Coronavirus Infections
Conditions
Keywords
Systemic hyperinflammation, cytokine storm, complement system, kinin-kallikrein system, C1 esterase inhibitor, Conestat alfa, Coronavirus Disease 19 (COVID-19), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Brief summary
The aim of this study is to analyze if administration of conestat alfa for 72 hours in addition to standard of care (SOC) in patients hospitalized with non-critical SARS-CoV-2 pneumonia (WHO Ordinal Scale Score 3 or 4) reduces the risk of disease progression to Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).
Detailed description
Systemic hyperinflammation is a hallmark of more severe stages of COVID-19 leading to acute respiratory distress syndrome, mechanical ventilation and ultimately death. In this stage, COVID-19 is associated with a decrease in suppressor and regulatory T cell counts and an extensive release of proinflammatory cytokines and biomarkers called a cytokine storm, which is thought to be the major driver of severe pneumonia caused by SARS-CoV-2. C1 esterase inhibitor (C1INH) is a member of the serpin superfamily of serine-protease inhibitors and is a strong inhibitor of the complement System (CS) and the kinin-kallikrein (KK) System. Conestat alfa is a recombinant human C1INH, that shares an identical protein structure with plasma-derived C1INH. The rationale of the current trial is based upon the following assumptions: In the context of COVID-19, conestat alfa treatment may 1) dampen uncontrolled complement activation and collateral lung damage and 2) reduce capillary leakage and subsequent pulmonary edema by direct inhibition of KK system. The aim of this study is to analyze administration of conestat alfa for 72 hours in addition to standard of care in patients hospitalized with non-critical SARS-CoV-2 pneumonia (WHO Ordinal Scale Score 3 or 4) and its association with clinical severity on day 7 after inclusion and the risk of disease progression to Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).
Interventions
DRUGConestat alfa
Conestat alfa (8400 Units (U) followed by 4200 U every 8 hours, 9 administrations in total) will be administered as a slow intravenous injection (5-10 minutes) over a 72 hour period.
Sponsors
Pharming Technologies B.V.
University Hospital, Basel, Switzerland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, open-label, parallel-group, controlled, multi-center clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Informed Consent as documented by signature * admitted to the hospital because of confirmed (by a positive SARS-CoV-2 PCR result) COVID-19 infection * evidence of pulmonary involvement on CT scan or X-ray of the chest (e.g. ground glass opacities) * symptom onset within the previous 10 days OR shortness of breath within the previous 5 days. Symptoms include fever or one respiratory symptom (patients presenting later may have already progressed to an inflammatory state that is potentially not amenable to C1INH treatment). Respiratory symptoms include cough, sore throat, hemoptysis, shortness of breath, runny nose, or chest pain. * expected to remain an inpatient over the next three calender days from time of enrolment * 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) 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%. Cardiovascular disease includes a history of coronary artery disease, cerebrovascular disease, peripheral artery disease, rheumatic heart disease, congenital heart disease and of recent (\< 3 months) deep vein thrombosis or pulmonary embolism. Chronic pulmonary disease includes a history of chronic obstructive pulmonary disease, asthma, occupational lung disease, interstitial lung disease or of pulmonary hypertension. Chronic renal disease is defined as a history of an estimated glomerular filtration rate (according to the Chronic Kidney Disease Epidemiology Collaboration equation) \< 60ml/min/1.73 m2 for at least three months.
