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

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ClinicalTrials.gov Identifier: NCT04933799
Recruitment Status : Recruiting
First Posted : June 22, 2021
Last Update Posted : June 22, 2021
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Giovanni Franchin, M.D, Ph.D, Bronx-Lebanon Hospital Center Health Care System

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
COVID-19 Pneumonia Drug: PF-06650833 Drug: Matching Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: The research Pharmacists are unblinded.
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : January 6, 2021
Estimated Primary Completion Date : March 6, 2022
Estimated Study Completion Date : May 6, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

Arm Intervention/treatment
Active Comparator: PF-06650833 + Standard of Care treatment
Subjects randomized to the PF-06650833 arm of the study will receive 400 mg PF-06650833 (2 x 200 mg tablets) of the MR formulation orally QD under fasted conditions (preferably at least 4 hours after and 1.5 hours before a meal). Subjects who cannot take tablets PO will receive PF-06650833 200 mg IR suspension formulation every 6 hours (NG tube or OG tube, or equivalent). Subjects for whom concomitant administration of a strong inhibitor of CYP3A4 (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 treatment targeting SARS-CoV-2.
Drug: PF-06650833

PF-06650833 is an investigational, highly potent and selective, reversible inhibitor of IRAK4. IRAK4 is a serine, threonine kinase that is a key intracellular signaling node downstream of the myddosome-associated Toll-Like Receptors (TLR) 1, 2, 4, 5, 6, 7, 8, 9 and 10, and the interleukin (IL)-1 family receptors (IL-1R, IL-18R and IL-33R) that mediate much of the innate immune signaling.

As an inhibitor of TLR signaling, PF-06650833 targets a different part of the immune system from the Janus kinase (JAK) inhibitors. Given the partial redundancy of innate immune signaling through IRAK4-independent TLR pathways and the lack of direct suppression of T- and B-cell signaling, PF-06650833 is unlikely to lead to exaggerated immunosuppression.

Other Name: IRAK 4 inhibitor

Placebo Comparator: Placebo + Standard of Care treatment
Placebo will match the Active comparator in dosage form, dosage, frequency and duration.
Drug: Matching Placebo
Placebo will match the study drug in dose, formulation, route and frequency.
Other Name: Placebo




Primary Outcome Measures :
  1. Worsening based on the NIAID Ordinal scale [ Time Frame: 29 days ]

    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.

    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.


Secondary Outcome Measures :
  1. Improvement based on the NIAID Ordinal scale [ Time Frame: 29 days ]
    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.

  2. Recovered based on the NIAID Ordinal scale [ Time Frame: 29 days ]
    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.

  3. mortality [ Time Frame: 29 days ]
    All-cause mortality at Day 29

  4. mortality [ Time Frame: 61 days ]
    All-cause mortality at Days 61

  5. Time to clinical improvement based on the NIAID Ordinal scale [ Time Frame: 29 days ]
    Time to clinical improvement (defined as an at least 1-point decrease on the 8-point NIAID ordinal scale of disease severity).

  6. Time to worsening based on the NIAID Ordinal scale [ Time Frame: 29 days ]
    Time to worsening (defined as an at least 1-point increase on the 8-point NIAID ordinal scale of disease severity)

  7. Percentage of subjects in each category of ordinal scale of disease severity [ Time Frame: 29 days ]
    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

  8. Change in disease severity based on the NIAID Ordinal scale [ Time Frame: 29 days ]
    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. Higher score means worsening outcomes.

  9. mechanical ventilatory support [ Time Frame: 29 days ]
    Proportion of subjects that have required mechanical ventilatory support through Day 29.

  10. Safety assessment by reporting of AEs [ Time Frame: 29 days ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

  11. subjects alive with resolution of respiratory insufficiency [ Time Frame: 29 days ]
    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 Day 29.

  12. subjects alive with resolution of respiratory insufficiency [ Time Frame: 61 days ]
    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 61.


