IRAK4 Inhibition in Treatment of COVID-19 With ARDS (I-RAMIC)
IRAK4 Inhibition in Treatment of COVID-19 With ARDS (I-RAMIC)
The purpose of this study is to assess the efficacy of PF-06650833 in addition to
 standard-of-care compared to standard-of-care treatment alone in improving outcomes in
 patients with COVID-19.
Proposed is a randomized, double-blind, placebo-controlled, parallel group Phase 2 study of
 the efficacy and safety of PF-06650833, an investigational drug, in hospitalized adult male
 and female patients with SARS-CoV-2-induced ARDS who need mechanical ventilation.

 The primary objective of this study is to assess the efficacy of PF-06650833 in addition to
 standard-of-care compared to standard-of-care treatment alone in improving outcomes in
 patients with COVID-19, evidence of increased inflammation, and ARDS requiring mechanical
 ventilation or extracorporeal membrane oxygenation at time of admission.

 The secondary objectives of this study are to evaluate:

 1. Proportion of patients alive, extubated, and receiving no more that low flow oxygen
 supplementation by nasal cannula or face mask (excluding extubation for compassionate
 purposes in terminal patients). This would correspond to an at least 2-point improvement
 in the National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale (1 =
 non hospitalized, no limitations on activity, and 8 = death) at Days 29 and 61

 2. Proportion of patients alive, extubated, and receiving any level oxygen supplementation,
 including non-invasive positive pressure ventilation or high flow oxygen device
 (excluding extubation for compassionate purposes in terminal patients). This would
 correspond to an at least 1-point improvement in the NIAID ordinal scale (1 = non
 hospitalized, no limitations on activity, and 8 = death) at Days 29 and 61

 3. Percentage of patients in each category of the NIAID 8-point ordinal scale of disease
 severity (Days 8, 15, 22, 29, and 61). The ordinal scale is an assessment of the
 clinical status at the first assessment of a given study day. The scale is as follows:

 -  Not hospitalized, no limitations on activities;

 -  Not hospitalized, limitation on activities and/or requiring home oxygen*

 -  Hospitalized, not requiring supplemental oxygen* - no longer requires ongoing
 medical care

 -  Hospitalized, not requiring supplemental oxygen* - requiring ongoing medical care
 (COVID-19 related or otherwise)

 -  Hospitalized, requiring supplemental oxygen*;

 -  Hospitalized, on non-invasive ventilation (NIV)** or high flow oxygen device;

 -  Hospitalized, on invasive mechanical ventilation or ECMO;

 -  Death

 -  For patients on chronic home O2 supplementation, supplemental O2 is defined as
 >= home O2 requirement.

 -  Use of NIV for chronic conditions [e.g. Obstructive sleep apnea (OSA)] is
 not applicable

 4. Mortality rate at Day 61

 5. Time to a 1-point improvement in the NIAID 8-point ordinal scale of disease severity

 6. Time to a 2-point improvement in the NIAID 8-point ordinal scale of disease severity

 7. Change from baseline in the ordinal scale from Day 1 to Days 3, 5, 8, 11, 15, 22, and

 8. Arterial partial pressure of oxygen (PaO2) / Fractional concentration of inspired oxygen
 (FiO2) ratio (or P/F ratio)

 9. Change of the Sequential Organ Failure Assessment (SOFA). The SOFA evaluates 6
 variables, each representing an organ system (one for the respiratory, cardiovascular,
 hepatic, coagulation, renal and neurological systems), and scored from 0 (normal) to 4
 (high degree of dysfunction/failure). Thus, the maximum score may range from 0 to 24.

 10. Duration (days) of mechanical ventilation

 11. Ventilator free days

 12. Safety as assessed by reporting of adverse events (AEs), changes in clinical laboratory
 parameters (e.g., haemoglobin (Hb), white blood cell (WBC) count, platelets, hepatic
 transaminases, bilirubin, serum creatinine)
INCLUSION CRITERIA

 1. Adult male and female patients, including women of childbearing potential, at least 18
 years of age, inclusive

 2. Participant (or legally authorized representative) capable of giving signed informed
 consent

 3. Laboratory-confirmed novel coronavirus (SARS-CoV-2) infection

 4. Clinical findings and an imaging study consistent with ARDS;

 5. PaO2 / FiO2 ratio < 300;

 6. A requirement for mechanical ventilation ≤ 48 hours prior to enrollment.

 7. Evidence of increased inflammation as assessed by hsCRP > ULN AND at least ONE of the
 following being > upper limit of normal (as available):

 1. ferritin

 2. procalcitonin

 3. D-dimer

 4. fibrinogen

 5. LDH

 6. PT/PTT

 EXCLUSION CRITERIA

 1. Suspected or known active systemic bacterial, viral (except SARS-CoV2 infection), or
 fungal infections

 2. Active herpes zoster infection

 3. Known active or latent tuberculosis (TB) or history of inadequately treated TB

 4. Active hepatitis B or hepatitis C

 5. Known history of human immunodeficiency virus (HIV) infection with a detectable viral
 load or CD4 count < 500 cells / mm3 (patients for whom documented viral load or CD4
 counts are available will be excluded)

 6. Active hematologic cancer

 7. Metastatic or intractable cancer

 8. Pre-existing neurodegenerative disease

 9. Severe hepatic impairment defined as Child-Pugh Class B or Class C at baseline

 10. Severe renal impairment with an estimated glomerular filtration rate (eGFR) < 45
 mL/min/1.73 m2

 11. Severe anemia (Hb < 8.0 g/dL)

 12. Any of the following abnormal laboratory values:

 1. absolute lymphocyte count <250 cells/mm3

 2. absolute neutrophil Count (ANC) <1000 cells/mm3

 3. Platelet count <50,000 cells/mm3

 4. ALT or AST > 5X ULN, or other evidence of hepatocellular synthetic dysfunction or
 total bilirubin > 2X ULN

 13. Any other medical condition or laboratory abnormality that may increase the risk of
 study participation or, in the investigator's judgment, make the participant
 inappropriate for the study

 14. Prohibited concomitant therapy (see section 1.12.7.2)

 15. Pregnancy (a negative urine or serum pregnancy test is required for inclusion)

 16. Immunocompromised patients, patients with known immunodeficiencies or taking potent
 immunosuppressive agents (e.g., azathioprine, cyclosporine)

 17. Anticipated survival < 72 hours as assessed by the Investigator.

 18. Participation in other clinical trials of investigational treatments for COVID-19

 19. Known history of nephrolithiasis