * Symptom onset within the previous 10 days AND at least one additional risk factor for progression to mechanical ventilation: 1) arterial hypertension, 2) \>50 years, 3) obesity (BMI\>30.0 kg/m2), 4) history of cardiovascular disease, 5) chronic pulmonary disease, 7) chronic renal disease, 6) C-reactive protein of \>35mg/L, 7) oxygen saturation at rest in ambient air of \<94%
Exclusion criteria
* Contraindications to the class of drugs under study (C1 esterase inhibitor); * History or suspicion of allergy to rabbits; * Women who are of childbearing potential and not using methods of contraception during the entire study period; * Pregnant or breastfeeding females or has a positive serum β-human chorionic gonadotropin (hCG) pregnancy test at screening; * Chronic liver disease (any Child-Pugh score B or C); * Currently admitted to an ICU or expected admission within the next 24 hours; and * Currently receiving invasive or non-invasive ventilation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | Assessed on each day after enrollment (worst status) with the use of the WHO Ordinal Scale and the score on day 7 will be analyzed stratified by its baseline value | The disease severity on the 7-point WHO Ordinal Scale on Day 7 was the primary objective of this study. This endpoint had been suggested by the WHO for clinical trials in patients with Covid-19. The ordinal scale measures illness severity over time. The higher score, the worst outcome: meaning score 1, no limitation in activities and score 7, death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Improvement | Daily until day 14 | Time from randomization to an improvement of (at least) two (score) points on the seven-category WHO Ordinal Scale or live discharge from hospital whichever came first within 14 days after enrollment |
| Invasive (Mechanical) or Non-invasive Ventilation | Daily until day 14. | Admission to ICU with invasive or non-invasive ventilation will be assessed. |
| Number of Days Hospitalized | between D0 and D90 | Amount of days the patient is hospitalized during participation in the study. |
Countries
United States
Participant flow
Recruitment details
Participants were randomized to two parallel groups in a 2:1 ratio to receive either rhC1INH (intervention) in addition to standard of care (SOC) or SOC treatment (control). Randomization was stratified by the study site before inclusion using randomly permuted block sizes of four.
Participants by arm
| Arm | Count |
|---|---|
| Ruconest Patients receive (150 U/ml) of Ruconest at a 50 U/kg dose (max dose of 4200 U) as a slow intravenous injection via a peripheral every 12 hours; for 4 days. A total of 8 doses will be administered.
Ruconest: Patients will be randomized to Ruconest or Standard of Care | 27 |
| Standard of Care SOC
Ruconest: Patients will be randomized to Ruconest or Standard of Care | 11 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ruconest | Standard of Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 7 Participants | 30 Participants |
| Age, Continuous | 55.93 years STANDARD_DEVIATION 11.84 | 55.18 years STANDARD_DEVIATION 8.99 | 55.55 years STANDARD_DEVIATION 10.42 |
| Body Mass Index | 34.58 kg/m^2 STANDARD_DEVIATION 6.07 | 30.54 kg/m^2 STANDARD_DEVIATION 8.55 | 32.56 kg/m^2 STANDARD_DEVIATION 7.31 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 25 Participants | 8 Participants | 33 Participants |
| Sex: Female, Male Female | 13 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Male | 14 Participants | 8 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 1 / 11 |
| other Total, other adverse events | 23 / 27 | 11 / 11 |
| serious Total, serious adverse events | 3 / 27 | 2 / 11 |
Outcome results
Primary
Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7
The disease severity on the 7-point WHO Ordinal Scale on Day 7 was the primary objective of this study. This endpoint had been suggested by the WHO for clinical trials in patients with Covid-19. The ordinal scale measures illness severity over time. The higher score, the worst outcome: meaning score 1, no limitation in activities and score 7, death.
Time frame: Assessed on each day after enrollment (worst status) with the use of the WHO Ordinal Scale and the score on day 7 will be analyzed stratified by its baseline value
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ruconest | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 1 | 6 Participants |
| Ruconest | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 2 | 20 Participants |
| Ruconest | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 3 | 0 Participants |
| Ruconest | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 4 | 1 Participants |
| Ruconest | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 5 | 0 Participants |
| Ruconest | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 6 | 0 Participants |
| Standard of Care | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 5 | 1 Participants |
| Standard of Care | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 1 | 0 Participants |
| Standard of Care | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 4 | 0 Participants |
| Standard of Care | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 2 | 8 Participants |
| Standard of Care | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 6 | 2 Participants |
| Standard of Care | Number of Participants With Each Score on WHO 7-point Outcome Scale at Day 7 | WHO ordinal scale 3 | 0 Participants |
p-value: 0.0346Wilcoxon rank test
Secondary
Invasive (Mechanical) or Non-invasive Ventilation
Admission to ICU with invasive or non-invasive ventilation will be assessed.
Time frame: Daily until day 14.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ruconest | Invasive (Mechanical) or Non-invasive Ventilation | Invasive (mechanical) ventilation | 0 Participants |
| Ruconest | Invasive (Mechanical) or Non-invasive Ventilation | Non-invasive ventilation | 12 Participants |
| Standard of Care | Invasive (Mechanical) or Non-invasive Ventilation | Invasive (mechanical) ventilation | 2 Participants |
| Standard of Care | Invasive (Mechanical) or Non-invasive Ventilation | Non-invasive ventilation | 7 Participants |
p-value: 0.1021WHO Ordinal Scale for Clin Improvement
Secondary
Number of Days Hospitalized
Amount of days the patient is hospitalized during participation in the study.
Time frame: between D0 and D90
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ruconest | Number of Days Hospitalized | 5.38 days | Standard Deviation 1.76 |
| Standard of Care | Number of Days Hospitalized | 11.27 days | Standard Deviation 16.01 |
p-value: 0.1615WHO Ordinal Scale
Secondary
Time to Clinical Improvement
Time from randomization to an improvement of (at least) two (score) points on the seven-category WHO Ordinal Scale or live discharge from hospital whichever came first within 14 days after enrollment
Time frame: Daily until day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ruconest | Time to Clinical Improvement | 3.32 days | Standard Error 0.32 |
| Standard of Care | Time to Clinical Improvement | 4.91 days | Standard Error 1.43 |
p-value: 0.4441WHO Ordinal Scale