COVID-19
Conditions
Brief summary
This is a single center, randomized, double-blind, placebo-controlled, exploratory phase II study enrolling 60 patients. We propose the administration of a blinded dose of an investigational product (IP) (clazakizumab or placebo \[0.9% saline\]) in patients with COVID-19 disease and signs of pulmonary involvement who have not yet required mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO). If a patient progresses to mechanical ventilation and/or ECMO or develops clinical signs of deteriorating COVID-19 disease, and there are no treatment related serious adverse events (SAEs), within the initial 14 day period after the first dose of the IP, at the discretion of the investigator or treating physician, open-label clazakizumab 25mg IV x 1 dose may be administered. A minimum of 24 hours should elapse between the first dose of IP and this dose of open-label clazakizumab. The patient will remain blinded as to the identity of the IP administered in the first dose.
Detailed description
Patients admitted to the hospital with COVID-19 disease with signs of pulmonary involvement will be randomized to receive the anti-IL-6 drug clazakizumab 25mg IV or placebo. Patients will be followed for improvements in clinical symptoms and laboratory parameters which are part of our COVID-19 lab panel described below. Patients will receive standard of care (SOC) supportive treatment and will be followed for 14 days. If a patient from either group progresses to the need for mechanical ventilation and/or ECMO, or develops clinical signs of deteriorating COVID-19 disease, and there are no serious treatment related SAEs, at the discretion of the investigator or treating physician, the patient may receive a single dose of open-label clazakizumab 25mg IV. A minimum of 24 hours should elapse between the first dose of IP and this dose of open-label clazakizumab. Enrolled patients will receive clazakizumab 25 mg or placebo (0.9% saline) given by IV infusion over 30 minutes. Clazakizumab will be administered in 50 mL of 0.9% saline on Day 1. COVID-19 lab panel and clinical parameters will be monitored to determine if patients are progressing towards need for ventilation and/or ECMO. The parameters below will be monitored and patient status will be assessed by the clinical team. If patients do develop these criteria, open-label clazakizumab 25 mg IV may be administered as discussed above. A minimum of 24 hours should elapse between the first dose of IP and this dose of open-label clazakizumab. Patients ventilated with or without ECMO will continue to be monitored post-treatment for signs of improvement, (i.e., decreasing FiO2 requirements, chest X-ray (CXR) improvements, C-reactive protein (CRP) reductions, extubation and discharge home) or death.
Interventions
DRUGClazakizumab
IV Infusion
Sponsors
Cedars-Sinai Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Blinded IP (clazakizumab or placebo) will be given initially, followed by the option of an open label dose of clazakizumab within the first 14 days of initial IP administration.
Intervention model description
We propose the administration of a blinded dose of an investigational product (IP) (clazakizumab or placebo \[0.9% saline\]) in patients with COVID-19 disease and signs of pulmonary involvement who have not yet required mechanical ventilation and/or ECMO. If a patient progresses to mechanical ventilation and/or ECMO or develops clinical signs of deteriorating COVID-19 disease, and there are no treatment related serious adverse events (SAEs), within the initial 14 day period after the first dose of the IP, at the discretion of the investigator or treating physician, open-label clazakizumab 25mg IV x 1 dose may be administered. A minimum of 24 hours should elapse between the first dose of IP and this dose of open-label clazakizumab. The patient will remain blinded as to the identity of the IP administered in the first dose.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>18 at the time of screening * Subject must be able to understand and provide informed consent * Hospitalized with COVID-19 (+) disease (confirmed by polymerase chain reaction (PCR) assay from any specimen (e.g. respiratory, blood, urine, stool, other bodily fluid)) * Not on mechanical ventilation and/or ECMO * Evidence of pulmonary involvement with at least 2 of the following: 1. Oxygen saturation (SpO2) at rest in ambient air with SpO2 ≤ 94% 2. Tachypnea with resting respiration rate \> 25 breaths/minute 3. Partial pressure of oxygen (PaO2) / fraction of inspired oxygen (FiO2) ≤ 300 mmHg 4. Chest imaging (radiograph, CT scan, or lung ultrasound) with abnormalities consistent COVID-19 pneumonia 5. C-reactive protein (CRP) \>35 mg/L
Exclusion criteria
* Previous hypersensitivity or allergic reactions to clazakizumab * Lactating or pregnant females * Subjects with latent Tuberculosis (TB) and who are not receiving treatment * Subjects with active TB * A significantly abnormal general serum screening lab result defined as a White Blood Count (WBC) \< 3.0 X 103/ml, a Hgb \< 8.0 g/dL, a platelet count \< 50 X 103/ml, a serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) \> 5x upper limit normal * Participation in another clinical trial investigating COVID-19 aimed agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Clazakizumab for the Treatment of Patients With COVID-19 Disease | 14 days | Number of severe adverse events (SAEs) that are unusual, unexpected, or assessed as related to the investigational product (IP) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Survival at 60 Days | 60 days | Number of patients alive at 60 days |
| Number of Patients Requiring the Dose of Open-label Clazakizumab | 14 days | Number of patients requiring the dose of open-label clazakizumab |
| Patient Survival at 28 Days | 28 days | Number of patients alive at 28 days |
| Number of Days in Hospital | 60 days | Number of days in hospital compared to placebo |
| Number of Patients Requiring Mechanical Ventilation and/or Extracorporeal Membrane Oxygenation (ECMO) | 14 days | Number of patients requiring mechanical ventilation and/or ECMO at 14 days after the first administered dose in comparison to placebo |
| Number of Days in Intensive Care Unit (ICU) | 60 days | Number of days in ICU compared to placebo |
Countries
United States
Participant flow
Recruitment details
Patients eligible for the study and who may benefit from the administration of clazakizumab will be identified by members of the inpatient team and referred to the study team. If a patient is eligible, the PI or Co-I will discuss the study with them. Treating physicians of COVID-19 patients will be made aware of the research offering. Patients will be asked if they can be approached about research options. Researchers may approach potential subjects who indicate they are interested.
