Evaluation of the Effects of Bradykinin Antagonists on Pulmonary Manifestations of COVID-19 Infections (AntagoBrad-Cov Study).

Study Overview
=================
Brief Summary
-----------------
The main objective of this study is to evaluate the efficacy of human C1 inhibitor, administered alone or in combination with icatibant (a specific bradykinin B2 receptor antagonist) on the pulmonary manifestations of COVID-19 infections.

Detailed Description
-----------------
Prospective, prospective, multicentre, double-blind, randomised, multi-centre study of three parallel groups of patients: Group 1 (n=15): standard of care + C1 inhibitor Group 2 (n=15): standard care + icatibant + C1 inhibitor Group 3 (n=15): standard support + placebo The study has two parts: A 4-day (96-hour) therapeutic part during which the patient will be evaluated nine times (H0, H4, H12, H24, H36, H48, H60, H72 and H96). A follow-up part of 6 days with at least two assessments (D7 and D10). The maximum duration of patient participation in the study will be 10 days.

Official Title
-----------------
Evaluation of the Effects of Bradykinin Antagonists on Pulmonary Manifestations of COVID-19 Infections (AntagoBrad-Cov Study).

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Drug: C1 Inhibitor Human
* Drug: Icatibant Injection
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient over 18 years of age, having read and signed the consent form for participation in the study after the reflection period (≤ 15 minutes) Patient screened for COVID+ by RT-PCR on nasopharyngeal swab Patient with at least three of the following respiratory signs: Temperature >38° C Non-productive dry cough Presence of crackling rales on auscultation Respiratory discomfort felt by the patient Heart rate > 90/min Respiratory rate >20/min O2 saturation ≤ 93% Patient whose clinical condition, in the opinion of the investigator, requires hospital monitoring. Patient who would have been monitored and treated outside of study participation, including prevention of thromboembolic risk with LMWH. Exclusion Criteria: Patient with pre-existing respiratory disease (cancer, COPD, asthma, emphysema) or smoking history of > 25 years) Patient with a known allergy to one of the study products Patient treated with anti TNF, IL1 or IL6 Patient requiring immediate intubation Patient on a low sodium diet Patient under protective custody, guardianship or trusteeship Patient not affiliated to the French social security system Patient participating in another therapeutic protocol Pregnant or likely to become pregnant (woman of childbearing age without effective contraception and without HCG dosage) Patient unable to understand informed information and/or give written informed consent: dementia, psychosis, consciousness disorders, non-French speaking patient

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, double-blind, multicentre, prospective study of three parallel groups of patients.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: standard care + C1 inhibitor<br>The C1 inhibitor will be used at a dose of 1000 units per slow infusion (two hours). Two infusions will be given 24 hours apart. These doses correspond to the usual doses used in the treatment of conditions in which the C1-Inhibitor is indicated. | Drug: C1 Inhibitor Human<br>* standard care + 1000 units of C1 inhibitor during 2 slow infusions of 500 units<br>Other: Placebo<br>* The placebo will be physiological serum presented in forms mimicking the C1-Inhibitor and the icatibant.<br>|
| Experimental: standard care + Icatibant + C1 inhibitor<br>The C1 inhibitor will be used at a dose of 1000 units per slow infusion (two hours). Two infusions will be given 24 hours apart. These doses correspond to the usual doses used in the treatment of conditions in which the C1-Inhibitor is indicated. The icatibant will be used in a single injection of 30 mg subcutaneously, preferably in the abdominal region. These doses correspond to the doses usually used in the treatment of conditions in which icatibant is indicated. | Drug: C1 Inhibitor Human<br>* standard care + 1000 units of C1 inhibitor during 2 slow infusions of 500 units<br>Drug: Icatibant Injection<br>* a single injection of 30 mg subcutaneously<br>|
| Placebo Comparator: standard care + placebo<br> | Other: Placebo<br>* The placebo will be physiological serum presented in forms mimicking the C1-Inhibitor and the icatibant.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy evaluation respiratory discomfort | To evaluate the efficacy of human C1 inhibitor, administered alone or in combination with icatibant (a specific bradykinin B2 receptor antagonist) on the pulmonary manifestations of COVID-19 infections. The evaluation of the treatment efficacy of the study is based on the clinical monitoring of the patient and particularly on the following combination of criteria as experienced by the patient : no respiratory discomfort heart rate between 60 and 90 /min respiratory rate less than 20/min O2 saturation greater than 94% without oxygen supply | 96 hours after the administration of treatment | 
| Efficacy evaluation heart rate between 60 and 90 /min | To evaluate the efficacy of human C1 inhibitor, administered alone or in combination with icatibant (a specific bradykinin B2 receptor antagonist) on the pulmonary manifestations of COVID-19 infections. The evaluation of the treatment efficacy of the study is based on the clinical monitoring of the patient and particularly on the following combination of criteria as experienced by the patient : no respiratory discomfort heart rate between 60 and 90 /min respiratory rate less than 20/min O2 saturation greater than 94% without oxygen supply | 96 hours after the administration of treatment | 
| Efficacy evaluation respiratory rate less than 20/min | To evaluate the efficacy of human C1 inhibitor, administered alone or in combination with icatibant (a specific bradykinin B2 receptor antagonist) on the pulmonary manifestations of COVID-19 infections. The evaluation of the treatment efficacy of the study is based on the clinical monitoring of the patient and particularly on the following combination of criteria as experienced by the patient : no respiratory discomfort heart rate between 60 and 90 /min respiratory rate less than 20/min O2 saturation greater than 94% without oxygen supply | 96 hours after the administration of treatment | 
| Efficacy evaluation O2 saturation greater than 94% without oxygen supply | To evaluate the efficacy of human C1 inhibitor, administered alone or in combination with icatibant (a specific bradykinin B2 receptor antagonist) on the pulmonary manifestations of COVID-19 infections. The evaluation of the treatment efficacy of the study is based on the clinical monitoring of the patient and particularly on the following combination of criteria as experienced by the patient : no respiratory discomfort heart rate between 60 and 90 /min respiratory rate less than 20/min O2 saturation greater than 94% without oxygen supply | 96 hours after the administration of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance evaluation | The tolerance of the study products will be assessed by collecting adverse events that occurred during the study period. | Day 10 |