Clinical trial NCT04414631: Conestat Alfa in the Prevention of Severe SARS-CoV-2 Infection in Hospitalized Patients With COVID-19
Official title: Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Severe SARS-CoV-2 Infection in Hospitalized Patients With COVID-19: a Randomized, Parallel-group, Open-label, Multi-center Pilot Trial (PROTECT-COVID-19).
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Coronavirus Infections
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)
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Pharming Technologies B.V.
First posted: 2020-06-04
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, open-label, parallel-group, controlled, multi-center clinical trial
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: Disease severity
timeFrame: on day 7
Secondary outcomes:
measure: Time to clinical improvement
timeFrame: within 14 days after enrolment
measure: Proportion of participants alive and not having required invasive or non-invasive ventilation
timeFrame: at 14 days after enrolment
measure: Proportion of subjects with an ALI (defined by PaO2/FiO2 ratio of <300mmHg)
timeFrame: within 14 days after enrolment
Other outcomes:
measure: Changes in the ordinal WHO scale
timeFrame: from baseline over 14 days
measure: Length of hospital stay in survivors
timeFrame: until day 28
measure: Proportion of participants progressing to mechanical ventilation
timeFrame: on day 7 and day 14
measure: Proportion of participants requiring ICU treatment
timeFrame: on day 7 and 14
measure: Length of ICU stay
timeFrame: until day 28
measure: 28 Ventilator-free days
timeFrame: until day 28
measure: All-cause mortality
timeFrame: time from randomisation to death within four weeks
measure: Changes in biomarker level CRP (mg/l)
timeFrame: until day 14
measure: Changes in biomarker level LDH (U/l)
timeFrame: until day 14
measure: Changes in biomarker level D- Dimer (yg/ml)
timeFrame: until day 14
measure: Changes in biomarker level Ferritin (ng/ml)
timeFrame: until day 14
measure: Changes in biomarker level Interleukin 6 (IL- 6) (pg/ml)
timeFrame: until day 14
measure: Changes in lymphocyte count (cells per microliter of blood)
timeFrame: until day 14
measure: Time to virological clearance of SARS-CoV-2 by PCR from upper or lower respiratory tract samples
timeFrame: time from enrolment to first of 2 negative assays at least 12 hours apart
measure: Proportion of patients receiving additional anti-inflammatory treatment such as tocilizumab or immunoglobulins
timeFrame: within 14 days
measure: Time to defervescence (temperature <38.0°C)
timeFrame: sustained for at least 48 hours
measure: Time to clinical improvement (defervescence, normalization of oxygen saturation (>93%) and respiratory rate) until day 28
timeFrame: until day 28
measure: Duration of supplemental oxygen
timeFrame: until day 28
measure: Change in pharmacokinetics of conestat alfa
timeFrame: at baseline, day 1, day 3, day 7, day 10 (during admission) and day 14 (1/- 2days) or discharge date
measure: Change in pharmacodynamics of conestat alfa (C1-inhibitor (CI-INH) concentration)
timeFrame: at baseline, day 1, day 3, day 7, day 10 (during admission) and day 14 (1/- 2days) or discharge date
Locations:
city: São Paulo
country: Brazil
facility: Práxis Pesquisa Medica
city: Monterey
country: Mexico
facility: Hospital Universitario "Dr. José Eleiterio González", Colinia Mitras Centro
state: Nuevo Leon Mexico
city: Basel
country: Switzerland
facility: University Hospital Basel, Division of Internal Medicine
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen, Klinik für Infektiologie/Spitalhygiene
city: Zürich
country: Switzerland
facility: Stadtspital Triemli, Departement Innere Medizin
Study officials:
affiliation: University Hospital Basel, Division of Internal Medicine
name: Michael Osthoff, PD Dr. med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Urwyler P, Charitos P, Moser S, Heijnen IAFM, Trendelenburg M, Thoma R, Sumer J, Camacho-Ortiz A, Bacci MR, Huber LC, Stussi-Helbling M, Albrich WC, Sendi P, Osthoff M. Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of severe SARS-CoV-2 infection in hospitalized patients with COVID-19: A structured summary of a study protocol for a randomized, parallel-group, open-label, multi-center pilot trial (PROTECT-COVID-19). Trials. 2021 Jan 4;22(1):1. doi: 10.1186/s13063-020-04976-x.