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

Coronavirus Infections Clinical Trial

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).

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04414631
• Other study ID #: 2020-01252; me20Osthoff3
• Status: Terminated
• Phase: Phase 2
• Start date: August 6, 2020
• Est. completion date: September 15, 2021

Study information

• Verified date: November 2021
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 80
• Est. completion date: September 15, 2021
• Est. primary completion date: September 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Coronavirus Infections
• COVID-19
• Infections

Intervention

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.

Locations

Country	Name	City	State
Brazil	Práxis Pesquisa Medica	São Paulo
Mexico	Hospital Universitario "Dr. José Eleiterio González", Colinia Mitras Centro	Monterey	Nuevo Leon Mexico
Switzerland	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

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland	Pharming Technologies B.V.

Countries where clinical trial is conducted

Brazil,  Mexico,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in the ordinal WHO scale	Changes in the ordinal WHO scale	from baseline over 14 days
Other	Length of hospital stay in survivors	Length of hospital stay in survivors	until day 28
Other	Proportion of participants progressing to mechanical ventilation	Proportion of participants progressing to mechanical ventilation	on day 7 and day 14
Other	Proportion of participants requiring ICU treatment	Proportion of participants requiring ICU treatment	on day 7 and 14
Other	Length of ICU stay	Length of ICU stay	until day 28
Other	28 Ventilator-free days	28 Ventilator-free days	until day 28
Other	All-cause mortality	All-cause mortality	time from randomisation to death within four weeks
Other	Changes in biomarker level CRP (mg/l)	Changes in biomarker level CRP	until day 14
Other	Changes in biomarker level LDH (U/l)	Changes in biomarker level LDH	until day 14
Other	Changes in biomarker level D- Dimer (yg/ml)	Changes in biomarker level D-Dimer	until day 14
Other	Changes in biomarker level Ferritin (ng/ml)	Changes in biomarker level Ferritin	until day 14
Other	Changes in biomarker level Interleukin 6 (IL- 6) (pg/ml)	Changes in biomarker level IL-6	until day 14
Other	Changes in lymphocyte count (cells per microliter of blood)	Changes in lymphocyte count	until day 14
Other	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
Other	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
Other	Time to defervescence (temperature <38.0°C)	Time to defervescence (temperature <38.0°C)	sustained for at least 48 hours
Other	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
Other	Duration of supplemental oxygen	Duration of supplemental oxygen	until day 28
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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