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Study terminated due to lack of enrollment reflecting the decrease in number of COVID infections. There were no safety and/or efficacy concerns involved in the decision to stop enrollment.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tofacitinib | Experimental | 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. |
|
| Placebo | Placebo Comparator | Matching placebo will be administered. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tofacitinib 10 mg | Drug | 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. |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
Updated at the time of results entry, presented are the last clinical status for participants in the study (high scores are better outcomes). |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. All adverse events are presented in the adverse event module. | Up to 14 days |
Inclusion Criteria:
Exclusion Criteria:
Medical Conditions:
Infection History:
• Suspected or known active systemic bacterial, fungal, or viral infections (with the exception of COVID-19) including but not limited to:
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:
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:
Other Exclusions:
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| Name | Affiliation | Role |
|---|---|---|
| Hyung Chun, MD | Yale University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Yale New Haven Health System | New Haven | Connecticut | 06511 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Tofacitinib | 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. Tofacitinib 10 mg: 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. |
| FG001 | Placebo | Matching placebo will be administered. Placebo: Matching placebo tablets will be administered. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Placebo group |
| BG001 | Tofacitinib | Tofacitinib group |
| BG002 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All participants randomized and receiving at least 1 dose. | Posted | Count of Participants | Participants | 14 days |
|
All Other Adverse Events and Serious Adverse Event data were collected up to 14 days, All Cause Mortality data were collected up to 90 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants received placebo and usual care. | 1 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute respiratory distress syndrome | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Hyung Chun, MD, FAHA | Yale School of Medicine | (203) 785-6012 | hyung.chun@yale.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 28, 2020 | Jan 7, 2025 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 18, 2024 | Jan 7, 2025 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C479163 | tofacitinib |
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|
| Placebo | Drug | Matching placebo tablets will be administered. |
|
| 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:
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). | 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:
| 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:
Updated at the time of results entry, the follow up time frame was adjusted. | Up to 14 days |
| Clinical Status | Clinical status on the NIAID 8-point ordinal scale at day 30 The scale is as follows:
Updated at the time of results entry, the follow up time frame was adjusted. | Up to 28 Days |
| Clinical Status | Clinical status on the NIAID 8-point ordinal scale at day 60 The scale is as follows:
| 60 Days |
| Clinical Status | Clinical status on the NIAID 8-point ordinal scale at day 90 The scale is as follows:
| 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). | 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). | 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). | 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. The outcome was updated to present the number of participants that were without invasive mechanical ventilation while on study. | 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. 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. | Day 7 (Day 5 to Day 9) |
| Total |
Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
|
|
| Secondary | 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:
Updated at the time of results entry, presented are the last clinical status for participants in the study (high scores are better outcomes). | All participants randomized and receiving at least 1 dose. | Posted | Count of Participants | Participants | Up to 14 days |
|
|
|
| Secondary | 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:
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). | All participants randomized and receiving at least 1 dose. | Posted | Count of Participants | Participants | Up to 14 days |
|
|
|
| Secondary | 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:
| Of those that "recovered" within 14 days. | Posted | Median | Full Range | days | Up to 14 days |
|
|
|
| Secondary | 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:
Updated at the time of results entry, the follow up time frame was adjusted. | Participants successfully follow up with. | Posted | Median | Full Range | days | Up to 14 days |
|
|
|
| Secondary | Clinical Status | Clinical status on the NIAID 8-point ordinal scale at day 30 The scale is as follows:
Updated at the time of results entry, the follow up time frame was adjusted. | Participants (alive at end of 14 days) successfully followed up with. | Posted | Count of Participants | Participants | Up to 28 Days |
|
|
|
| Secondary | Clinical Status | Clinical status on the NIAID 8-point ordinal scale at day 60 The scale is as follows:
| Participants (alive at end of 14 days) successfully followed up with. | Posted | Count of Participants | Participants | 60 Days |
|
|
|
| Secondary | Clinical Status | Clinical status on the NIAID 8-point ordinal scale at day 90 The scale is as follows:
| Participants (alive at end of 14 days) successfully followed up with. | Posted | Count of Participants | Participants | 90 Days |
|
|
|
| Secondary | 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). | Participants successfully followed up with post study. | Posted | Count of Participants | Participants | Up to 28 Days |
|
|
|
| Secondary | 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). | Participants successfully followed up with post study. | Posted | Count of Participants | Participants | 60 Days |
|
|
|
| Secondary | 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). | Participants successfully followed up with post study. | Posted | Count of Participants | Participants | 90 Days |
|
|
|
| Secondary | Mechanical Ventilatory Support | Proportion of patients requiring mechanical ventilatory support. | All participants randomized and receiving at least 1 dose. | Posted | Count of Participants | Participants | Up to 14 Days |
|
|
|
| Secondary | Mechanical Ventilatory Support Duration | Duration of invasive mechanical ventilation (days). | Only those on invasive mechanical ventilation (days). | Posted | Median | Full Range | days | Up to 14 Days |
|
|
|
| Secondary | 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. | All participants randomized and receiving at least 1 dose. | Posted | Count of Participants | Participants | Up to 14 Days |
|
|
|
| Secondary | Additional Intervention | Did the patient receive an intervention with additional immunomodulatory agent (i.e. IL-6 targeting therapy)? (y/n) | All participants randomized and receiving at least 1 dose. | Posted | Count of Participants | Participants | Up to 14 days |
|
|
|
| Secondary | 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. | All data collected on all participants | Posted | Mean | Standard Deviation | log10 (copies/mL) | Day 7 (Day 5 to Day 9) |
|
|
|
| Other Pre-specified | Adverse Events | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. All adverse events are presented in the adverse event module. | Not Posted | Up to 14 days | Participants |
| 11 |
| 2 |
| 11 |
| 10 |
| 11 |
| EG001 | Tofacitinib | Participants received Tofacitinib and usual care. | 1 | 13 | 2 | 13 | 12 | 13 |
| Death | General disorders | Systematic Assessment |
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| Pneumonia | Infections and infestations | Systematic Assessment |
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| Acute respiratory distress syndrome | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Alanine aminotransferase increased | Investigations | Systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | Systematic Assessment |
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| Atrial fibrillation | Cardiac disorders | Systematic Assessment |
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| Bacteraemia | Infections and infestations | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Embolism | Vascular disorders | Systematic Assessment |
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| Fungaemia | Infections and infestations | Systematic Assessment |
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| Hyperglycaemia | Metabolism and nutrition disorders | Systematic Assessment |
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| Hypoalbuminaemia | Metabolism and nutrition disorders | Systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | Systematic Assessment |
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| Hypoxia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Leukocytosis | Blood and lymphatic system disorders | Systematic Assessment |
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| Lymphocyte count decreased | Investigations | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Non-cardiac chest pain | General disorders | Systematic Assessment |
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| Pericardial effusion | Cardiac disorders | Systematic Assessment |
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| Pneumonia | Infections and infestations | Systematic Assessment |
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| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Sinus bradycardia | Cardiac disorders | Systematic Assessment |
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| Sinus tachycardia | Cardiac disorders | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Hospitalized, on non-invasive ventilation or high flow oxygen devices |
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| Hospitalized, requiring supplemental oxygen |
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| Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (CovID19/otherwise) |
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| Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care |
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| Not hospitalized, limitation on activities and/or requiring home oxygen |
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| Not hospitalized, no limitations on activities |
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| Not hospitalized, limitation on activities and/or requiring home oxygen |
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| Not hospitalized, no limitations on activities |
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| Not hospitalized, no limitations on activities |
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| Not hospitalized, limitation on activities and/or requiring home oxygen |
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| Not hospitalized, no limitations on activities |
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| SARS-CoV-2 Viral Load: N Gene 7 DAYS |
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| SARS-CoV-2 Viral Load: ORF1ab Gene BASELINE |
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| SARS-CoV-2 Viral Load: ORF1ab Gene 7 DAYS |
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