Inhibition of Bradykinin in COVID-19 Infection With Icatibant (ICASARS)

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

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.

Study Overview

• Status: Completed
• Conditions: SARS CoV 2 Infection
• Intervention / Treatment: Drug: Icatibant; Drug: 0.9% Sodium Chloride Injection

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 Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Antrim
    • Belfast, Antrim, United Kingdom, BT14 6AB
      • Mater Infirmorum Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age >18 years.
2. Documented evidence of COVID-19 and symptom onset of 7 days or less
3. Acute hypoxia which will be defined as either low resting saturations <94% or supplementary oxygen to maintain oxygen saturations at >94%

Exclusion Criteria:

1. Patients known to be pregnant or breastfeeding.
2. Patients with unstable ischaemic heart disease or acute stroke
3. Patients enrolled in other clinical trials of an investigational medicine within the previous 28 day period
4. Patients who refuse to have blood samples taken.
5. Known hypersensitivity to Icatibant
6. 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).
7. Patients with chronic heart or lung disease whose oxygen levels are reduced, but are unchanged from baseline

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Belfast Health and Social Care Trust
• Collaborators: Queen's University, Belfast
• Investigators: Principal Investigator: Joe Kidney, MD, Belfast Health and Social Care Trust

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2022
• Primary Completion (Actual): June 9, 2023
• Study Completion (Actual): July 7, 2023

Study Registration Dates

• First Submitted: May 11, 2022
• First Submitted That Met QC Criteria: June 6, 2022
• First Posted (Actual): June 7, 2022

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Bradykinin; Interleukin-6 (IL-6); Alveolar-arterial gradient
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Infections; Communicable Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Bradykinin B2 Receptor Antagonists; Bradykinin Receptor Antagonists; Icatibant
• Other Study ID Numbers: 21036JK-AS; 2021-005851-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No