Survival TRial Using CytoKines in COVID-19 (STRUCK Trial)

Study Overview
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Brief Summary
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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.

Official Title
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Prospective-randomized Adaptive Study, With Active Control to Evaluate the Efficacy and Safety of Interleukin (IL)-17 Inhibitor Treatment Versus Low Doses of IL-2 Versus Indirect IL-6 Inhibitor in Hospitalized Patients With Severe Forms of COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Biological: Ixekizumab
* Biological: Aldesleukin
* Drug: Colchicine
* Drug: Standard of care (SOC)


Participation Criteria
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Eligibility Criteria
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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 Respiratory rate ≥ 24 IRPM (for adults) or O2 saturation <93% or No improvement in O2 saturation, despite oxygen supply or Arterial hypotension; or Changes in capillary filling time; or Changes in the level of consciousness; or Oliguria; 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: Age <18 years; Refuse to sign the Informed Consent Form; Patient's decision that their involvement is not in their interest; Severe known liver disease (eg cirrhosis, with aminotransferase levels> 5 times the reference value limit); Pregnancy or breastfeeding period; Severe bacterial infection; Severe diarrhea; Diverticulitis or intestinal perforation; Infection known as HIV; Presence of one of the following uncontrolled or unstable cardiovascular diseases: stroke, ECG confirmed acute ischemia or myocardial infarction and / or clinically significant dysrhythmia; • Known history of gastrointestinal bleeding, uncontrolled peptic ulcer or uncontrolled duodenal ulcer; Known history of hemophilia or other bleeding disorders; History of organ transplantation, congenital immunodeficiency;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IL-17 inhibitor (Ixekizumab)<br>Patients will receive study medication Ixekizumab 80 mg per week, (SC) once a week for 4 weeks or until discharge. | Biological: Ixekizumab<br>* 80 mg of IL-17 inhibitor<br>* Other names: Taltz;|
| Experimental: IL-2 (Aldesleukin)<br>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. | Biological: Aldesleukin<br>* 1.5 million IU (low-dose) of IL-2<br>* Other names: Proleukin;|
| Experimental: Indirect IL-6 inhibitor (Colchicine)<br>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. | Drug: Colchicine<br>* 0.5 mg of indirect IL-6 inhibitor<br>|
| Active Comparator: Standard of care<br>Standard treatment, supplementation of O2 ventilation + standard treatment of the institution, which may include Dexamethasone according to the institutional protocol. | Drug: Standard of care (SOC)<br>* Active comparator (Corticoids and antiretrovirals)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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. | 

Secondary Outcome Measures

| Outcome Measure | 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)) | 
| 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)) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colchicine, Ixekizumab, Cytokine storm, Lung vasculitis, Recombinant Human Interleukin-2