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).
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).
Drug: Conestat 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.
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
Práxis Pesquisa Medica
São Paulo, Brazil
Hospital Universitario "Dr. José Eleiterio González", Colinia Mitras Centro
Monterey, Nuevo Leon Mexico, Mexico
University Hospital Basel, Division of Internal Medicine
Basel, Switzerland
Kantonsspital St. Gallen, Klinik für Infektiologie/Spitalhygiene
St. Gallen, Switzerland
Stadtspital Triemli, Departement Innere Medizin
Zürich, Switzerland
Michael Osthoff, PD Dr. med., Principal Investigator
University Hospital Basel, Division of Internal Medicine