Tofacitinib in Hospitalized Patients With COVID-19 Pneumonia

Covid19 Clinical Trial

Official title:

A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-design Trial of Tofacitinib in Hospitalized Participants With COVID-19 Pneumonia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04469114
• Other study ID #: 34810620.0.1001.0071
• Status: Completed
• Phase: Phase 3
• Start date: September 16, 2020
• Est. completion date: January 9, 2021

Study information

• Verified date: July 2020
• Source: Hospital Israelita Albert Einstein
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 289
• Est. completion date: January 9, 2021
• Est. primary completion date: January 9, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Covid19
• Pneumonia

Intervention

Drug:
• Tofacitinib 10 mg
Tofacitinib 10mg administered orally twice daily for 14 days or until hospital discharge
• Placebo
Tofacitinib-matching placebo administered orally twice daily for 14 days or until hospital discharge

Locations

Country	Name	City	State
Brazil	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	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	Hospital Israelita Albert Einstein	Sao Paulo
Brazil	Beneficência Portuguesa	São Paulo
Brazil	BP Mirante	São Paulo
Brazil	Instituto do Coração	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
Hospital Israelita Albert Einstein	Pfizer

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death or respiratory failure until Day 28	1, 2 or 3 on the 8-point National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity. The minimum value is 1 (worst outcome) and the maximum value is 8 (best outcome).; Death.; Hospitalized, on invasive mechanical ventilation or ECMO.; Hospitalized, on non-invasive ventilation or high-flow oxygen devices.; Hospitalized, requiring supplemental oxygen.; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise).; Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care.; Not hospitalized, limitation on activities and/or requiring home oxygen.; Not hospitalized, with no limitations on activities.	28 days
Secondary	National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity at Day 14	NIAID ordinal scale of disease severity	14 days
Secondary	Status of alive and not on mechanical ventilation or ECMO at Day 14 and 28 NIAID ordinal scale of disease severity at Day 14	Categories 3 to 8 in the National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity at Day 14 and Day 28	14 and 28 days
Secondary	Status of requiring supplemental oxygen at Day 28	Categories 1 to 4 in the National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity	28 days
Secondary	Status of being alive and not hospitalized at Day 14 and 28	Categories 7 and 8 in the National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of disease severity	14 and 28 days
Secondary	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	NIAID ordinal scale of disease severity	28 days
Secondary	Number of patients with cure	Number of patients with resolution of fever, cough, and need for ventilatory or oxygen support.	28 days
Secondary	Number of patients at the ICU or on ventilatory support at Day 28	Number of patients at the ICU or on ventilatory support	28 days
Secondary	Number of days free from mechanical ventilation at 28 days	Number of days free from mechanical ventilation	28 days
Secondary	Number of days in hospital	Number of days in hospital	28 days
Secondary	Number of days in ICU	Number of days in ICU	28 days
Secondary	Death or respiratory failure at Day 28	Categories 1 to 3 in the National Institute of Allergy and Infectious Diseases (NIAID)	28 days