Conestat Alfa in the Prevention of Severe SARS-CoV-2 Infection in Hospitalized Patients With COVID-19

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).

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).

Study Overview

• Status: Terminated
• Conditions: Coronavirus Infections
• Intervention / Treatment: Drug: Conestat alfa

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).

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 09090-790
    • Praxis Pesquisa Medica
• Mexico
  • Nuevo Leon Mexico
    • Monterey, Nuevo Leon Mexico, Mexico, C.P 64460
      • Hospital Universitario "Dr. José Eleiterio González", Colinia Mitras Centro
• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel, Division of Internal Medicine
  • St. Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen, Klinik für Infektiologie/Spitalhygiene
  • Zürich, Switzerland, 8063
    • Stadtspital Triemli, Departement Innere Medizin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: active treatment arm; treatment with conestat alfa in addition to standarf of care	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.
No Intervention: Standard of care treatment arm; Standard of care treatment established at the centers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease severity	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.	on day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to clinical improvement	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)	within 14 days after enrolment
Proportion of participants alive and not having required invasive or non-invasive ventilation	Proportion of participants alive and not having required invasive or non-invasive ventilation	at 14 days after enrolment
Proportion of subjects with an ALI (defined by PaO2/FiO2 ratio of <300mmHg)	Proportion of subjects with an ALI (defined by PaO2/FiO2 ratio of <300mmHg)	within 14 days after enrolment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the ordinal WHO scale	Changes in the ordinal WHO scale	from baseline over 14 days
Length of hospital stay in survivors	Length of hospital stay in survivors	until day 28
Proportion of participants progressing to mechanical ventilation	Proportion of participants progressing to mechanical ventilation	on day 7 and day 14
Proportion of participants requiring ICU treatment	Proportion of participants requiring ICU treatment	on day 7 and 14
Length of ICU stay	Length of ICU stay	until day 28
28 Ventilator-free days	28 Ventilator-free days	until day 28
All-cause mortality	All-cause mortality	time from randomisation to death within four weeks
Changes in biomarker level CRP (mg/l)	Changes in biomarker level CRP	until day 14
Changes in biomarker level LDH (U/l)	Changes in biomarker level LDH	until day 14
Changes in biomarker level D- Dimer (yg/ml)	Changes in biomarker level D-Dimer	until day 14
Changes in biomarker level Ferritin (ng/ml)	Changes in biomarker level Ferritin	until day 14
Changes in biomarker level Interleukin 6 (IL- 6) (pg/ml)	Changes in biomarker level IL-6	until day 14
Changes in lymphocyte count (cells per microliter of blood)	Changes in lymphocyte count	until day 14
Time to virological clearance of SARS-CoV-2 by PCR from upper or lower respiratory tract samples	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
Proportion of patients receiving additional anti-inflammatory treatment such as tocilizumab or immunoglobulins	Proportion of patients receiving additional anti-inflammatory treatment such as tocilizumab or immunoglobulins	within 14 days
Time to defervescence (temperature <38.0°C)	Time to defervescence (temperature <38.0°C)	sustained for at least 48 hours
Time to clinical improvement (defervescence, normalization of oxygen saturation (>93%) and respiratory rate) until day 28	Time to clinical improvement (defervescence, normalization of oxygen saturation (>93%) and respiratory rate)	until day 28
Duration of supplemental oxygen	Duration of supplemental oxygen	until day 28
Change in pharmacokinetics of conestat alfa	Peak serum concentration of conestat alfa will be measured	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)	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

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Pharming Technologies B.V.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2020
• Primary Completion (Actual): September 15, 2021
• Study Completion (Actual): September 15, 2021

Study Registration Dates

• First Submitted: May 19, 2020
• First Submitted That Met QC Criteria: June 2, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Actual): November 9, 2021
• Last Update Submitted That Met QC Criteria: November 1, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: cytokine storm; Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2); C1 esterase inhibitor; Coronavirus Disease 19 (COVID-19); Systemic hyperinflammation; complement system; kinin-kallikrein system; Conestat alfa
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Coronavirus Infections; Infections; Communicable Diseases; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein
• Other Study ID Numbers: 2020-01252; me20Osthoff3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No