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

• ClinicalTrials.gov Identifier: NCT05407597
• Recruitment Status: Completed
• First Posted: June 7, 2022
• Last Update Posted: September 7, 2023
• Sponsor: Belfast Health and Social Care Trust
• Collaborator: Queen's University, Belfast
• Information provided by (Responsible Party): Belfast Health and Social Care Trust

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 (Clinical Trial)
• Actual 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)
• 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 16, 2022
• Actual Primary Completion Date: June 9, 2023
• Actual Study Completion Date: July 7, 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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United Kingdom

Mater Infirmorum Hospital

Belfast, Antrim, United Kingdom, BT14 6AB

Sponsors and Collaborators

Belfast Health and Social Care Trust

Queen's University, Belfast

Investigators

• Principal Investigator: Joe Kidney, MD; Belfast Health and Social Care Trust

More Information

• Responsible Party: Belfast Health and Social Care Trust
• ClinicalTrials.gov Identifier: NCT05407597
• Other Study ID Numbers: 21036JK-AS; 2021-005851-35 ( EudraCT Number )
• First Posted: June 7, 2022
• Last Update Posted: September 7, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Belfast Health and Social Care Trust:

Bradykinin; Alveolar-arterial gradient; Interleukin-6 (IL-6)

Additional relevant MeSH terms:

Infections; Communicable Diseases; COVID-19; Disease Attributes; Pathologic Processes; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Icatibant; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Bradykinin B2 Receptor Antagonists; Bradykinin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors