Tofacitinib for Treatment of Moderate COVID-19

Study Overview
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Brief Summary
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The purpose of this randomized, double blinded, placebo controlled study is to assess the efficacy and safety of tofacitinib in hospitalized adult (18-99 years old) patients with SARS-CoV-2 and pneumonia who require supplemental oxygen and have serologic markers of inflammation but do not need mechanical ventilation.

Detailed Description
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The purpose of this randomized, double blinded, placebo controlled Phase 2b study is to assess the efficacy and safety of tofacitinib in hospitalized adult (18-99 years old) male and female patients with SARS-CoV-2 and pneumonia who require supplemental oxygen and have serologic markers of inflammation but do not need mechanical ventilation (see Inclusion criteria). Sixty patients will be recruited to receive tofacitinib or placebo in addition to standard of care (SOC) in a 1:1 ratio. Subjects will be screened during hospitalization. Patients with confirmed SARS-CoV-2 infection, and meeting all other Inclusion and Exclusion criteria, will be randomized to either treatment with tofacitinib or placebo in addition to SOC during hospitalization (dose adjusted, if required), with the exception of pre-specified immunomodulatory agents (as documented in the inclusion/exclusion criteria). Tofacitinib will be administered in a dose of 10 mg PO BID until return to their clinical baseline (as defined by need for supplementary oxygen), and will continue to be administered at 5 mg PO BID for a total duration of therapy of 14 days; follow-up off tofacitinib will continue up to Day 90. We anticipate completion of subject recruitment in 6 months.

Official Title
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Investigation of Tofacitinib to Mitigate the Impact of COVID-19 (I-TOMIC) in Moderate SARS-CoV-2 (MODERATE I-TOMIC)

Conditions
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COVID-19 Pneumonia

Intervention / Treatment
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* Drug: Tofacitinib 10 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. Participants with laboratory-confirmed novel coronavirus (SARS-CoV-2) infection as determined by polymerase chain reaction (PCR) or other commercially available or public health assay prior to Day 1. Participants with evidence of pneumonia assessed by radiographic imaging (chest x ray or chest CT scan) AND Requiring ≥ 3L O2 OR ≥ 2L O2 and hsCRP > 70 mg/L Participants who are hospitalized and receiving supportive care for COVID-19. Participant (or legally authorized representative/surrogate) capable of giving signed informed consent. Exclusion Criteria: Medical Conditions: Require mechanical ventilation or ECMO on Day 1 at the time of randomization. Have current, or history of, venous thromboembolism (deep vein thrombosis or pulmonary embolism). Have a personal or first-degree family history of blood clotting disorders. Participants who are immunocompromised, with known immunodeficiencies, or taking potent immunosuppressive agents (eg, azathioprine, cyclosporine). Participants with any current malignancy or lymphoproliferative disorders that requires active treatment Females of child bearing potential who are pregnant or breastfeeding Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk associated with study participation or, in the investigator's judgment, make the participant inappropriate for the study. Anticipated survival < 72 hours as assessed by the Investigator. Infection History: • Suspected or known active systemic bacterial, fungal, or viral infections (with the exception of COVID-19) including but not limited to: Secondary bacterial pneumonia; Active herpes zoster infection; Known active tuberculosis or history of inadequately treated tuberculosis; Known HBV, HCV, or HIV. Prior/Concomitant Therapy: Have received any of the following treatment regimens specified in the timeframes outlined below: Within 4 weeks prior to the first dose of study intervention: Prior treatment with any JAK inhibitors, potent immunosuppressants, or any biologic agents including IL-6 inhibitors (eg, tocilizumab) or IL-1 inhibitors (eg, anakinra); Prior treatment with any potent cytochrome P450 inducer, such as rifampin, within the past 28 days or 5 half-lives, whichever is longer. Within 48 hours prior to the first dose of study intervention: o Treatment with herbal supplements. Received >/= 20 mg/day of prednisone or equivalent for >/=14 consecutive days in the 4 weeks prior to screening. Diagnostic Assessments: Severe hepatic impairment, defined as Child-Pugh class C. Severe anemia (hemoglobin <8 g/dL). ANY of the following abnormalities in clinical laboratory tests at screening, confirmed by a single repeat, if deemed necessary: WBC <1000/mm3 Absolute lymphocyte count <500 cells/mm3; Absolute neutrophil count <1000 cells/mm3. Alanine transaminase/aspartate transaminase (ALT/AST) > 5 times the upper limit of normal; Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2); Other Exclusions: Known allergy to tofacitinib. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tofacitinib<br>Tofacitinib will be administered in a dose of 10 mg PO BID until return to their clinical baseline (as defined by supplementary oxygen requirement), and then will continue to be administered at 5 mg PO BID for a total treatment duration of 14 days. | Drug: Tofacitinib 10 mg<br>* Tofacitinib will be administered in a dose of 10 mg twice daily by mouth (PO BID) until return to their clinical baseline (as defined by supplementary oxygen requirement), and then will continue to be administered at 5 mg PO BID for a total treatment duration of 14 days.<br>|
| Placebo Comparator: Placebo<br>Matching placebo will be administered. | Drug: Placebo<br>* Matching placebo tablets will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Severity | The primary objective of this study is to determine whether tofacitinib improves the clinical outcomes of patients with moderate SARS-CoV-2 infection as determined by the primary outcome measure: Proportion of subjects alive and not needing any form of mechanical ventilation, high flow oxygen, or ECMO by day 14. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement | Clinical improvement as measured by NIAID 8-point ordinal scale (i.e., 1 = death and 8 = Not hospitalized, no limitations on activities) at day 14. The scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | 14 days | 
| Clinical improvement | Clinical improvement as measured by NIAID 8-point ordinal scale (i.e., 1 = death and 8 = Not hospitalized, no limitations on activities) (days 3 through day 14): The scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | Up to 14 days | 
| Time to recovery | Time to recovery [ Time Frame: Day 1 through Day 14] (Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities) | Up to 14 days | 
| Time to clinical improvement | Time to clinical improvement (defined as a 2-point increase on the NIAID 8-point ordinal scale (i.e., 1 = death and 8 = Not hospitalized, no limitations on activities). The scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | 30 days | 
| Clinical status | Clinical status on the NIAID 8-point ordinal scale at day 30 The scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | 30 Days | 
| Clinical status | Clinical status on the NIAID 8-point ordinal scale at day 60 The scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | 60 Days | 
| Clinical status | Clinical status on the NIAID 8-point ordinal scale at day 90 The scale is as follows: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities. | 90 Days | 
| Mortality | Mortality rate at day 30 | 30 Days | 
| Mortality | Mortality rate at day 60 | 60 Days | 
| Mortality | Mortality rate at day 90 | 90 Days | 
| Mechanical Ventilatory Support | Proportion of patients requiring mechanical ventilatory support. | Up to 14 Days | 
| Mechanical Ventilatory Support Duration | Duration of invasive mechanical ventilation (days). | Up to 14 Days | 
| Freedom from mechanical ventilation | Invasive mechanical ventilation free days. | Up to 14 Days | 
| Adverse events | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. | Up to 14 days | 
| Additional intervention | Did the patient receive an intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy)? (y/n) | Up to 14 days | 
| Viral titer | Change in SARS-CoV-2 viral titers during intervention. | Up to 14 days |