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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.
Full description
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:
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 or high-flow oxygen devices**.
Hospitalized, on invasive mechanical ventilation or ECMO.
Death.
For subjects on chronic home O2 supplementation (pre-morbid state), supplemental O2 is defined as ≥ home O2 requirement.
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
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
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.
Participant (or legally authorized representative) capable of giving signed informed consent.
Laboratory-confirmed novel coronavirus (SARS-CoV-2) infection.
Evidence of pneumonia assessed by ALL of the following:
Evidence of increased inflammation as assessed by hsCRP > ULN AND at least ONE of the following being > ULN (as available):
Exclusion criteria
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.
Suspected or known active systemic bacterial, viral (except SARS-CoV2 infection) or fungal infections
Active herpes zoster infection.
Known active or latent tuberculosis (TB) or history of inadequately treated TB.
Active hepatitis B or hepatitis C.
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).
Active hematologic cancer.
Metastatic or intractable cancer.
Pre-existing neurodegenerative disease.
Proven bacterial pneumonia, other serious infection, sepsis, and/septic shock.
Requirement for mechanical ventilation, or extracorporeal membrane oxygenation.
Severe hepatic impairment defined as Child-Pugh Class B or Class C at baseline.
Severe renal impairment with an estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2.
Known history of nephrolithiasis.
Severe anemia (Hb <8.0 g/dL).
Any of the following abnormal laboratory vales:
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.
Prohibited concomitant therapy.
Pregnancy (a negative urine or serum pregnancy test is required for inclusion) or breastfeeding.
Immunocompromised patients, patients with known immunodeficiencies or taking potent immunosuppressive agents (eg, azathioprine, cyclosporine).
Anticipated survival <72 hours as assessed by the Investigator.
Participation in other clinical trials of investigational treatments for COVID-19.
Primary purpose
Allocation
Interventional model
Masking
68 participants in 2 patient groups, including a placebo group
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Central trial contact
Swati Namballa, MBBS; Giovanni Franchin, M.D, Ph.D
Data sourced from clinicaltrials.gov
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