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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
Recruitment Status : Recruiting
First Posted : June 4, 2020
Last Update Posted : August 11, 2020
Sponsor:
Collaborator:
Pharming Technologies B.V.
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

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

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 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
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


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



Primary Outcome Measures :
  1. 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 :
  1. 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)

  2. 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

  3. 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:
  1. Changes in the ordinal WHO scale [ Time Frame: from baseline over 14 days ]
    Changes in the ordinal WHO scale

  2. Length of hospital stay in survivors [ Time Frame: until day 28 ]
    Length of hospital stay in survivors

  3. Proportion of participants progressing to mechanical ventilation [ Time Frame: on day 7 and day 14 ]
    Proportion of participants progressing to mechanical ventilation

  4. Proportion of participants requiring ICU treatment [ Time Frame: on day 7 and 14 ]
    Proportion of participants requiring ICU treatment

  5. Length of ICU stay [ Time Frame: until day 28 ]
    Length of ICU stay

  6. 28 Ventilator-free days [ Time Frame: until day 28 ]
    28 Ventilator-free days

  7. All-cause mortality [ Time Frame: time from randomisation to death within four weeks ]
    All-cause mortality

  8. Changes in biomarker level CRP (mg/l) [ Time Frame: until day 14 ]
    Changes in biomarker level CRP

  9. Changes in biomarker level LDH (U/l) [ Time Frame: until day 14 ]
    Changes in biomarker level LDH

  10. Changes in biomarker level D- Dimer (yg/ml) [ Time Frame: until day 14 ]
    Changes in biomarker level D-Dimer

  11. Changes in biomarker level Ferritin (ng/ml) [ Time Frame: until day 14 ]
    Changes in biomarker level Ferritin

  12. Changes in biomarker level Interleukin 6 (IL- 6) (pg/ml) [ Time Frame: until day 14 ]
    Changes in biomarker level IL-6

  13. Changes in lymphocyte count (cells per microliter of blood) [ Time Frame: until day 14 ]
    Changes in lymphocyte count

  14. 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

  15. 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

  16. Time to defervescence (temperature <38.0°C) [ Time Frame: sustained for at least 48 hours ]
    Time to defervescence (temperature <38.0°C)

  17. 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)

  18. Duration of supplemental oxygen [ Time Frame: until day 28 ]
    Duration of supplemental oxygen

  19. 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

  20. 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)



Information from the National Library of Medicine

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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, i.e. fever or one respiratory symptom (patients presenting later may have already progressed to an inflammatory state that is potentially not amenable to C1INH treatment)
  • 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%

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
  • 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

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


Contacts
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Contact: Michael Osthoff, PD Dr. med. +41 61 328 6828 michael.osthoff@usb.ch

Locations
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Switzerland
University Hospital Basel, Division of Internal Medicine Recruiting
Basel, Switzerland, 4031
Contact: Michael Osthoff, PD Dr. med.    +41 61 328 6828    michael.osthoff@usb.ch   
Contact: Stephan Moser, MD         
Principal Investigator: Michael Osthoff, PD Dr. med         
Sub-Investigator: Marten Trendelenburg, Prof. med         
Sub-Investigator: Parham Sendi, Prof. med.         
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Pharming Technologies B.V.
Investigators
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Principal Investigator: Michael Osthoff, PD Dr. med. University Hospital Basel, Division of Internal Medicine
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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: August 11, 2020
Last Verified: July 2020

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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:
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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Infection
Communicable Diseases
Coronavirus Infections
Severe Acute Respiratory Syndrome
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Complement C1 Inhibitor Protein
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs