Table 5d. Janus Kinase Inhibitors: Selected Clinical Trial Data

Last Updated: February 29, 2024

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for JAK inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

Table 5d. Janus Kinase Inhibitors: Selected Clinical Trial Data
Methods	Results	Limitations and Interpretation
RECOVERY: Open-Label RCT of Baricitinib Versus Usual Care in the United Kingdom¹
Key Inclusion Criterion Hospitalized with suspected or laboratory-confirmed SARS-CoV-2 infection Key Exclusion Criteria eGFR <15 mL/min/1.73m² ANC <500 cells/mm³ Evidence of active TB Interventions BAR 4 mg PO daily for 10 days or until hospital discharge, whichever came first (n = 4,148) SOC (n = 4,008) Primary Endpoint 28-day all-cause mortality Key Secondary Endpoints Time to discharge from hospital Composite of MV, ECMO, or death within 28 days	Participant Characteristics Mean age 58 years; 66% men; 80% White Median of 9 days of symptoms at enrollment 91% with laboratory-confirmed SARS-CoV-2 infection At baseline: 42% received ≥1 doses of a COVID-19 vaccine. 95% received corticosteroids; 23% received tocilizumab; 20% received RDV. 6% not on supplemental oxygen; 68% on conventional oxygen; 24% on NIV; 3% on MV Primary Outcome 28-day all-cause mortality: 12% in BAR arm vs. 14% in SOC arm (age-adjusted rate ratio 0.87; 95% CI, 0.77–0.98; P = 0.028) Secondary Outcomes Hospital discharge within 28 days: 80% in BAR arm vs. 78% in SOC arm (age-adjusted rate ratio 1.10; 95% CI, 1.04–1.15; P = 0.002) Median time to discharge: 8 days in both arms Composite of MV, ECMO, or death within 28 days: 16% in BAR arm vs. 17% in SOC arm (age-adjusted risk ratio 0.89; 95% CI, 0.81–0.98; P = 0.016)	Key Limitation Open-label study Interpretation In patients who were hospitalized for COVID-19, the use of BAR reduced the risk of death.
COV-BARRIER: Double-Blind, Placebo-Controlled, Randomized Trial of Baricitinib in Hospitalized Adults in 12 Countries in Asia, Europe, North America, and South America²
Key Inclusion Criteria Laboratory-confirmed SARS-CoV-2 infection Evidence of pneumonia or active, symptomatic COVID-19 ≥1 elevated inflammatory marker (CRP, D-dimer, LDH, or ferritin) Key Exclusion Criteria Required MV or ECMO Receiving immunosuppressants (including high-dose corticosteroids) Previously received CCP or IVIG ANC <1,000 cells/µL ALC <200 cells/µL ALT or AST >5 times ULN eGFR <30 mL/min Interventions BAR 4 mg PO once daily for up to 14 days (n = 764) Placebo (n = 761) Primary Endpoint Clinical progression or death by Day 28 Key Secondary Endpoint Mortality by Day 28	Participant Characteristics Mean age 58 years; 63% men 79% received corticosteroids; 19% received RDV; 13% received oxygen but no steroids. Primary Outcome Clinical progression or death by Day 28: 28% in BAR arm vs. 31% in placebo arm (OR 0.85; 95% CI, 0.67–1.08; P = 0.18) Secondary Outcomes Mortality by Day 28: 8% in BAR arm vs. 13% in placebo arm (HR 0.57; 95% CI, 0.41–0.78; P = 0.0018) Mortality by Day 28 for those receiving corticosteroids at baseline: 9% in BAR arm vs. 14% in placebo arm (HR 0.63; 95% CI, 0.45–0.89)	Key Limitation Results from the ACTT-2 trial prompted a protocol amendment that limited enrollment to patients who required oxygen at baseline. Interpretation Although the primary outcome of clinical progression or death was not significantly different between the arms, treatment with BAR was associated with reduced mortality in hospitalized adults with COVID-19 who were not receiving MV (see the addendum below for results in patients who required MV or ECMO). For patients who were receiving oxygen but not corticosteroids at baseline, the primary and secondary outcomes were similar to the outcomes for the overall study population.
COV-BARRIER Addendum: Double-Blind, Placebo-Controlled, Randomized Trial of Baricitinib in Hospitalized Adults on Mechanical Ventilation or Extracorporeal Membrane Oxygenation in Argentina, Brazil, Mexico, and the United States³