Other Outcome Measures:
  1. Change from baseline in inflammatory parameters [ Time Frame: 29 days ]
    Change from baseline in inflammatory parameters (eg, high-sensitivity C-reactive protein [hsCRP], procalcitonin, ferritin, D-dimers, lactate dehydrogenase [LDH], fibrinogen, prothrombin time/partial thromboplastin time [PT/PTT], and troponin) in peripheral blood. • Linear mixed effects model that utilizes the longitudinal measurements will be used. The model will include fixed effects for baseline measurements, treatment, visit/time and treatment by visit/time interaction, age group, remdesivir use.

  2. cytokine panel. Units of measurement for all cytokines in the panel is pg/ml [ Time Frame: 29 days ]
    Change from baseline in cytokine panel (interferon[IFN]-gamma, interleukin [IL]-1 Beta , IL 2, IL 4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17, tumor necrosis factor alpha [TNF alpha ], IL-2R [sCD25]), as available in peripheral blood.• Linear mixed effects model that utilizes the longitudinal measurements will be used. The model will include fixed effects for baseline measurements, treatment, visit/time and treatment by visit/time interaction, age group, remdesivir use.

  3. SARS-CoV-2 viral load [ Time Frame: 29 days ]
    Change from baseline in SARS-CoV-2 viral load (in nasopharyngeal swabs, blood, and/or saliva), as available

  4. ICU admission [ Time Frame: 29 days ]
    Proportion of subjects that have required ICU admission

  5. mechanical ventilation [ Time Frame: 29 days ]
    Duration (days) of mechanical ventilation.

  6. Ventilator free [ Time Frame: 29 days ]
    Ventilator free days.

  7. Pharmacokinetics of PF-06650833 [ Time Frame: 15 days ]
    Blood samples for analysis of PF-06650833 exposure will be collected at baseline (before the first dose), and at trough before the second dose (if applicable), and at trough on Days 8 and 15, as available.

  8. Pharmacokinetics of PF-06650833 metabolites [ Time Frame: 15 days ]
    Blood samples for analysis of PF-06650833 may be used for determination of metabolites including PF-06787899 and PF 06787900. PF-06650833 may cause the manifestation of atypical, needle-like crystals (that are likely principally precipitates of metabolites of PF-06650833) in urine sediment.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04933799


Contacts
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Contact: Swati Namballa, MBBS 4087180207 snamball@bronxcare.org
Contact: Giovanni Franchin, M.D, Ph.D 6462456260 GFranchi@bronxcare.org

Locations
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United States, New York
Bronx-Lebanon Hospital Center Health Care System Recruiting
Bronx, New York, United States, 10457
Contact: Swati Namballa, MBBS    408-718-0207    snamball@bronxcare.org   
Contact: Giovanni Franchin, M.D, Ph.D    6462456260      
Principal Investigator: Giovanni Franchin, M.D, Ph.D         
Sub-Investigator: Adrish Muhammad, M.D         
Sub-Investigator: Diana Ronderos, M.D         
Sponsors and Collaborators
Giovanni Franchin, M.D, Ph.D
Pfizer
Investigators
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Principal Investigator: Giovanni Franchin, M.D, Ph.D Bronx-Lebanon Hospital Center Health Care System
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Responsible Party: Giovanni Franchin, M.D, Ph.D, Study Principal Investigator, Bronx-Lebanon Hospital Center Health Care System
ClinicalTrials.gov Identifier: NCT04933799    
Other Study ID Numbers: PNA-COV
First Posted: June 22, 2021    Key Record Dates
Last Update Posted: June 22, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Giovanni Franchin, M.D, Ph.D, Bronx-Lebanon Hospital Center Health Care System:
COVID-19 Pneumonia
Viral Pneumonia
Pneumonia
COVID-19
COVID
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
IRAK 4 Inhibitor
SARS-CoV-2 Pneumonia
IRAK-4 Inhibitor in SARS-CoV-2 Pneumonia
Additional relevant MeSH terms:
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Pneumonia
Inflammation
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections