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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

Tracking Information
First Submitted Date  ICMJE May 19, 2020
First Posted Date  ICMJE June 4, 2020
Last Update Posted Date August 11, 2020
Actual Study Start Date  ICMJE August 6, 2020
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 2, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 2, 2020)
  • 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)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 2, 2020)
  • 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)
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Conestat Alfa in the Prevention of Severe SARS-CoV-2 Infection in Hospitalized Patients With COVID-19
Official Title  ICMJE 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).
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Coronavirus Infections
Intervention  ICMJE 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.
Study Arms  ICMJE
  • Active Comparator: active treatment arm
    treatment with conestat alfa in addition to standarf of care
    Intervention: Drug: Conestat alfa
  • No Intervention: Standard of care treatment arm
    Standard of care treatment established at the centers
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 2, 2020)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michael Osthoff, PD Dr. med. +41 61 328 6828 michael.osthoff@usb.ch
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04414631
Other Study ID Numbers  ICMJE 2020-01252; me20Osthoff3
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Hospital, Basel, Switzerland
Study Sponsor  ICMJE University Hospital, Basel, Switzerland
Collaborators  ICMJE Pharming Technologies B.V.
Investigators  ICMJE
Principal Investigator: Michael Osthoff, PD Dr. med. University Hospital Basel, Division of Internal Medicine
PRS Account University Hospital, Basel, Switzerland
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP