ICASARS: Inhibition of Bradykinin in COVID-19 Infection With Icatibant

Sponsor

Belfast Health and Social Care Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT05407597

Collaborator

Queen's University, Belfast (Other)

Enrollment

Location

Arms

13.6

Anticipated Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
SARS CoV 2 Infection	Drug: Icatibant Drug: 0.9% Sodium Chloride Injection	Phase 2/Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

32 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients will be randomly allocated to receive either Icatibant (30mg) or 0.9% Sodium Chloride (3mls)Patients will be randomly allocated to receive either Icatibant (30mg) or 0.9% Sodium Chloride (3mls)

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Patients and investigators will be blinded to treatment allocation. An unblinded research nurse will administer the study medication.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 12, 2022

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Icatibant and Standard of care (SOC) Icatibant will be given as a single, subcutaneous injection	Drug: Icatibant 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.
Placebo Comparator: 0.9% Sodium Chloride and Standard of care (SOC) Placebo will be given as a single, subcutaneous injection	Drug: 0.9% Sodium Chloride Injection 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.

Arm

Intervention/Treatment

Active Comparator: Icatibant and Standard of care (SOC)

Icatibant will be given as a single, subcutaneous injection

Drug: Icatibant

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.

Placebo Comparator: 0.9% Sodium Chloride and Standard of care (SOC)

Placebo will be given as a single, subcutaneous injection

Drug: 0.9% Sodium Chloride Injection

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.

Outcome Measures

Primary Outcome Measures

Change in Oxygenation [Baseline and 3 hours after study drug administration]
Alveolar-arterial gradient (Arterial blood gas sampling and FIO2 measurement)

Secondary Outcome Measures

Change in Blood pressure [Baseline and 3 hours after study drug administration]
Systolic and diastolic blood pressure (mmHg)
Change in mean arterial pressure (MAP) [Baseline and 3 hours after study drug administration]
Measurement of mean arterial pressure (mmHg)
Change in heart rate [Baseline and 3 hours after study drug administration]
Measurement of pulse (beats/minute)

Other Outcome Measures

Change in interleukin-6 levels [Baseline and 3 hours after study drug administration]
Blood sample will be taken for measurement of serum IL-6 (pg/ml)
Change in retinal vessel size (As measured by optical coherence tomography) [Baseline and 3 hours after study drug administration]
OCT retinal imaging of both eyes. Retinal vasculature will be assessed.
Oxygen requirements and saturations 24 hours post study drug [Approximately 24 hours after study drug administration]
Documentation of oxygen required and oxygen saturations

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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