IRAK 4 Inhibitor (PF-06650833) in Hospitalized Patients With COVID-19 Pneumonia and Exuberant Inflammation.

A Randomized , Double-Blind, Placebo-Controlled, Parallel Group, Phase 2 Trial Assessing the Efficacy and Safety of PF-06650833 in Hospitalized Patients With COVID-19 Pneumonia and Exuberant Inflammation.

The aim of the current clinical study is to evaluate the efficacy and safety of inhibition of Interleukin-1 receptor associated kinase 4 (IRAK4) in ameliorating the proinflammatory state and improving outcomes in severe COVID-19.

Study Design 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 severe COVID-19 and pneumonia, who require supplemental oxygen (O2) support but, who do not need mechanical ventilation or ECMO, to maintain adequate oxygenation.

Patients with confirmed severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) infection, and meeting all other inclusion and exclusion criteria, will be randomized within 3 days of screening to receive PF-06650833 400 mg modified release (MR) tablets (2 x 200 mg tablets) or matching placebo administered orally once daily (QD), under fasted conditions (preferably about 4 hours after and 1.5 before a meal) for up to 28 days (or until discharged from the hospital should this occur earlier). Subjects unable to take tablets by mouth will receive a 200 mg dose of PF-06650833 as an immediate release (IR) suspension or matching placebo administered orally (via nasogastric [NG] or orogastric [OG] tube) every 6 hours, under fasted conditions (as feasible, and preferably about 4 hours after and 1.5 before a meal). Subjects for whom concomitant administration of a strong inhibitor of cytochrome P450 (CYP) 3A4 (eg, ritonavir) will have the dose reduced to either 200 mg MR or IR QD. All dosing of study drug will be in addition to current hospital SOC treatment, that must include some treatment targeting SARS-CoV-2 (eg, remdesivir, if available under emergency use authorization, and/or other targeted anti-viral therapies considered SOC treatment, some of which may also be experimental). Subjects will be assessed daily while hospitalized for a variety of clinical, biomarker, safety, pharmacokinetic (PK), and laboratory parameters.

Number of Study Sites One study site: BronxCare Health System (Bronx Care Hospital; additional site[s] may be added).

Study Population The study population will be derived from patients admitted to the hospital, and will consist of adult male and female patients with severe COVID-19 (pneumonia requiring oxygenation support), aged ≥18, with laboratory-confirmed SARS-CoV-2 infection.

Number of Participants Approximately 68 patients will be recruited to receive PF-06650833 in addition to SOC or placebo plus SOC treatment in a 1:1 ratio. This study utilizes an adaptive design with sample size re-estimation at the interim analysis, with the maximum sample size at 136 subjects.

Outcome Variables

The 8-point National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows:

1. Not hospitalized, no limitations on activities.

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

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

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

5. Hospitalized, requiring supplemental oxygen*.

6. Hospitalized, on non-invasive ventilation or high-flow oxygen devices**.

7. Hospitalized, on invasive mechanical ventilation or ECMO.

8. Death.

   • For subjects on chronic home O2 supplementation (pre-morbid state), supplemental O2 is defined as ≥ home O2 requirement.

     • Use of non-invasive ventilation for chronic conditions (eg, Obstructive sleep apnea [OSA]) is not applicable.

Primary Outcome Variable

• Proportion of subjects worsened at end of treatment (Day 29), as defined by categories 7 and 8 in the 8-point NIAID scale of disease severity.

Secondary Outcome Variables

• Proportion of subjects improved at end of treatment (Day 29), as defined by categories 1, 2, 3, and 4 in the 8-point NIAID ordinal scale of disease severity.
• Proportion of subjects recovered at end of treatment (Day 29), as defined by categories 1, 2, and 3 in the 8-point NIAID ordinal scale of disease severity.
• All-cause mortality at Days 29 and 61, respectively.
• Time to clinical improvement (defined as an at least 1-point decrease on the 8-point NIAID ordinal scale of disease severity).
• Time to worsening (defined as an at least 1-point increase on the 8-point NIAID ordinal scale of disease severity).
• Percentage of subjects in each category of the 8-point NIAID ordinal scale of disease severity at Days 3, 5, 8, 11, 15, 22, and 29.
• Change in the 8-point NIAID ordinal scale of disease severity from Day 1 to Days 3, 5, 8, 11, 15, 22, and 29, as available.
• Proportion of subjects that have required mechanical ventilatory support through Day 29.
• Safety as assessed by reporting of AEs, changes in clinical laboratory parameters (eg, hemoglobin [Hb], white blood cells [WBCs], platelets, hepatic transaminases, serum creatinine [SCr], bilirubin).
• Proportion of subjects alive with resolution of respiratory insufficiency (defined as not requiring supplemental oxygen to maintain oxygen saturation by pulse oximetry [SpO2] >94% while breathing room air) at Days 29 and 61.

Inclusion Criteria:

1. Hospitalized adult male and female patients, including women of childbearing potential, at least 18 years of age, inclusive. Women of childbearing potential must agree to the protocol-specific contraception requirements.

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

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

4. Evidence of pneumonia assessed by ALL of the following:

   1. Radiographic imaging (eg, chest x-ray, chest computed tomography [CT] scan, etc.); AND
   2. Clinical assessment (evidence of rales/crackles on exam); AND
   3. SpO2 ≤94% on room air.

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

   1. Ferritin;
   2. Procalcitonin;
   3. D-dimer;
   4. Fibrinogen;
   5. LDH;
   6. PT/PTT.

Exclusion Criteria:

1. Other medical condition other than COVID-19 or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study, eg, acute coronary syndrome.

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

3. Active herpes zoster infection.

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

5. Active hepatitis B or hepatitis C.

   • Patients with positive hepatitis B surface antigen (HBsAg) will be excluded. Patients who are HBsAg negative but hepatitis B core antibody (HBcAb) positive will need a negative hepatitis B virus deoxyribonucleic acid (HBV DNA) to be allowed to enroll in the study; if the HBV DNA is positive, they will be not eligible.
   • Patients with a positive test for hepatitis C virus (hepatitis C virus antibody; HCV Ab) will need a negative hepatitis C virus ribonucleic acid (HCV RNA; or negative HCV Ab test) and normal liver function (as assessed by liver transaminases and bilirubin within protocol-permitted limits, and no other evidence of compromised liver synthetic ability (eg, albumin and coagulation tests within protocol-permitted limits) to be allowed to enroll in the study, provided other eligibility criteria are met.

6. Known history of human immunodeficiency virus (HIV) infection with a detectable viral load or CD4 count <500 cells/mm3 (or patients for whom documentation of viral load or CD4 counts are not available) will be excluded; patients on highly active anti retroviral treatment, undetectable HIV viral load, and CD4 counts ≥500 cells/mm3 would be eligible).

7. Active hematologic cancer.

8. Metastatic or intractable cancer.

9. Pre-existing neurodegenerative disease.

10. Proven bacterial pneumonia, other serious infection, sepsis, and/septic shock.

11. Requirement for mechanical ventilation, or extracorporeal membrane oxygenation.

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

13. Severe renal impairment with an estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2.

14. Known history of nephrolithiasis.

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

16. Any of the following abnormal laboratory vales:

    1. Absolute lymphocyte count <500 cells/mm3;
    2. Absolute neutrophil count (ANC) <1500 cells/mm3;
    3. Platelet count <50,000 cells/mm3;
    4. ALT or AST >5X ULN, or total bilirubin >2X ULN, or other evidence of hepatocellular synthetic dysfunction.

17. 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.

18. Prohibited concomitant therapy.

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

20. Immunocompromised patients, patients with known immunodeficiencies or taking potent immunosuppressive agents (eg, azathioprine, cyclosporine).

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

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