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| Name | Class |
|---|---|
| Conselho Nacional de Desenvolvimento Científico e Tecnológico | OTHER_GOV |
| Science Valley Research Institute | OTHER |
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Currently, there are few approved treatments for COVID-19, antiretroviral (remdesivir) and corticoids. With about 15% of COVID-19 patients suffering from severe disease health system will be overwhelmed. Treatments approaches to inhibit viral replication (antiretroviral and extended spectrum antiviral drugs), such as Remdesivir and Hydroxychloroquine are being used. In severe cases, by CT scans investigators are able to observe that these patients seem to be dying with fibrosis and lung vasculitis. It is hypothesised that targeting vasculitis and lung inflammation secondary to the viral infection may help patients' survival (reducing mortality) and/or decrease time in mechanical ventilators. It is proposed a 4-arm trial, converted to 2 after interim analysis (60 patients for the initial phase, sample size recalculation after initial analysis and 2 arms beyond). In initial phase, IL-6 indirect inhibitor (colchicine), in first arm; IL-17 inhibitor, an innovative target never tested (at this moment) in COVID-19 severe patients, in second study arm. Both approaches (indirect IL-6 and Il-17) are related to modulation of inflammatory immune response. Finally, in third arm, IL-2 low dose. This cytokine was identified as Treg upregulation. Treg levels decrease in hepatitis C virus (HCV) associated vasculitis and increase in vasculitis resolution. In fourth arm, control group, standard of care. Initially, for the first 60 included patients, the study will comprise 4 arms (15 patients per arm, randomization ratio 1:1:1:1). An interim effectiveness and safety analysis at this point will guide the selection of one single treatment strategy (adaptative study) to be carried on after that, comparatively with the control group. The multi-site trial planned enrollment duration of 4-6 months and for each participant will be approximately 4 weeks. This trial will bring complementary data to the global effort in COVID-19 cases resolution.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IL-17 inhibitor (Ixekizumab) | Experimental | Patients will receive study medication Ixekizumab 80 mg per week, (SC) once a week for 4 weeks or until discharge. |
|
| IL-2 (Aldesleukin) | Experimental | 1.5 million IU per day (SC) for 7 days or until discharge. Patients will receive study medication Aldesleukin 1.5 million IU per day (SC), for 7 days or until discharge. |
|
| Indirect IL-6 inhibitor (Colchicine) | Experimental | Patients will receive study medication colchicine 0.5 mg every 8 hours for 3 days (PO), followed by 4 weeks (+/-7 days) 0.5 mg twice daily. If a dose is missed, it should not be replaced. |
|
| Standard of care | Active Comparator | Standard treatment, supplementation of O2 ventilation + standard treatment of the institution, which may include Dexamethasone according to the institutional protocol. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ixekizumab | Biological | 80 mg of IL-17 inhibitor |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ordinal scale of seven World Health Organization (WHO) categories of IL-17 inhibitor versus low dose IL-2 versus indirect IL-6 inhibitor (colchicine) versus standard treatment in the treatment of severe COVID-19 | proportion of patients with clinical improvement, defined by an increase of two points in the ordinal scale of seven WHO categories | On the 21st day of study, since inclusion. |
| Measure | Description | Time Frame |
|---|---|---|
| Time until independence from oxygen therapy in days | During the follow-up period (30 days (+/- 2)) | |
| Ventilator free days (in days) | During the follow-up period (30 days (+/- 2)) | |
| Measure | Description | Time Frame |
|---|---|---|
| Correlation among the inflammatory proteins D-dimer, C- reactive protein (CRP), Lactate Dehydrogenase (LDH) Test, and ferritin with: | 7 points WHO original scale; b. Time until independence from oxygen therapy; c. Need for mechanical ventilation; d. Days free of mechanical ventilation; e. Mortality | During the follow-up period (30 days (+/- 2)) |
Inclusion Criteria:
Positive result in the quantitative real-time PCR (qPCR) test for SARS-CoV-2 in the respiratory tract;
Pneumonia confirmed by chest imaging and
IMPORTANT: The presence of increased respiratory rate or desaturation (items "a" and "b") are criteria for hospital admission. Items "c" to "g" are considered criteria for ICU admission
Following the recommendations of The São Paulo State Health Secretariat, resolution SS-28 of 03-Mar-2020, prepared by the Hospital das Clínicas of Medical School-USP.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Fernando Rodrigues, MD, PhD | Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, USP, SP, Brazil | Principal Investigator |
| Eduardo Ramacciotti, MD, PhD | Hospital e Maternidade Dr. Christóvão da Gama, Grupo Leforte, Santo André, SP, Brazil | Study Chair |
| Leandro B Agati, PhD | Hospital Leforte Liberdade, SP, Brazil | Study Director |
| Esper Kallas, MD, PhD | Hospital das Clinicas de Sao Paulo (USP) | Study Chair |
| Renato D Lopes, MD, PhD | Duke University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Faculdade de Medicina de Ribeirão Preto - USP | Ribeirão Preto | São Paulo | Brazil | |||
| Hospital e Maternidade Christovão da Gama |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D000080424 | Cytokine Release Syndrome |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C549079 | ixekizumab |
| C082598 | aldesleukin |
| D003078 | Colchicine |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
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This is a multicenter, adaptive, open-label, randomized study design (1: 1: 1: 1 ratio), with an active comparator, superiority study, in severe to critical COVID19 subjects.
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| Aldesleukin | Biological | 1.5 million IU (low-dose) of IL-2 |
|
|
| Colchicine | Drug | 0.5 mg of indirect IL-6 inhibitor |
|
| Standard of care (SOC) | Drug | Active comparator (Corticoids and antiretrovirals) |
|
| Assessment of worsening pulmonary involvement, defined as the presence of one of these criteria (absence or presence) |
Need to increase the inspired fraction of O2 (FIO2) to keep oxygen saturation stable or the need for mechanical ventilation; b. Increase in the number and / or extension of affected lung areas on chest computed tomography. |
| At some point in Day 7, Day 14 and Day 28 |
| In patients who needed mechanical ventilation, time to indicate mechanical ventilation | (calculated in days, from entry into the protocol until orotracheal intubation, up to 45 days) | Day 0 up to 45 days |
| Duration of hospitalization, in survivors | In days | On day 28 |
| Analysis of in-hospital mortality | Day 0 up to 45 days |
| Analysis of general mortality | During the follow-up period (30 days (+/- 2)) |
| Changes from baseline of cytokine storm surrogate markers: white blood counts, lymphocyte counts, neutrophils counts, C-Reactive protein (CRP), ferritin (if applicable), D-dimer (if applicable) |
Changes from baseline of cytokine storm surrogate markers: white blood counts, lymphocyte counts, neutrophils counts, CRP, ferritin (if applicable), D-dimer (if applicable) |
| at Day 0, Day 2, Day 4, Day 7, Day 14, Day 21 and Day 28 after randomization; |
| Change in Score for Sepsis (SOFA score) | On days 7 and 14 of randomization |
| Analysis of secondary infections | During the follow-up period (30 days (+/- 2)) |
| Qualitative and quantitative assessment of treatment- related adverse effects assessed by the Common Terminology Criteria for Adverse Event (CTCAE) version 5.0. | Within the first month |
| Santo André |
| São Paulo |
| 09030-010 |
| Brazil |
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |