Treatment of COVID-19 Patients With Anti-interleukin Drugs

A Prospective, Randomized, Factorial Design, Interventional Study to Compare the Safety and Efficacy of Combinations of Blockade of Interleukin-6 Pathway and Interleukin-1 Pathway to Best Standard of Care in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 Patients With Acute Hypoxic Respiratory Failure and Systemic Cytokine Release Syndrome

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04330638

Acronym

COV-AID

Enrollment

342

Registered

2020-04-01

Start date

2020-04-03

Completion date

2021-05-21

Last updated

2023-03-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

COVID-19

Keywords

Acute Lung Injury, Hypoxia, Acute Respiratory Distress Syndrome, Corona virus, COVID-19, SARS (Severe Acute Respiratory Syndrome), Systemic Cytokine release Syndrome

Brief summary

The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6 and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome

Detailed description

There are currently no treatments directed at halting the cytokine storm and acute lung injury to stop the progression from manageable hypoxia to frank respiratory failure and ARDS in patients with COVID-19 infection. Preventing progression from early acute hypoxia and cytokine release syndrome to frank hypoxic respiratory failure and ARDS could have a huge impact on the foreseeable overflow of the ICU units. In ventilated patients, preventing the onset of ARDS, or shortening ICU stay could also be crucial in this regard. The clinical status after 15 days treatment is evaluated to measure the effectiveness of tocilizumab, tocilizumab and anakinra, siltuximab, siltuximab and anakinra and anakinra on restoring lung homeostasis,using single IV injection (siltuximab or tocilizumab) combined or not with daily subcutaneous injections of anakinra until 28 days or hospital discharge, whichever is first. During the treatment period, daily clinical assesments of severity, daily laboratory check-up, measurements of oxygen saturation (pulse oximetry) in relation to FiO2, regular arterial blood gas measurements, regular chest X-rays, chest CT scans on indication will be performed.

Interventions

OTHERUsual Care

Usual Care

DRUGAnakinra

Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first

DRUGSiltuximab

Siltuximab will be given via single IV infusion at a dose of 11 mg/kg

DRUGTocilizumab

Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection

Study design

Allocation

RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Recent ( ≥ 6 days of flu-like symptoms or malaise yet ≤16 days of flu-like symptoms or malaise prior to randomization) infection with COVID-19. * Confident COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID-19 within this period. * In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (\<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable COVID-19 infected. In all cases, this needs confirmation by later seroconversion. * Presence of hypoxia defined as PaO2/FiO2 below 350 while breathing room air in upright position or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation * signs of cytokine release syndrome defined as ANY of the following: 1. serum ferritin concentration \>1000 mcg/L and rising since last 24h 2. single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device or mechanical ventilation 3. lymphopenia defined as \<800 lymphocytes/microliter) and two of the following extra criteria * Ferritin \> 700 mcg/L and rising since last 24h * increased LDH (above 300 IU/L) and rising last 24h * D-Dimers \> 1000 ng/mL and rising since last 24h * CRP above 70mg/L and rising since last 24h and absence of bacterial infection * if three of the above are present at admission, no need to document 24h rise * Chest X-ray or CT scan showing bilateral infiltrates within last 2 days * Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients * Age ≥ 18yrs * Male or Female * Willing and able to provide informed consent or legal representative willing to provide informed consent

Exclusion criteria

* Patients with known history of serious allergic reactions, including anaphylaxis, to any of the study medications, or any component of the product. * mechanical ventilation \> 24 h at Randomization * Patient on ECMO at time of screening * clinical frailty scale above 3 (This frailty score is the patient status before first symptoms of COVID-19 episode.) * active bacterial or fungal infection * unlikely to survive beyond 48h * neutrophil count below 1500 cells/microliter * platelets below 50.000/microliter * Patients enrolled in another investigational drug study * patients on high dose systemic steroids (\> 20 mg methylprednisolone or equivalent) for COVID-19 unrelated disorder * patients on immunosuppressant or immunomodulatory drugs * patients on current anti-IL1 or anti-IL6 treatment * signs of active tuberculosis * serum transaminase levels \>5 times upper limit of normal * bowel perforation or diverticulitis * pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening) * Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. Woùmen of childbearing potential must consistently and correctly use (during the entire treatment period and 3 months after last reatment) 1 highly effective method for contraception.

Design outcomes

Primary

Measure	Time frame	Description
Time to Clinical Improvement	at day 15	Time to Clinical Improvement is defined as the time from randomization to either an increase of at least two points on a six category ordinal scale from the status at randomization or live discharge from the hospital.The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome

Secondary

Measure	Time frame	Description
Time Until Independence From Supplemental Oxygen or Discharge	during hospital admission (up to 28 days)	—
Time Until Independence From Invasive Ventilation	during hospital admission (up to 54 days)	—
Number of Days in ICU	during hospital admission (up to 28 days)	—
Number of Days in ICU in Patients Ventilated at Day of Randomization	during hospital admission (up to 28 days)	—
Number of Days Without Supplemental Oxygen Use	during hospital admission (up to 28 days)	—
Number of Invasive Ventilator Days	during hospital admission (up to 28 days)	—
Time Untill Discharge	during hospital admission (up to 28 days)	—
Number of Invasive Ventilator-free Days	during hospital admission (up to 28 days)	—
Number of Invasive Ventilator-free Days in Patients Ventilated at Day of Randomization	during hospital admission (up to 28 days)	—
Percentage of Days in ICU	first 28 days after randomization	Number of days the participants were ventilated, relative to the number of days participants were alive during the first 28 days after randomization. This was calculated as the number of days with need for invasive ventilation / number of days alive during first 28 days, multiplied by 100 (to obtain a percentage).
Percentage of Invasive Ventilator Days	the first 28 days after randomization	Number of days the participant spent in the ICU, relative to the number of days the patient was alive during the first 28 days after randomization. This was calculated as the number of days in ICU during first 28 days / number of days alive during first 28 days, multiplied by 100 (to obtain a percentage).
Time Until First Use of High-flow Oxygen Device, Ventilation, or Death	during hospital admission (up to 28 days)	—
Number of Invasive Ventilator Days in Patients Ventilated at Day of Randomization	during hospital admission (up to 28 days)	—

Countries

Belgium

Participant flow

Recruitment details

Between April 4th and December 6th, 2020, 342 patients were randomized. In the first randomization, 230 patients were assigned to the no IL-1 blockade group and 112 to the IL-1 blockade group, of which all received at least one dose of anakinra. In the second randomization, 115 patients were assigned to the no IL-6 blockade group, and 227 to the IL-6 blockade group, of which 114 were allocated to receive tocilizumab and 113 siltuximab.

Pre-assignment details

111 received siltuximab at day 1, 2 received no siltuximab due to withdrawal of consent. 113 received tocilizumab at day 1, 1 was not administered for unknown reason.

Participants by arm

Arm	Count
Blockade Patients receiving Anakinra, patients receiving Siltuximab, patients receiving Tocilizumab, patients receiving Anakinra and Siltuximab, patients receiving Anakinra and Tocilizumab	339
No Blockade Participants receiving no IL1 blockade + participants receiving no IL6 blockade	345
Total	684

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Adverse Event	9	10	15	6	10	5
Overall Study	Lost to Follow-up	3	2	3	2	3	0
Overall Study	Other	2	2	5	1	3	2
Overall Study	Withdrawal by Subject	4	0	0	0	0	0

