Sarilumab Treatment In cytoKinE Storm Caused by Infection With COVID-19

Phase 2

• Conditions: COVID-19 Drug Treatment
• Interventions: Drug: Sarilumab

• Registration Number: NCT04661527
• Lead Sponsor: Clinica Universidad de Navarra, Universidad de Navarra

Brief Summary

Phase II, one-arm, open label, multicentric study, to evaluate treatment of severe COVID-19 with sarilumab prior to entry into the intensive care unit (ICU).

Detailed Description

Phase II, one-arm, open label, multicentric study, to evaluate treatment of severe COVID-19 with sarilumab prior to entry into the intensive care unit (ICU).

The primary objective of the trial is to evaluate the impact of sarilumab on the progression of COVID 19-associated respiratory failure as measured by the change in a severity rating on a 7-point severity index. Secondary objectives include the evaluation of safety of the drug and the assessment of the impact of Sarilumab on markers of systemic inflammation and the coagulation cascade, on mortality, and on oxygenation.

The trial has two phases. Firstly, patients with pneumonia in the setting of COVID-19 who meet inclusion criteria and have no exclusion criteria will be treated with 2 doses of 200 mg IV of Sarilumab in 24 hours. After internal review, if no AE are detected and if there is no significant improvement, the next 55 patients will be treated with two doses of 400 mg IV in 24 hours.

Study Timeline

• Status Verified: 2020-04
• Study Start: 2020-04-22
• Study First Submitted: 2020-09-10
• Study First Submitted QC: 2020-12-09
• Study First Posted: 2020-12-10
• Last Update Submitted: 2020-12-14
• Last Update Posted: 2020-12-16
• Primary Completion: 2020-12-30
• Study Completion: 2020-12-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Written informed consent prior to performing study procedures. Oral consent will be accepted in order to avoid paper handling. Written consent by patient or representatives will be obtained as soon as possible.

   In the case of a vital emergency without the possibility of prior consent, a patient may be included in the study if the recommendations of the legislation are followed (RD 1090/2015, article 7), as stated in section 10.3 of the protocol.

2. Patient must be, in the investigator opinion, able to comply with all the protocol procedures.

3. Negative pregnancy test in case of fertile women*

4. Age >= 18

5. Infection by COVID-19 confirmed by rtPCR or other validated tests

6. Hospitalized (or documentation of a plan to admit to the hospital if the patient is in the emergency department) with illness of any duration, with evidence of pneumonia, and severe disease as defined by at least one of the following:

   1. High oxygen requirements (face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula)
   2. Lymphocytes < 0.8 x 109/L
   3. Serum ferritin > 300ng/mL
   4. Increased levels of D-dimer (> 1500 ng/mL) or D-dimer progressively increasing (over 3 consecutive measurements) and reaching ≥ 1000 ng/mL.
   5. CPR > 10 mg/dL, or increasing over 24 hours

Exclusion Criteria

Patients with any of the following exclusion criteria could not be included in the trial:

1. Hypersensitivity to the active substance or any of the excipients listed in section 6
2. Treatment with anti-IL 6, anti-IL-6R antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days
3. Alkylating agents including cyclophosphamide (CYC) within 6 months of baseline
4. Cyclosporine (CsA), azathioprine (AZA) or mycophenolate mofetil (MMF) or leflunomide within 4 weeks of baseline.
5. Alkylating agents including cyclophosphamide (CYC) within 6 months of baseline
6. Tumor necrosis factor (TNF) inhibitors within 2-8 weeks (etanercept within 2 weeks, infliximab, certolizumab, golimumab, or adalimumab within 8 weeks), or after at least 5 half-lives have elapsed, whichever is longer.
7. Intravenous immunoglobulin (IVIG) within the past 5 months or plans to receive during the study period
8. Current use of chronic oral corticosteroids for a non-COVID-19-related condition in a dose higher than prednisone 10 mg or equivalent per day
9. Current treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs)/immunosuppressive agents
10. Patients who have received immunosuppressive antibody therapy within the past 5 months, including intravenous immunoglobulin
11. AST/ALT values > 5 x normal.
12. Neutropenia (< 0.5 x 109/L).
13. Sever thrombocytopenia (< 50 x 109/L).
14. Sepsis caused by an alternative pathogen.
15. Diverticulitis with risk of perforation.
16. Ongoing infectious dermatitis.
17. Patients with another active infection, including localized infections.
18. Pregnant or breast-feeding females will be excluded
19. Positive serology for following infection: HIV, Hepatitis B, or C.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sarilumab arm	Sarilumab	-

Primary Outcome Measures

Name	Time	Method
Change in a severity rating on a 7-point ordinal scale	15 days	Impact of sarilumab on the progression of COVID-19 associated respiratory failure. A significant improvement in a 7-point severity index is anticipated to occur with treatment with sarilumab.

Secondary Outcome Measures

Name	Time	Method
Duration of mechanical ventilation	28 days	Duration of mechanical ventilation measured by days of ventilation since treatment
Patients requiring mechanical ventilation	28 days	Number and proportion of patients requiring mechanical ventilation
Time to improvement in oxygenation for at least 48 hours	28 days	Increase in SpO2/FiO2 of 50 or more compared to nadir SpO2/FiO2
Percentage of patients reporting each severity rating on a 7-point severity ordinal scale	28 days	Proportion of patients in each severity category at the end fo follow-up
Number of ventilator free days in the first 28 days	28 days	Number of ventilator free days in the first 28 days
Evaluate the safety of sarilumab in patients with severe pneumonia caused by COVID 19	28 days	All adverse events will be recorded in the CRF.; Adverse Event is defined as any event that results in worsening of the health of the subject of the clinical trial, regardless of relationship to the experimental therapy. It can be any symptom, sign, illness or experience, including abnormal results of diagnostic procedures, that develops or worsens in severity during the course of the study.; Serious Adverse Event are defined as any AE that is: * Fatal; * Life-threatening\*; * Requires or prolongs hospital stay; * Results in persistent or significant disability or incapacity
Change from baseline in PaO2/FiO2 in patients on mechanical ventilation	since day of intubation until day of extubation or up to day 28	PaO2/FiO2 will be measured daily until extubation or day 28.
Changes from baseline in white blood cell count if available on V2, V3, V4, V5, and V6	28 days	Changes in white blood count on visits number 2, 3 ,4, 5 and 6.
Changes from baseline in platelet cell count if available on V2, V3, V4, V5, and V	28 days	Changes in platelet counts on visits number 2, 3 ,4, 5 and 6.
Organ failure	28 days	Events of organ failure after treatment: DIC, cardiac, hepatic, renal, cardiovascular
Time to saturation > 93.9% on room air	28 days	Improvement on oxygenation using a threshold of SaO2 of 94% or better when breathing room air as a sign of improvement.
Changes from baseline in hemoglobin levels if available on V2, V3, V4, V5, and V6	28 days	Changes in hemoglobin on visits number 2, 3 ,4, 5 and 6.
Changes from baseline in Aspartate transaminase (AST) leves if available on V2, V3, V4, V5, and V6	28 days	Indicates improvement or worsening of liver function
Changes from baseline in Troponin leves if available on V2, V3, V4, V5, and V6	28 days	Indicates potential myocardial involvement.
Changes from baseline in creatinine leves if available on V2, V3, V4, V5, and V6	28 days	Indicates improvement or worsening of renal function
Time to resolution of fever without antipyretics for at least 48 hours (Tº > 36.6ºC - axilla; > 37.2ºC -oral; > 37.8 -rectal or tympanic)	28 days	Resolution of fever.
Changes from baseline in D-Dimer leves if available on V2, V3, V4, V5, and V6	28 days	Changes in D-dimer levels on visits number 2, 3 ,4, 5 and 6.
Number of deaths due to any cause	28 days	All-cause mortality
Changes from baseline in Ferritin leves if available on V2, V3, V4, V5, and V6	28 days	Indicates improvement or worsening of inflammation.
Changes from baseline in blilirrubin leves if available on V2, V3, V4, V5, and V6	28 days	Indicates improvement or worsening of liver function
Changes from baseline in Alanine transaminase (ALT) leves if available on V2, V3, V4, V5, and V6	28 days	Indicates improvement or worsening of liver function
Changes from baseline in C Reactive protein if available on V2, V3, V4, V5, and V6	28 days	Indicates improvement or worsening of inflammation.
Changes from baseline in blood urea nitrogen leves if available on V2, V3, V4, V5, and V6	28 days	Indicates improvement or worsening of renal function

Trial Locations

Locations (2)

Clínica Universidad de Navarra, Universidad de Navarra; 🇪🇸 Pamplona, Navarra, Spain

Hospital Universitario Infanta Leonor; 🇪🇸 Madrid, Spain