Clinical trial NCT04469114: Tofacitinib in Hospitalized Patients With COVID-19 Pneumonia
Official title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-design Trial of Tofacitinib in Hospitalized Participants With COVID-19 Pneumonia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Lead sponsor: Hospital Israelita Albert Einstein
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2020-07-13
Enrollment: 289
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Death or respiratory failure until Day 28
timeFrame: 28 days
Secondary outcomes:
measure: National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity at Day 14
timeFrame: 14 days
measure: Status of alive and not on mechanical ventilation or ECMO at Day 14 and 28 NIAID ordinal scale of disease severity at Day 14
timeFrame: 14 and 28 days
measure: Status of requiring supplemental oxygen at Day 28
timeFrame: 28 days
measure: Status of being alive and not hospitalized at Day 14 and 28
timeFrame: 14 and 28 days
measure: National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity at Day 14 NIAID ordinal scale of disease severity at Day 28
timeFrame: 28 days
measure: Number of patients with cure
timeFrame: 28 days
measure: Number of patients at the ICU or on ventilatory support at Day 28
timeFrame: 28 days
measure: Number of days free from mechanical ventilation at 28 days
timeFrame: 28 days
measure: Number of days in hospital
timeFrame: 28 days
measure: Number of days in ICU
timeFrame: 28 days
measure: Death or respiratory failure at Day 28
timeFrame: 28 days
Other outcomes:
Locations:
city: Aracaju
country: Brazil
facility: Centro de Pesquisa Clínica do Coração
city: Bragança Paulista
country: Brazil
facility: Hospital Universitário São Francisco de Assis Na Providência de Deu
city: Bragança Paulista
country: Brazil
facility: Irmandade do Sr. Bom Jesus dos Passos da Santa Casa de Misericórdia de Bragança Paulista
city: Brasilia
country: Brazil
facility: Hospital do Coração do Brasil
city: Campinas
country: Brazil
facility: Instituto de Pesquisa Clínica de Campinas
city: Caraguatatuba
country: Brazil
facility: Hospital Regional do Litoral Norte
city: Fortaleza
country: Brazil
facility: Unimed Fortaleza Sociedade Corporativa Médica LTD
city: Itanhaem
country: Brazil
facility: Hospital Regional Jorge Rossmann
city: Lajeado
country: Brazil
facility: Hospital Bruno Born
city: Passo Fundo
country: Brazil
facility: Hospital São Vicente de Paulo
city: Sao Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
city: São José Do Rio Preto
country: Brazil
facility: Fundação Faculdade Regional de Medicina de São José do Rio Preto
city: São José Dos Campos
country: Brazil
facility: Hospital Regional de Registro
city: São José Dos Campos
country: Brazil
facility: Hospital Regional de São José dos Campos
city: São Paulo
country: Brazil
facility: Beneficência Portuguesa
city: São Paulo
country: Brazil
facility: BP Mirante
city: São Paulo
country: Brazil
facility: Instituto do Coração
Study officials:
References:
citation: Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, Spagl M, Seeber C, Piechotta V, Metzendorf MI, Golinski M, Moerer O, Stephani C, Mikolajewska A, Kluge S, Stegemann M, Laudi S, Skoetz N. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Jun 13;6(6):CD015209. doi: 10.1002/14651858.CD015209.
citation: Guimaraes PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, Kalil Filho R, Junior VM, Soeiro AM, Tognon AP, Veiga VC, Martins PA, Moia DDF, Sampaio BS, Assis SRL, Soares RVP, Piano LPA, Castilho K, Momesso RGRAP, Monfardini F, Guimaraes HP, Ponce de Leon D, Dulcine M, Pinheiro MRT, Gunay LM, Deuring JJ, Rizzo LV, Koncz T, Berwanger O; STOP-COVID Trial Investigators. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jul 29;385(5):406-415. doi: 10.1056/NEJMoa2101643. Epub 2021 Jun 16.