Baseline characteristics

Characteristic	Total	Blockade	No Blockade
6-category ordinal scale for clinical improvement at day of randomization IL-1: Hospitalized, not requiring supplemental oxygen (5)	6 Participants	1 Participants	5 Participants
6-category ordinal scale for clinical improvement at day of randomization IL-1: Hospitalized, on invasive mechanical ventilation (2)	36 Participants	14 Participants	22 Participants
6-category ordinal scale for clinical improvement at day of randomization IL-1: Hospitalized, on non-invasive ventilation or high flow oxygen devices (3)	128 Participants	44 Participants	84 Participants
6-category ordinal scale for clinical improvement at day of randomization IL-1: Hospitalized, requiring supplemental oxygen (4)	169 Participants	50 Participants	119 Participants
6-category ordinal scale for clinical improvement at day of randomization IL-6: Hospitalized, not requiring supplemental oxygen (5)	6 Participants	5 Participants	1 Participants
6-category ordinal scale for clinical improvement at day of randomization IL-6: Hospitalized, on invasive mechanical ventilation (2)	39 Participants	22 Participants	17 Participants
6-category ordinal scale for clinical improvement at day of randomization IL-6: Hospitalized, on non-invasive ventilation or high flow oxygen devices (3)	128 Participants	89 Participants	39 Participants
6-category ordinal scale for clinical improvement at day of randomization IL-6: Hospitalized, requiring supplemental oxygen (4)	169 Participants	111 Participants	58 Participants
Age, Continuous IL-1	65 years	67 years	64 years
Age, Continuous IL-6	65 years	65 years	64 years
Body Mass Index (BMI) IL-1	28 kg/m^2	28 kg/m^2	28 kg/m^2
Body Mass Index (BMI) IL-6	28 kg/m^2	28 kg/m^2	28 kg/m^2
Co-existing conditions IL-1: Arterial hypertension	161 Participants	57 Participants	104 Participants
Co-existing conditions IL-1: Cardiovascular disease	70 Participants	29 Participants	41 Participants
Co-existing conditions IL-1: Chronic kidney disease	37 Participants	14 Participants	23 Participants
Co-existing conditions IL-1 Diabetes mellitus	95 Participants	37 Participants	58 Participants
Co-existing conditions IL-6: Arterial hypertension	161 Participants	115 Participants	46 Participants
Co-existing conditions IL-6: Cardiovascular disease	70 Participants	46 Participants	24 Participants
Co-existing conditions IL-6: Chronic kidney disease	37 Participants	25 Participants	12 Participants
Co-existing conditions IL-6 Diabetes mellitus	95 Participants	59 Participants	36 Participants
Concommitant medication at day of randomization IL-1: Antibiotics	158 Participants	58 Participants	100 Participants
Concommitant medication at day of randomization IL-1: Glucocorticoids	213 Participants	72 Participants	141 Participants
Concommitant medication at day of randomization IL-1: Hydroxychloroquine	40 Participants	18 Participants	22 Participants
Concommitant medication at day of randomization IL-1: Remdesivir	17 Participants	6 Participants	11 Participants
Concommitant medication at day of randomization IL-6: Antibiotics	158 Participants	103 Participants	55 Participants
Concommitant medication at day of randomization IL-6: Glucocorticoids	213 Participants	141 Participants	72 Participants
Concommitant medication at day of randomization IL-6: Hydroxychloroquine	40 Participants	25 Participants	15 Participants
Concommitant medication at day of randomization IL-6: Remdesivir	17 Participants	11 Participants	6 Participants
CRP at day of randomization IL-1	129 mg/mL	148 mg/mL	123 mg/mL
CRP at day of randomization IL-6	129 mg/mL	129 mg/mL	129 mg/mL
days of hospitalization at randomization IL-1	2 days	3 days	2 days
days of hospitalization at randomization IL-6	2 days	3 days	2 days
Days of symptoms at randomization IL-1	10 days	10 days	10 days
Days of symptoms at randomization IL-6	10 days	10 days	10 days