Key Inclusion Criteria Laboratory-confirmed SARS-CoV-2 infection Evidence of pneumonia or active, symptomatic COVID-19 ≥1 elevated inflammatory markers (CRP, D-dimer, LDH, or ferritin) Receiving MV or ECMO at baseline Key Exclusion Criteria Receiving immunosuppressants (including high-dose corticosteroids) Previously received CCP or IVIG ANC <1,000 cells/µL ALC <200 cells/µL ALT or AST >5 times ULN eGFR <30 mL/min Interventions BAR 4 mg PO once daily for up to 14 days (n = 51) Placebo (n = 50) Key Endpoints Mortality by Day 28 Number of ventilator-free days Duration of hospitalization	Participant Characteristics Mean age 59 years; 55% men 86% received corticosteroids; 2% received RDV. Outcomes Mortality by Day 28: 39% in BAR arm vs. 58% in placebo arm (HR 0.54; 95% CI, 0.31–0.96; P = 0.030) No significant difference between arms in number of ventilator-free days or duration of hospitalization	Key Limitations Very small sample size Exploratory analysis High mortality in placebo arm Interpretation In critically ill patients with COVID-19 who were receiving MV or ECMO, treatment with BAR decreased mortality.
ACTT-2: Double-Blind, Placebo-Controlled, Randomized Trial of Baricitinib Plus Remdesivir in Hospitalized Adults With COVID-19 in 8 Countries in Europe, North America, and Asia⁴
Key Inclusion Criteria Positive SARS-CoV-2 PCR result Radiographic infiltrates; SpO₂ ≤94% on room air; or required supplemental oxygen, MV, or ECMO Key Exclusion Criteria Receiving glucocorticoids for COVID-19 indications ALT or AST >5 times ULN Impaired renal function Interventions BAR 4 mg PO once daily for 14 days or until hospital discharge, plus RDV IV for 10 days or until hospital discharge (n = 515) Placebo PO once daily for 14 days or until hospital discharge, plus RDV IV for 10 days or until hospital discharge (n = 518) Primary Endpoint Time to recovery by Day 28 Key Secondary Endpoints Clinical status at Day 15, as measured by an OS Mortality by Day 28	Participant Characteristics Mean age 55 years; 63% men; 48% White, 15% Black, 10% Asian At baseline: 13% not on supplemental oxygen 55% on conventional oxygen 21% on HFNC oxygen or NIV 11% on MV or ECMO Primary Outcomes Median time to recovery by Day 28: 7 days in BAR arm vs. 8 days in placebo arm (rate ratio 1.16; 95% CI, 1.01–1.32; P = 0.03) Median time to recovery for those receiving HFNC oxygen or NIV: 10 days in BAR arm vs. 18 days in placebo arm (rate ratio for recovery 1.51; 95% CI, 1.10–2.08) Secondary Outcomes Odds of improvement in clinical status at Day 15 were greater in BAR arm than in placebo arm (OR 1.3; 95% CI, 1.0–1.6). Mortality by Day 28: 5% in BAR arm vs. 8% in placebo arm (HR 0.65; 95% CI, 0.39–1.09)	Key Limitations Not powered to detect difference in mortality between arms Steroids not part of SOC Interpretation Compared with RDV alone, BAR plus RDV reduced recovery time and improved clinical status, particularly for patients who were receiving HFNC oxygen or NIV at baseline.
ACTT-4: Double-Blind, Placebo-Controlled, Randomized Trial of Remdesivir With Baricitinib Versus Dexamethasone for Hospitalized Patients Requiring Supplemental Oxygen in Japan, Mexico, Singapore, South Korea, and the United States⁵
Key Inclusion Criteria Hospitalized and required conventional oxygen, HFNC oxygen, or NIV Laboratory-confirmed SARS-CoV-2 infection Key Exclusion Criterion Receipt of CCP or >1 dose of DEX 6 mg (or equivalent) or BAR before enrollment Interventions RDV IV for ≤10 days plus BAR 4 mg PO daily for ≤14 days plus DEX placebo IV (n = 516) RDV IV for ≤10 days plus BAR placebo PO plus DEX 6 mg IV daily for ≤10 days (n = 494) Primary Endpoint MV-free survival by Day 29 Key Secondary Endpoints Clinical status at Day 15, as measured by an OS Time to recovery Key Safety Endpoints Occurrence of treatment-related AEs Occurrence of SAEs	Participant Characteristics Median age 58 years; 58% men; 58% White, 34% Hispanic/Latinx