Conestat Alfa in the Prevention of Severe SARS-CoV-2 Infection in Hospitalized Patients With COVID-19
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| ClinicalTrials.gov Identifier: NCT04414631 |
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Recruitment Status :
Terminated
(Aim to enroll 120 patients deemed not sufficient to show a difference in the primary outcome measure. Standard of care treatment recently changed in Switzerland adding further heterogeneity to trial population when including future participants.)
First Posted : June 4, 2020
Last Update Posted : November 9, 2021
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Sponsor:
University Hospital, Basel, Switzerland
Collaborator:
Pharming Technologies B.V.
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Coronavirus Infections | Drug: Conestat alfa | Phase 2 |
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 (Clinical Trial) |
| Actual Enrollment : | 80 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | Randomized, open-label, parallel-group, controlled, multi-center clinical trial |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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). |
| Actual Study Start Date : | August 6, 2020 |
| Actual Primary Completion Date : | September 15, 2021 |
| Actual Study Completion Date : | September 15, 2021 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
COVID-19 (Coronavirus Disease 2019)
Drug Information available for:
Conestat alfa
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: active treatment arm
treatment with conestat alfa in addition to standarf of care
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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. |
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No Intervention: Standard of care treatment arm
Standard of care treatment established at the centers
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Primary Outcome Measures :
- Disease severity [ Time Frame: 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 Outcome Measures :
- Time to clinical improvement [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: within 14 days after enrolment ]Proportion of subjects with an ALI (defined by PaO2/FiO2 ratio of <300mmHg)
Other Outcome Measures:
- Changes in the ordinal WHO scale [ Time Frame: from baseline over 14 days ]Changes in the ordinal WHO scale
- Length of hospital stay in survivors [ Time Frame: until day 28 ]Length of hospital stay in survivors
- Proportion of participants progressing to mechanical ventilation [ Time Frame: on day 7 and day 14 ]Proportion of participants progressing to mechanical ventilation
- Proportion of participants requiring ICU treatment [ Time Frame: on day 7 and 14 ]Proportion of participants requiring ICU treatment
- Length of ICU stay [ Time Frame: until day 28 ]Length of ICU stay
- 28 Ventilator-free days [ Time Frame: until day 28 ]28 Ventilator-free days
- All-cause mortality [ Time Frame: time from randomisation to death within four weeks ]All-cause mortality
- Changes in biomarker level CRP (mg/l) [ Time Frame: until day 14 ]Changes in biomarker level CRP
- Changes in biomarker level LDH (U/l) [ Time Frame: until day 14 ]Changes in biomarker level LDH
- Changes in biomarker level D- Dimer (yg/ml) [ Time Frame: until day 14 ]Changes in biomarker level D-Dimer
- Changes in biomarker level Ferritin (ng/ml) [ Time Frame: until day 14 ]Changes in biomarker level Ferritin
- Changes in biomarker level Interleukin 6 (IL- 6) (pg/ml) [ Time Frame: until day 14 ]Changes in biomarker level IL-6
- Changes in lymphocyte count (cells per microliter of blood) [ Time Frame: until day 14 ]Changes in lymphocyte count
- Time to virological clearance of SARS-CoV-2 by PCR from upper or lower respiratory tract samples [ Time Frame: 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 [ Time Frame: within 14 days ]Proportion of patients receiving additional anti-inflammatory treatment such as tocilizumab or immunoglobulins
- Time to defervescence (temperature <38.0°C) [ Time Frame: 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 [ Time Frame: until day 28 ]Time to clinical improvement (defervescence, normalization of oxygen saturation (>93%) and respiratory rate)
- Duration of supplemental oxygen [ Time Frame: until day 28 ]Duration of supplemental oxygen
- Change in pharmacokinetics of conestat alfa [ Time Frame: 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) [ Time Frame: 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)
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| Ages Eligible for Study: | 18 Years to 85 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04414631
Locations
| Brazil | |
| Práxis Pesquisa Medica | |
| São Paulo, Brazil, 09090-790 | |
| Mexico | |
| Hospital Universitario "Dr. José Eleiterio González", Colinia Mitras Centro | |
| Monterey, Nuevo Leon Mexico, Mexico, C.P 64460 | |
| Switzerland | |
| University Hospital Basel, Division of Internal Medicine | |
| Basel, Switzerland, 4031 | |
| Kantonsspital St. Gallen, Klinik für Infektiologie/Spitalhygiene | |
| St. Gallen, Switzerland, 9007 | |
| Stadtspital Triemli, Departement Innere Medizin | |
| Zürich, Switzerland, 8063 | |
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Pharming Technologies B.V.
Investigators
| Principal Investigator: | Michael Osthoff, PD Dr. med. | University Hospital Basel, Division of Internal Medicine |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | University Hospital, Basel, Switzerland |
| ClinicalTrials.gov Identifier: | NCT04414631 |
| Other Study ID Numbers: |
2020-01252; me20Osthoff3 |
| First Posted: | June 4, 2020 Key Record Dates |
| Last Update Posted: | November 9, 2021 |
| Last Verified: | November 2021 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by University Hospital, Basel, Switzerland:
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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) |
Additional relevant MeSH terms:
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COVID-19 Complement C1 Inhibitor Protein Infections Communicable Diseases Coronavirus Infections Disease Attributes Pathologic Processes Pneumonia, Viral Pneumonia Respiratory Tract Infections |
Virus Diseases Coronaviridae Infections Nidovirales Infections RNA Virus Infections Lung Diseases Respiratory Tract Diseases Complement Inactivating Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |