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

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.