At baseline: 85% on low-flow oxygen 15% on HFNC oxygen or NIV Mean of 8 days of symptoms at enrollment Primary Outcome MV-free survival by Day 29: 87% in BAR arm vs. 88% in DEX arm (risk difference 0.6%; 95% CI, -3.6% to 4.8%; P = 0.91) Secondary Outcomes Odds of improvement in clinical status at Day 15 were similar between arms (OR 1.01; 95% CI, 0.80–1.27). For those on low-flow oxygen at baseline: OR 0.91; 95% CI, 0.70–1.17 For those on HFNC oxygen or NIV at baseline: OR 1.64; 95% CI, 0.92–2.90 Median time to recovery: 6 days in BAR arm vs. 5 days in DEX arm (rate ratio 1.04; 95% CI, 0.91–1.19) Safety Outcomes Occurrence of treatment-related AEs: 4% in BAR arm vs. 10% in DEX arm (risk difference 6.0%; 95% CI, 2.8%–9.3%; P = 0.0004) Occurrence of SAEs: 28% in BAR arm vs. 36% in DEX arm (risk difference 7.7%; 95% CI, 1.8%–13.4%; P = 0.012) Most SAEs and treatment-related AEs were laboratory abnormalities.	Key Limitations Study closed before enrolling 1,500 patients, as it was unlikely to show a difference between arms. Study was not powered to detect differences between BAR and DEX in the subgroup of patients on HFNC oxygen or NIV at baseline. Few patients died or required MV, which may have decreased the power to detect a difference between arms for MV-free survival. Treatment-related differences in AEs for BAR arm vs. DEX arm were mainly related to laboratory abnormalities, not clinical events. The clinical relevance of these differences in laboratory abnormalities is unclear. Interpretation In hospitalized patients who required conventional oxygen, HFNC oxygen, or NIV, the use of BAR or DEX resulted in similar MV-free survival by Day 29.
STOP-COVID: Double-Blind, Placebo-Controlled, Randomized Trial of Tofacitinib in Hospitalized Patients With COVID-19 Pneumonia in Brazil⁶
Key Inclusion Criteria Laboratory-confirmed SARS-CoV-2 infection COVID-19 pneumonia on CXR or CT Hospitalized for <72 hours Key Exclusion Criteria Receiving NIV, MV, or ECMO at baseline History of or current thrombosis Immunosuppression or active cancer treatment Interventions Tofacitinib 10 mg PO twice daily for up to 14 days or until hospital discharge (n = 144) Placebo (n = 145) Primary Endpoint Mortality or respiratory failure by Day 28 Key Secondary Endpoint Mortality by Day 28	Participant Characteristics Mean age 56 years; 35% women Median of 10 days from symptom onset to randomization At baseline: 75% on supplemental oxygen 13% on HFNC oxygen Use of glucocorticoids: 79% at baseline, 89% during hospitalization Primary Outcome Mortality or respiratory failure by Day 28: 18% in tofacitinib arm vs. 29% in placebo arm (risk ratio 0.63; 95% CI, 0.41–0.97; P = 0.04) Secondary Outcome Mortality by Day 28: 2.8% in tofacitinib arm vs. 5.5% in placebo arm (HR 0.49; 95% CI, 0.15–1.63)	Key Limitations Small sample size RDV not available during trial Interpretation When compared with placebo, use of tofacitinib led to a lower risk of mortality or respiratory failure among hospitalized adults with COVID-19 pneumonia, most of whom received glucocorticoids.
Key: AE = adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BAR = baricitinib; CCP = COVID-19 convalescent plasma; CRP = C-reactive protein; CT = computed tomography; CXR = chest X-ray; DEX = dexamethasone; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate; HFNC = high-flow nasal cannula; IV = intravenous; IVIG = intravenous immunoglobulin; JAK = Janus kinase; LDH = lactate dehydrogenase; MV = mechanical ventilation; NIV = noninvasive ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PO = oral; RCT = randomized controlled trial; RDV = remdesivir; SAE = serious adverse event; SOC = standard of care; SpO₂ = oxygen saturation; TB = tuberculosis; ULN = upper limit of normal

References

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Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;385(5):406-415. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34133856.