SCIL-1Ra in COVID-19 Feasibility & PK/PD (SCIL_COV19)

Subcutaneous and Intravenous IL-1Ra (Anakinra) in COVID-19 Infection - Feasibility & Pharmacokinetics/Pharmacodynamics Study

The current COVID-19 pandemic is a worldwide healthcare crisis. Of concern is the large number of patients that are/will require mechanical ventilation, and the associated strain that this will place on healthcare resources. At present, there are no specific therapeutic interventions directed at COVID-19 infection. However, observational data suggest that there is a subgroup of patients that demonstrate a hyperinflammatory response in response to COVID-19 and have a higher requirement for Critical Care and higher mortality.

There is a strong case for the use of the naturally occurring anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) in these patients. Anakinra is a recombinant form of IL-1Ra that is licensed for clinical use. Success of use of anakinra in COVID-19 trials will be greatly enhanced by robust scientific evidence and established pharmacokinetics which inform the most effective dosing regimens. The latter is especially important when, as in the case of anakinra, drug supplies are limited, the drug has short half-life and clinical ease of application is critical.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Anakinra 100Mg/0.67Ml Inj Syringe

Detailed Description

The investigators plan a small trial of an existing drug in patients with COVID-19 at Salford Royal NHS Foundation Trust (SRFT) and Manchester Foundation Trust (MFT). The investigators will recruit patients with suspected or confirmed COVID-19 infection within 24 hours of being transfer in a Critical Care department. The investigators have been testing interleukin-1 receptor antagonist: IL-1Ra (known as Anakinra) for many years. Marketed as a treatment for rheumatoid arthritis and for some rare autoimmune diseases, we have shown Anakinra also reduces or blocks inflammation in a number of other conditions e.g. stroke and brain haemorrhage. The investigators have found it to be safe, easily administered and well tolerated. As part of the global response to the SARS-COV-2 pandemic, researchers have identified drugs that repurposing existing drugs. Anakinra has been proposed as a candidate therapy for COVID-19 and will be used in REMAP-CAP clinical trial as an intravenous (IV) therapy four times daily (qds). Whilst there is uncertainty about the therapeutic benefits, the investigators wish to explore the theory that they can achieve comparable concentrations in the blood using a subcutaneous (SC) injection twice daily (bd), as observed with IV therapy qds. We will randomise up to 40 patients to receive either SC Anakinra twice daily or IV Anakinra four-times daily for 14 days (or until discharge from CCU). They will measure changes in biomarkers in both groups and use the data to inform a mathematical model to simulate the effect the drug may have on the body. The aim is to the provide evidence that a lower dose SC Anakinra is as effective as higher dose IV.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Manchester Univesity NHS Foundation Trust
  • Salford, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Tust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient age 18 or above.
• Clinically suspected/proven COVID-19.
• Requiring organ support with one or more of:
• Non-invasive or invasive ventilatory support
• Receiving infusion of vasopressor or inotropes or both.
• No concomitant health problems that, in the opinion of the PI or designee in agreement with the treating clinician, would interfere with participation, administration of study drug or assessment of outcomes including safety.

Exclusion Criteria:

