COVID 19, Pneumonia, SARS-CoV 2
Conditions
Brief summary
The purpose of this prospective, Phase 2, multicenter, blinded, randomized placebo controlled study is to demonstrate that early treatment with mavrilimumab prevents progression of respiratory failure in patients with severe COVID-19 pneumonia and clinical and biological features of hyper-inflammation.
Detailed description
This prospective, Phase 2, multi-center, blinded randomized placebo-controlled study is designed to demonstrate that early treatment with mavrilimumab prevents progression of respiratory failure in patients with severe Covid-19 pneumonia and clinical and biological features of hyper-inflammation. The study population includes patients who have severe pneumonia, defined as hospitalization due to Covid-19 with abnormal chest imaging and SpO2 \<92% on room air or requirement for supplemental oxygen. Enrollment: The study will be performed in approximately 4 months total, starting from the first patient enrolled with enrollment expected to complete within 2 months. Follow-up period: The follow-up period is 60 days for each patient enrolled. A total of 60 patients will be randomized using a 1:1 allocation ratio: 30 subjects will receive mavrilimumab, and 30 subjects will receive placebo infusion. The investigator, clinical team, and subject will be blinded to treatment assignment. Participants will be identified by regular review of hospitalized COVID19 patients to evaluate for inclusion and exclusion criteria. Participants will then be approached in the standard manner by study investigator and coordinator/research nurse. Research interventions will take place in the hospital in accordance with privacy standards. The study team is informed on all study procedures and requirements with daily meetings and the opportunity to continuously update through secure channels. In this multicenter consortium, each participating site will have their own IND for patients enrolled at their site. Data collection will occur at each of the 4 academic centers, and data analysis and randomization scheme will be performed by one site, Cleveland Clinic C5 Research.
Interventions
DRUGMavrilimumab
Treatment infusion
DRUGPlacebos
Placebo infusion
Sponsors
Kiniksa Pharmaceuticals, Ltd.
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(must meet all): 1. Written informed consent must be obtained before any assessment is performed 2. Documented COVID19 pneumonia defined as positive SARS-CoV2 test AND abnormalities/ infiltrates on chest x-ray or computed tomography AND active fever or documented fever within 24-48 hours or ongoing anti-pyretic use to suppress fever 3. Hypoxia (Room air SpO2 \<92% or requirement for supplemental oxygen) 4. Increased serum inflammatory marker (CRP \> 5 mg/dL) 5. Severity of disease warrants inpatient hospitalization
Exclusion criteria
1. Onset of COVID-19 symptoms \>14 days 2. Age \< 18 years-old 3. Hospitalized \>7 days 4. Mechanically ventilated 5. Serious concomitant illness which in the opinion of the investigator precludes the patient from enrolling in the trial, including (but not limited to): * History of immunodeficiency (congenital or acquired) * Neutropenia (absolute neutrophil count \<1,500/mm3) * History of solid-organ or bone marrow transplant * History of current systemic autoimmune or autoinflammatory disease(s) requiring systemic immune-modulating drugs * History of myeloproliferative disorder or active malignancy receiving cytotoxic chemotherapy * Pre-existing severe pulmonary disease (i.e. steroid dependent asthma, COPD on home oxygen, or other restrictive/obstructive lung disease requiring home oxygen) * Pre-existing severe left ventricular systolic dysfunction (i.e. LVEF \<35%) * Known or suspected active tuberculosis (TB), latent TB, or history of incompletely treated TB or at high risk for latent TB (from exposure or prior incarceration) * History of active or latent viral hepatitis (i.e. Hepatitis B or C) * Concomitant uncontrolled systemic bacterial or fungal infection * Concomitant viral infection other than COVID-19 (e.g. Influenza, other respiratory viruses) * History of chronic liver disease with portal hypertension * History of end-stage renal disease on chronic renal replacement therapy 6. Recent treatment with cell-depleting biological therapies (e.g., anti-CD20) within 12 months, cell-depleting biological therapies (such as anti-tumor necrosis factor \[TNF\], anakinra, anti-Interleukin \[IL\]-6 receptor \[e.g. tocilizumab\], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer), treatment with alkylating agents within 12 weeks, treatment with cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks 7. Recent treatment with intramuscular live (attenuated) vaccine within 4 weeks 8. Chronic or recent corticosteroid use \> 10 mg/day 9. Pregnant. Breast-feeding women are eligible with the decision to continue or discontinue breast-feeding during therapy taking into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother 10. Enrolled in another investigational study using immunosuppressive therapy 11. Known hypersensitivity to mavrilimumab or any of its excipients 12. In the opinion of the investigator, unable to comply with the requirements to participate in the study 13. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug. Such methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject * Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects Alive and Off of Oxygen at Day 14 | Day 14 | Number and percentage of subjects alive and off of oxygen at day 14 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Alive and Without Respiratory Failure at Day 28 | Day 28 | Number and percentage of subjects that are alive and without respiratory failure at Day 28 |
| Mortality at Day 28 | Day 28 | Number and percentage of patients that expired by Day 28 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention One-time Mavrilimumab infusion at 6mg/kg via IV | 21 |
| Control One-time placebo infusion via IV | 19 |
| Total | 40 |
Baseline characteristics
| Characteristic | Total | Intervention | Control |
|---|---|---|---|
| Age, Continuous | 55.75 years STANDARD_DEVIATION 15.97 | 56.7 years STANDARD_DEVIATION 13.49 | 54.8 years STANDARD_DEVIATION 18.44 |
| History of Diabetes | 17 Participants | 8 Participants | 9 Participants |
| History of Hyperlipidemia | 18 Participants | 7 Participants | 11 Participants |
| History of Hypertension | 22 Participants | 10 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 8 Participants | 8 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 | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 19 Participants | 11 Participants | 8 Participants |
| Region of Enrollment United States | 40 Participants | 21 Participants | 19 Participants |
| Sex: Female, Male Female | 14 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Male | 26 Participants | 14 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 21 | 4 / 19 |
| other Total, other adverse events | 12 / 21 | 8 / 19 |
| serious Total, serious adverse events | 5 / 21 | 4 / 19 |
Outcome results
Primary
Subjects Alive and Off of Oxygen at Day 14
Number and percentage of subjects alive and off of oxygen at day 14
Time frame: Day 14
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Subjects Alive and Off of Oxygen at Day 14 | 12 Participants |
| Control | Subjects Alive and Off of Oxygen at Day 14 | 9 Participants |
Secondary
Mortality at Day 28
Number and percentage of patients that expired by Day 28
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Mortality at Day 28 | 1 Participants |
| Control | Mortality at Day 28 | 3 Participants |
Secondary
Number of Subjects Alive and Without Respiratory Failure at Day 28
Number and percentage of subjects that are alive and without respiratory failure at Day 28
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Subjects Alive and Without Respiratory Failure at Day 28 | 20 Participants |
| Control | Number of Subjects Alive and Without Respiratory Failure at Day 28 | 15 Participants |