Tofacitinib suppresses pro-inflammatory signaling that may be important pathogenetically to progression to more severe lung disease and acute respiratory distress syndrome (ARDS) in patients with COVID-19. The purpose of the study is to assess the safety and efficacy of tofacitinib plus standard pharmacologic and supportive measures in treating hospitalized participants with COVID-19 pneumonia.
COVID-19 is a viral disease caused by a novel coronavirus, severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), that can cause severe pneumonia and ARDS. Respiratory viral load
may peak within 5 days after onset, while symptoms are still mild. Many patients rapidly
(within 1 to 2 weeks of infection) develop dyspnea and pneumonia and require hospitalization
for respiratory support.
Preliminary clinical data from COVID-19 patients indicate that severe symptoms with
SARS-CoV-2 infection are associated with an exaggerated immune response driven by interleukin
(IL)-6 IL-10, tumor necrosis factor (TNF)α, and other cytokines. The ultimate result is
progressive destruction of the alveolar epithelium leading to pneumonia and/or ARDS.
Moreover, the exudative phase of ARDS is thought to be due to an influx of myeloid cells
(neutrophils and macrophages) and elevations of inflammatory cytokines, with higher levels of
both IL-6 and IL-8 levels being correlated with increased mortality. Therefore,
immunomodulatory therapy may be beneficial in reducing the deleterious effects of lung
inflammation and mitigating progressive lung injury.
Tofacitinib is an inhibitor of Janus kinase (JAKs) 1 and 3, with partial selectivity to JAK
2. Tofacitinib suppresses pro-inflammatory signaling that may be important pathogenetically
to progression to more severe lung disease and ARDS in patients with COVID-19.
The purpose of the study is to assess the safety and efficacy of tofacitinib plus standard
pharmacologic and supportive measures in treating hospitalized participants with COVID-19
pneumonia.
Participants with laboratory confirmed SARS-CoV-2 infection as determined by a positive PCR,
who have agreed to participate, will be screened within 72h hours after admission to the
hospital to determine eligibility.
Eligible participants will be randomized on Day 1 to the tofacitinib plus standard of care
treatment group or the placebo plus standard of care treatment group in a 1:1 ratio,
stratified by site. Participants will receive treatment for up to 14 days or until discharge
from the hospital, whichever is earlier.
Participants will be assessed daily (up to Day 28) while hospitalized for clinical, safety,
and laboratory parameters. Follow-up visits will occur on Day 14 and on Day 28.
Drug: Tofacitinib 10 mg
Tofacitinib 10mg administered orally twice daily for 14 days or until hospital discharge
Drug: Placebo
Tofacitinib-matching placebo administered orally twice daily for 14 days or until hospital discharge
Inclusion Criteria:
1. Male or female participants older than 18 years
2. Laboratory-confirmed novel coronavirus (SARS-CoV-2) infection as determined by
polymerase chain reaction (PCR) prior to Day 1.
3. Evidence of pneumonia assessed by radiographic imaging (chest x-ray or chest CT scan).
4. Hospitalized for less than 72 hours and receiving supportive care for COVID-19
Exclusion Criteria:
1. Require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal
membrane oxygenation (ECMO) on Day 1 at the time of randomization
2. History of or known current thrombosis. Only if current thrombosis is suspected by the
investigator, imaging testing is recommended (per local guidance) to exclude
thrombosis.
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. Severe hepatic impairment, defined as Child-Pugh class C.
7. Severe anemia (hemoglobin <8 g/dL).
8. Absolute lymphocyte count <500 cells/mm;
9. Absolute neutrophil count <1000 cells/mm.
10. Known allergy to tofacitinib.
11. 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.
12. Suspected or known active systemic bacterial, fungal, or viral infections (with the
exception of COVID-19) including but not limited to: active herpes zoster infection;
known active tuberculosis or history of inadequately treated tuberculosis; known B
hepatitis, C hepatitis, or HIV.
13. Have received any of these within 4 weeks prior to the first dose of study
intervention: any JAK inhibitors, potent immunosuppressants, or any biologic agents
including IL-6 inhibitors (eg, tocilizumab) or IL-1 inhibitors (eg, anakinra) within
the past 30 days; any potent cytochrome P450 inducer, such as rifampin, within the
past 28 days or 5 half-lives, whichever is longer.
14. Have received estrogen-containing contraception or treatment with herbal supplements
within 48 hours prior to the first dose of study intervention.
15. Have received treatment with corticosteroids equivalent to prednisone or
methylprednisolone >20 mg/day for equal or more than 14 consecutive days prior to
screening.
16. Current participation in other trials.
Centro de Pesquisa Clínica do Coração
Aracaju, Brazil
Hospital Universitário São Francisco de Assis Na Providência de Deu
Bragança Paulista, Brazil
Irmandade do Sr. Bom Jesus dos Passos da Santa Casa de Misericórdia de Bragança Paulista
Bragança Paulista, Brazil
Hospital do Coração do Brasil
Brasilia, Brazil
Instituto de Pesquisa Clínica de Campinas
Campinas, Brazil
Hospital Regional do Litoral Norte
Caraguatatuba, Brazil
Unimed Fortaleza Sociedade Corporativa Médica LTD
Fortaleza, Brazil
Hospital Regional Jorge Rossmann
Itanhaem, Brazil
Hospital Bruno Born
Lajeado, Brazil
Hospital São Vicente de Paulo
Passo Fundo, Brazil
Hospital Israelita Albert Einstein
Sao Paulo, Brazil
Fundação Faculdade Regional de Medicina de São José do Rio Preto
São José Do Rio Preto, Brazil
Hospital Regional de Registro
São José Dos Campos, Brazil
Hospital Regional de São José dos Campos
São José Dos Campos, Brazil
Beneficência Portuguesa
São Paulo, Brazil
BP Mirante
São Paulo, Brazil
Instituto do Coração
São Paulo, Brazil