Tofacitinib for Treatment of Moderate COVID-19

Phase 2TerminatedNCT04415151

Yale University24 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

COVID-19 Pneumonia

Interventions

Tofacitinib 10 mgDRUG

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.

PlaceboDRUG

Matching placebo tablets will be administered.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. 2. 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. 3. 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 4. Participants who are hospitalized and receiving supportive care for COVID-19. 5. Participant (or legally authorized representative/surrogate) capable of giving signed informed consent. Exclusion Criteria: Medical Conditions: 1. Require mechanical ventilation or ECMO on Day 1 at the time of randomization. 2. Have current, or history of, venous thromboembolism (deep vein thrombosis or pulmonary embolism). 3. Have a personal or first-degree family history of blood clotting disorders. 4. Participants who are immunocompromised, with known immunodeficiencies, or taking potent immunosuppressive agents (eg, azathioprine, cyclosporine). 5. Participants with any current malignancy or lymphoproliferative disorders that requires active treatment 6. Females of child bearing potential who are pregnant or breastfeeding 7. 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. 8. 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.

Locations (1)

Yale New Haven Health System

New Haven, Connecticut, United States

Outcomes

Primary Outcomes

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.

Time frame: 14 days

Secondary Outcomes

Clinical Improvement (Last Measure)

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: 1. Death 2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities. Updated at the time of results entry, presented are the last clinical status for participants in the study (high scores are better outcomes).

Time frame: Up to 14 days

Clinical Improvement (Improved Score)

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: 1. Death 2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities. Added at the time of results entry: this outcome presents those that improved at least 2 or more levels on the clinical scale (high scores are better outcomes).

Data from ClinicalTrials.gov

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Time frame: 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: 1. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 2. Not hospitalized, limitation on activities and/or requiring home oxygen 3. Not hospitalized, no limitations on activities)

Time frame: 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: 1. Death 2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities. Updated at the time of results entry, the follow up time frame was adjusted.

Time frame: Up to 14 days

Clinical Status

Clinical status on the NIAID 8-point ordinal scale at day 30 The scale is as follows: 1. Death 2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities. Updated at the time of results entry, the follow up time frame was adjusted.

Time frame: Up to 28 Days

Clinical Status

Clinical status on the NIAID 8-point ordinal scale at day 60 The scale is as follows: 1. Death 2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities.

Time frame: 60 Days

Clinical Status

Clinical status on the NIAID 8-point ordinal scale at day 90 The scale is as follows: 1. Death 2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities.

Time frame: 90 Days

Mortality

Mortality rate at day 30 (28 Days- updated at time of results entry). Presented are a count of those participants that expired (all-cause) through the 28 day follow up. This outcome includes counts of those that expired during the study period (see adverse events All-Cause Mortality).

Time frame: Up to 28 Days

Mortality

Mortality rate at day 60 (updated at time of results entry). Presented are a count of those participants that expired (all-cause) through the 60 day follow up. This outcome includes counts of those that expired during the study period (see adverse events All Cause Mortality).

Time frame: 60 Days

Mortality

Mortality rate at day 90. Presented are a count of those participants that expired (all-cause) through the 90 day follow up. This outcome includes counts of those that expired during the study period (see adverse events All-Cause Mortality).

Time frame: 90 Days

Mechanical Ventilatory Support

Proportion of patients requiring mechanical ventilatory support.

Time frame: Up to 14 Days

Mechanical Ventilatory Support Duration

Duration of invasive mechanical ventilation (days).

Time frame: Up to 14 Days

Freedom From Mechanical Ventilation

Invasive mechanical ventilation free days. The outcome was updated to present the number of participants that were without invasive mechanical ventilation while on study.

Time frame: Up to 14 Days

Additional Intervention

Did the patient receive an intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy)? (y/n)

Time frame: Up to 14 days

Viral Titer

Change in SARS-CoV-2 viral titers during intervention. Upon entry of results, the time frame was updated to Day 7 to reflect the data collected in the terminated study. Nasopharyngeal (NP) swab were used and the visit window for Day 7 could include days between Day 5 to Day 9. Imputation for \< LLOQ: N gene: "\<200" is imputed to 2.0 log10 copies/mL (log10(200) - 0.3). ORF1ab gene: "\<3000" is imputed to 3.2 log10 copies/mL (log10(3000) - 0.3). Missing Data were not imputed.

Time frame: Day 7 (Day 5 to Day 9)