Inhibition of Bradykinin in COVID-19 Infection With Icatibant

Study Overview
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Brief Summary
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There is excess accumulation of bradykinin during symptomatic SARS CoV-2 lung infection. Bradykinin causes oedema in the lung, with reduced oxygen. It also causes vasodilation, hypotension and cytokine release.

Detailed Description
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In a normal reaction to a wound, such as after surgery, there is stimulation of pain nerves (called c-fibres), swelling and clotting. When people are hospitalized with COVID-19 they usually have a cough (lung c-fibre stimulation), swelling in the lung and clotting. Bradykinin is a chemical that is released in response to inflammation. It causes C-fibre stimulation, dilation of vessels with oedema (swelling), lowered blood pressure and release of inflammatory cytokines. Normally the production of bradykinin is carefully balanced in the body. Some people have a tendency to release bradykinin. This results in spontaneous swelling - it is called hereditary episodic angioedema (HAE). There has been a treatment for HAE which has been in use since 2008. It is a medication called Icatibant. This blocks the effect of bradykinin at one of its receptors. It is given by injection under the skin. It has a short half life of approximately 1.5 hours. The primary aim of the study is to see if treatment with Icatibant will improve blood oxygen levels. COVID-19 patients attending hospital with early symptom onset and low oxygen levels will screened for inclusion in the trial. Patients will be randomly allocated into one of two groups. One group will be given the study drug, Icatibant. The other group will be given a placebo injection containing saline water. Patients and research investigators will be blinded to treatment allocation. Prior to receiving Icatibant/placebo, patients will have baseline measurements carried out. Blood pressure, Mean arterial pressure, heart rate, oxygen saturations and Fraction of inspired oxygen (FiO2) measurement will be carried out. Patients will undergo an arterial blood gas test. Part of the blood taken will be used for the measurement of interleukin-6 (IL-6) and part will be stored for future use. Patients will also have a retinal photograph of both eyes to assess the retinal vessel size. These measurements will be repeated 3 hours after receiving Icatibant/placebo. A blood sample will also be taken from a group of control participants who do not have COVID-19 infection. The control blood samples will be analysed for IL-6 and part will also be stored for future use. The results will be compared to the baseline blood sample results taken from the COVID-19 positive trial patients.

Official Title
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Prospective, Randomised, Double-blind Trial of Icatibant Compared to Placebo in Patients With Early Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) Infection

Conditions
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SARS CoV 2 Infection

Intervention / Treatment
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* Drug: Icatibant
* Drug: 0.9% Sodium Chloride Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years. Documented evidence of COVID-19 and symptom onset of 7 days or less Acute hypoxia which will be defined as either low resting saturations <94% or supplementary oxygen to maintain oxygen saturations at >94% Exclusion Criteria: Patients known to be pregnant or breastfeeding. Patients with unstable ischaemic heart disease or acute stroke Patients enrolled in other clinical trials of an investigational medicine within the previous 28 day period Patients who refuse to have blood samples taken. Known hypersensitivity to Icatibant Patients who at time of consent are likely to require imminent non-invasive/ invasive ventilatory support or patients already established on continuous positive airway pressure (CPAP). Patients with chronic heart or lung disease whose oxygen levels are reduced, but are unchanged from baseline

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomly allocated to receive either Icatibant (30mg) or 0.9% Sodium Chloride (3mls)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Icatibant and Standard of care (SOC)<br>Icatibant will be given as a single, subcutaneous injection | Drug: Icatibant<br>* Solution for injection, 30mg (3mls) administered as a single subcutaneous injection SARS CoV-2 patients will receive all supportive treatment and medications that are used as standard of care including but not limited to Dexamethasone, Remdesivir, Tocilizumab and antibiotics.<br>|
| Placebo Comparator: 0.9% Sodium Chloride and Standard of care (SOC)<br>Placebo will be given as a single, subcutaneous injection | Drug: 0.9% Sodium Chloride Injection<br>* Solution for injection (3mls) administered as a single subcutaneous injection SARS CoV-2 patients will receive all supportive treatment and medications that are used as standard of care including but not limited to Dexamethasone, Remdesivir, Tocilizumab and antibiotics.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oxygenation | Alveolar-arterial gradient (Arterial blood gas sampling and FIO2 measurement) | Baseline and 3 hours after study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Blood pressure | Systolic and diastolic blood pressure (mmHg) | Baseline and 3 hours after study drug administration | 
| Change in mean arterial pressure (MAP) | Measurement of mean arterial pressure (mmHg) | Baseline and 3 hours after study drug administration | 
| Change in heart rate | Measurement of pulse (beats/minute) | Baseline and 3 hours after study drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bradykinin, Alveolar-arterial gradient, Interleukin-6 (IL-6)