Exclusion criteria
* Contraindications to the class of drugs under study (C1 esterase inhibitor), e.g. known hypersensitivity or allergy to class of drugs or the investigational product * Treatment with tocilizumab or another Il-6R or Il-6 inhibitor before enrolment * History or suspicion of allergy to rabbits * Women who are pregnant or breast feeding * Active or planned treatment with any other complement inhibitor * Liver cirrhosis (any Child-Pugh score) * Incapacity or inability to provide informed consent * Currently admitted to an ICU or expected admission within the next 24 hours * Currently receiving invasive or non-invasive ventilation (with the exception of high-flow oxygen therapy). * In the opinion of the treating time, death is deemed to be imminent and inevitable within the next 24 hours * Participation in another study with investigational drug within the 30 days preceding and during the present study with the following exemptions: 1) participation in COVID-19 drug trials started at least 48 hours before admission (e.g. postexposure prophylaxis with hydroxychloroquine) and 2) participation in COVID-19 drug trials during ICU admission * Previous enrolment into the current study * Enrolment of the investigator, his/her family members, employees and other dependent persons * Any uncontrolled or significant concurrent illness that would put the patient at a greater risk or limit compliance with the study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease severity | on day 7 | Disease severity on the 7-point Ordinal World Health Organization (WHO) scale (for the current study, score 0 will be omitted and score 6 and 7 will be combined). The ordinal scale measures illness severity over time. This endpoint has been suggested by WHO for clinical trials in patients with COVID-19. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to clinical improvement | within 14 days after enrolment | Time to clinical improvement (time from randomisation to an improvement of two points on the seven-category WHO ordinal scale or live discharge from hospital, whichever came first) |
| Proportion of participants alive and not having required invasive or non-invasive ventilation | at 14 days after enrolment | Proportion of participants alive and not having required invasive or non-invasive ventilation |
| Proportion of subjects with an ALI (defined by PaO2/FiO2 ratio of <300mmHg) | within 14 days after enrolment | Proportion of subjects with an ALI (defined by PaO2/FiO2 ratio of \<300mmHg) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Length of hospital stay in survivors | until day 28 | Length of hospital stay in survivors |
| Proportion of participants progressing to mechanical ventilation | on day 7 and day 14 | Proportion of participants progressing to mechanical ventilation |
| Proportion of participants requiring ICU treatment | on day 7 and 14 | Proportion of participants requiring ICU treatment |
| Length of ICU stay | until day 28 | Length of ICU stay |
| Changes in the ordinal WHO scale | from baseline over 14 days | Changes in the ordinal WHO scale |
| Changes in biomarker level D- Dimer (yg/ml) | until day 14 | Changes in biomarker level D-Dimer |
| Changes in biomarker level Ferritin (ng/ml) | until day 14 | Changes in biomarker level Ferritin |
| Changes in biomarker level Interleukin 6 (IL- 6) (pg/ml) | until day 14 | Changes in biomarker level IL-6 |
| 28 Ventilator-free days | until day 28 | 28 Ventilator-free days |
| Time to virological clearance of SARS-CoV-2 by PCR from upper or lower respiratory tract samples | time from enrolment to first of 2 negative assays at least 12 hours apart | Time to virological clearance of SARS-CoV-2 by PCR from upper or lower respiratory tract samples |
| Proportion of patients receiving additional anti-inflammatory treatment such as tocilizumab or immunoglobulins | within 14 days | Proportion of patients receiving additional anti-inflammatory treatment such as tocilizumab or immunoglobulins |
| Time to defervescence (temperature <38.0°C) | sustained for at least 48 hours | Time to defervescence (temperature \<38.0°C) |
| Time to clinical improvement (defervescence, normalization of oxygen saturation (>93%) and respiratory rate) until day 28 | until day 28 | Time to clinical improvement (defervescence, normalization of oxygen saturation (\>93%) and respiratory rate) |
| Duration of supplemental oxygen | until day 28 | Duration of supplemental oxygen |
| Change in pharmacokinetics of conestat alfa | at baseline, day 1, day 3, day 7, day 10 (during admission) and day 14 (1/- 2days) or discharge date | Peak serum concentration of conestat alfa will be measured |
| Change in pharmacodynamics of conestat alfa (C1-inhibitor (CI-INH) concentration) | at baseline, day 1, day 3, day 7, day 10 (during admission) and day 14 (1/- 2days) or discharge date | Change in pharmacodynamics of conestat alfa (C1-inhibitor (CI-INH) concentration) |
| Changes in lymphocyte count (cells per microliter of blood) | until day 14 | Changes in lymphocyte count |
| All-cause mortality | time from randomisation to death within four weeks | All-cause mortality |
| Changes in biomarker level CRP (mg/l) | until day 14 | Changes in biomarker level CRP |
| Changes in biomarker level LDH (U/l) | until day 14 | Changes in biomarker level LDH |
Countries
Brazil, Mexico, Switzerland
Outcome results
None listed