Pre-assignment details
Of the total 105 participants ages 18 years and older screened, 17 were enrolled in this single center, randomized, double-blind, placebo-controlled, exploratory phase II study.
Participants by arm
| Arm | Count |
|---|---|
| Clazakizumab 25 mg in 50 mL of 0.9% saline given by IV infusion x 1 dose over 30 minutes | 8 |
| Placebo 50 mL of 0.9% saline given by IV infusion x 1 dose over 30 minutes | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 2 |
| Overall Study | Withdrawn by subject due to dementia | 0 | 1 |
Baseline characteristics
| Characteristic | Clazakizumab | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 4 Participants | 10 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 13.44 | 60 years STANDARD_DEVIATION 13.14 | 59 years STANDARD_DEVIATION 13.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 2 / 8 |
| other Total, other adverse events | 2 / 8 | 2 / 8 |
| serious Total, serious adverse events | 2 / 8 | 3 / 8 |
Outcome results
Primary
Safety of Clazakizumab for the Treatment of Patients With COVID-19 Disease
Number of severe adverse events (SAEs) that are unusual, unexpected, or assessed as related to the investigational product (IP)
Time frame: 14 days
Population: Enrolled patients who received the initial dose of the IP were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clazakizumab | Safety of Clazakizumab for the Treatment of Patients With COVID-19 Disease | SAEs within 14 days | 3 Adverse Events |
| Clazakizumab | Safety of Clazakizumab for the Treatment of Patients With COVID-19 Disease | Adverse Events (AEs) and SAEs overall | 6 Adverse Events |
| Placebo | Safety of Clazakizumab for the Treatment of Patients With COVID-19 Disease | SAEs within 14 days | 3 Adverse Events |
| Placebo | Safety of Clazakizumab for the Treatment of Patients With COVID-19 Disease | Adverse Events (AEs) and SAEs overall | 8 Adverse Events |
Comparison: The null hypothesis is that there is no difference in the use of clazakizumab as a treatment compared to placebo in reducing or eliminating the incidence of severe adverse events among patients with COVID-19.p-value: 0.1Chi-squared
Secondary
Number of Days in Hospital
Number of days in hospital compared to placebo
Time frame: 60 days
Population: Enrolled patients who received the initial dose of the IP were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clazakizumab | Number of Days in Hospital | 17.5 Days | Standard Deviation 16.62 |
| Placebo | Number of Days in Hospital | 18.75 Days | Standard Deviation 13.6 |
Secondary
Number of Days in Intensive Care Unit (ICU)
Number of days in ICU compared to placebo
Time frame: 60 days
Population: Enrolled patients who received the initial dose of the IP were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clazakizumab | Number of Days in Intensive Care Unit (ICU) | 30.5 Days | Standard Deviation 34.65 |
| Placebo | Number of Days in Intensive Care Unit (ICU) | 11.67 Days | Standard Deviation 3.06 |
Secondary
Number of Patients Requiring Mechanical Ventilation and/or Extracorporeal Membrane Oxygenation (ECMO)
Number of patients requiring mechanical ventilation and/or ECMO at 14 days after the first administered dose in comparison to placebo
Time frame: 14 days
Population: Enrolled patients who received the initial dose of the IP were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clazakizumab | Number of Patients Requiring Mechanical Ventilation and/or Extracorporeal Membrane Oxygenation (ECMO) | 1 Participants |
| Placebo | Number of Patients Requiring Mechanical Ventilation and/or Extracorporeal Membrane Oxygenation (ECMO) | 2 Participants |
Comparison: Null hypothesis is that there is no change in the need for mechanical ventilation and/or ECMO at 14 days after the first administered dose in comparison to placebo.p-value: 0.1Fisher Exact
Secondary
Number of Patients Requiring the Dose of Open-label Clazakizumab
Number of patients requiring the dose of open-label clazakizumab
Time frame: 14 days
Population: Enrolled patients who received the initial dose of the IP were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clazakizumab | Number of Patients Requiring the Dose of Open-label Clazakizumab | 2 Participants |
| Placebo | Number of Patients Requiring the Dose of Open-label Clazakizumab | 5 Participants |
Secondary
Patient Survival at 28 Days
Number of patients alive at 28 days
Time frame: 28 days
Population: Enrolled patients who received the initial dose of the IP were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clazakizumab | Patient Survival at 28 Days | 7 Participants |
| Placebo | Patient Survival at 28 Days | 7 Participants |
Secondary
Patient Survival at 60 Days
Number of patients alive at 60 days
Time frame: 60 days
Population: Enrolled patients who received the initial dose of the IP were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clazakizumab | Patient Survival at 60 Days | 6 Participants |
| Placebo | Patient Survival at 60 Days | 6 Participants |