D-dimers at day of randomization IL-1	1011 ng/mL	1091 ng/mL	1000 ng/mL
D-dimers at day of randomization IL-6	1011 ng/mL	1000 ng/mL	1099 ng/mL
Ferritin at day of randomization IL-1	1687 µg/L	1672 µg/L	1688 µg/L
Ferritin at day of randomization IL-6	1687 µg/L	1680 µg/L	1749 µg/L
ICU at day of randomization IL-1	172 Participants	60 Participants	112 Participants
ICU at day of randomization IL-6	172 Participants	113 Participants	59 Participants
IL-1B at day of randomization IL-1	56 fg/mL	44 fg/mL	60 fg/mL
IL-1B at day of randomization IL-6	56 fg/mL	52 fg/mL	74 fg/mL
IL-1-RA at day of randomization IL-1	916 ng/mL	940 ng/mL	903 ng/mL
IL-1-RA at day of randomization IL-6	916 ng/mL	931 ng/mL	885 ng/mL
IL-6 at day of randomization IL-1	9 pg/mL	8 pg/mL	10 pg/mL
IL-6 at day of randomization IL-6	9 pg/mL	9 pg/mL	8 pg/mL
LDH at day of randomization IL-1	435 IU/L	445 IU/L	430 IU/L
LDH at day of randomization IL-6	435 IU/L	435 IU/L	435 IU/L
Lymphocyte count at day of randomization IL-1	0.7 10^3 cells /µL	0.7 10^3 cells /µL	0.7 10^3 cells /µL
Lymphocyte count at day of randomization IL-6	0.7 10^3 cells /µL	0.6 10^3 cells /µL	0.7 10^3 cells /µL
PaO2/FiO2 ratio at day of randomization IL-1	150 ratio	135 ratio	154 ratio
PaO2/FiO2 ratio at day of randomization IL-6	150 ratio	155 ratio	144 ratio
Race/Ethnicity, Customized IL-1: Asian	7 Participants	1 Participants	6 Participants
Race/Ethnicity, Customized IL-1:Black	9 Participants	1 Participants	8 Participants
Race/Ethnicity, Customized IL-1: Middle Eastern-Arabian	40 Participants	11 Participants	29 Participants
Race/Ethnicity, Customized IL-1 : Other	8 Participants	1 Participants	7 Participants
Race/Ethnicity, Customized IL-1 : white	278 Participants	98 Participants	180 Participants
Race/Ethnicity, Customized IL-6: Asian	7 Participants	4 Participants	3 Participants
Race/Ethnicity, Customized IL-6: Black	9 Participants	8 Participants	1 Participants
Race/Ethnicity, Customized IL-6 : Middle Eastern-Arabian	40 Participants	27 Participants	13 Participants
Race/Ethnicity, Customized IL-6: Other	8 Participants	4 Participants	4 Participants
Race/Ethnicity, Customized IL-6 : white	278 Participants	184 Participants	94 Participants
Sex/Gender, Customized IL-1: Female	77 Participants	25 Participants	52 Participants
Sex/Gender, Customized IL-1: Male	265 Participants	87 Participants	178 Participants
Sex/Gender, Customized IL-6: Female	77 Participants	52 Participants	25 Participants
Sex/Gender, Customized IL-6: Male	265 Participants	175 Participants	90 Participants
Smoking IL-1: Current	18 Participants	7 Participants	11 Participants
Smoking IL-1: Former	101 Participants	34 Participants	67 Participants
Smoking IL-1:No	162 Participants	54 Participants	108 Participants
Smoking IL-6: Current	18 Participants	15 Participants	3 Participants
Smoking IL-6: Former	101 Participants	65 Participants	36 Participants
Smoking IL-6: No	162 Participants	101 Participants	61 Participants
SOFA score at day of randomization IL-1	3 units on a scale	3 units on a scale	3 units on a scale
SOFA score at day of randomization IL-6	3 units on a scale	3 units on a scale	3 units on a scale
Vasopressor use at day of randomization IL-1	21 Participants	10 Participants	11 Participants
Vasopressor use at day of randomization IL-6	21 Participants	12 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	9 / 74	10 / 44	15 / 75	6 / 36	10 / 81	5 / 32
other Total, other adverse events	37 / 74	25 / 44	15 / 75	17 / 36	35 / 81	17 / 32
serious Total, serious adverse events	14 / 74	12 / 44	21 / 75	8 / 36	15 / 81	9 / 32

Outcome results

Primary

Time to Clinical Improvement

Time to Clinical Improvement is defined as the time from randomization to either an increase of at least two points on a six category ordinal scale from the status at randomization or live discharge from the hospital.The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome

Time frame: at day 15