• More than 24h has elapsed since CCU admission.
• Death is deemed to be imminent and inevitable during the next 24h.
• One or more of: the patient, substitute decision-maker or the attending physician are not committed to full active treatment.
• Known condition resulting in ongoing immunosuppression including neutropenia (count < 1.5 x 10^9/L) prior to hospitalisation, malignancy, latent tuberculosis or chronic liver disease (if known).
• Previous or current treatment with anakinra or medication suspected of interacting with anakinra, listed in the drug SmPC, known at the time of trial entry or previous participation in this trial.
• Known to have received active treatment in a clinical trial of an investigational immunomodulatory agent (not including corticosteroids) within 30 days prior to study entry.
• Known to be pregnant or breast feeding or inability to reliably confirm that the patient is not pregnant.
• Known allergy to anakinra or any of the excipients listed in the drug SmPC
• Known allergy to other products that are produced by DNA technology using the micro-organism E. coli (e.g. Escherichia coli derived protein).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: HEALTH_SERVICES_RESEARCH
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Subcutaneous Arm; 100mg anakinra SC will be administered subcutaneously at consistent times that are convenient and practical for the patients and research/nursing staff providing there is a minimum 8 hours and maximum 16 hours between administrations.	Drug: Anakinra 100Mg/0.67Ml Inj Syringe; 100 mg interleukin-1 receptor antagonist (r-meth-Hu-IL-1Ra), anakinra; marketed as Kineret® in 0.67 mL prefilled syringe for single use; Other Names: Kineret
ACTIVE_COMPARATOR: Intravenous Arm; 100mg anakinra in 100mL 0.9% NaCl will be administered intravenously four times a day every 6 hours.	Drug: Anakinra 100Mg/0.67Ml Inj Syringe; 100 mg interleukin-1 receptor antagonist (r-meth-Hu-IL-1Ra), anakinra; marketed as Kineret® in 0.67 mL prefilled syringe for single use; Other Names: Kineret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma IL-1Ra levels	Plasma IL-1Ra levels from Day 1 to Day 7 following administration of SC anakinra in patients with SARS-CoV-2	1 week
Plasma IL-6 levels	Plasma IL-6 levels from Day 1 to Day 7 following administration of SC anakinra in patients with SARS-CoV-2	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma markers	Plasma markers including IL-6 from Day 1 to Day 14 in all participants	2 weeks
Plasma markers	Plasma markers including CRP from Day 1 to Day 14 in all participants	2 weeks
Plasma markers	Plasma markers including CXCL9 from Day 1 to Day 14 in all participants	2 weeks
Plasma markers	Plasma markers including IL-1 from Day 1 to Day 14 in all participants	2 weeks
Plasma markers	Plasma markers including IL-2 from Day 1 to Day 14 in all participants	2 weeks
Plasma markers	Plasma markers including HMBG-1 from Day 1 to Day 14 in all participants	2 weeks
Plasma markers	Plasma markers including IL-33 from Day 1 to Day 14 in all participants	2 weeks
Safety Endpoints related to the Serious adverse reactions of the IMP	Safety endpoints include: a. Severe fatal or life-threatening serious adverse reactions (duration of IMP plus 30h from last dose).	2 weeks
Safety Endpoints related to the anaphylactic reactions of the IMP	Safety endpoints include: b. Anaphylactic/anaphylactoid reactions (duration of IMP plus 30h from last dose).	2 weeks
Safety Endpoints related to neutropenia caused by the IMP	Safety endpoints include: c. Severe neutropenia (< 1.5 x 109 /L) (duration of IMP)	2 weeks
Safety Endpoints related to any severe laboratory abnormalities	Safety endpoints include: d. IMP related severe laboratory abnormalities (duration of IMP)	2 weeks
Feasibility endpoints related to IMP and deviations	Feasibility endpoints include protocol deviations in terms of timing and delivery of scheduled medication.	2 weeks
Exploratory Data on Clinical efficacy by time to recovery	Exploratory data on clinical efficacy as defined by: a. Time to recovery defined by hospital discharge or improvement of two points on the ordinal scale: not hospitalised; hospitalised without need for supplemental oxygen; requiring supplemental oxygen; requiring HFNC or non-invasive mechanical ventilation; requiring ECMO or mechanical intervention; dead. Improvement mechanical ventilation (from recruitment to time of ventilation)	4 weeks
Exploratory Data on Clinical efficacy	Exploratory data on clinical efficacy as defined by: b. Ventilation free days (at 28 days)	4 weeks
Exploratory Data on Clinical efficacy of the ordinal scale	Exploratory data on clinical efficacy as defined by: c. Status on the above ordinal scale (at 14 and 28 days)	4 weeks

Collaborators and Investigators

• Sponsor: University of Manchester
• Investigators: Principal Investigator: Timothy Felton, Dr, University of Manchester

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 28, 2020
• Primary Completion (ACTUAL): August 31, 2020
• Study Completion (ACTUAL): December 23, 2020

Study Registration Dates

• First Submitted: June 12, 2020
• First Submitted That Met QC Criteria: July 7, 2020
• First Posted (ACTUAL): July 8, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 30, 2021
• Last Update Submitted That Met QC Criteria: April 27, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: 282110; 2020-001636-95 (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