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

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Biological: Ixekizumab; Biological: Aldesleukin; Drug: Colchicine; Drug: Standard of care (SOC)

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Ribeirão Preto, SP, Brazil
      • Faculdade de Medicina de Ribeirão Preto - USP
    • Santo André, SP, Brazil, 09030-010
      • Hospital e Maternidade Christovão da Gama

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

  1. Respiratory rate ≥ 24 IRPM (for adults) or
  2. O2 saturation <93% or
  3. No improvement in O2 saturation, despite oxygen supply or
  4. Arterial hypotension; or
  5. Changes in capillary filling time; or
  6. Changes in the level of consciousness; or
  7. 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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: IL-17 inhibitor (Ixekizumab); Patients will receive study medication Ixekizumab 80 mg per week, (SC) once a week for 4 weeks or until discharge.	Biological: Ixekizumab; 80 mg of IL-17 inhibitor; Other Names: Taltz
EXPERIMENTAL: IL-2 (Aldesleukin); 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; 1.5 million IU (low-dose) of IL-2; Other Names: Proleukin
EXPERIMENTAL: Indirect IL-6 inhibitor (Colchicine); 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; 0.5 mg of indirect IL-6 inhibitor
ACTIVE_COMPARATOR: Standard of care; 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); Active comparator (Corticoids and antiretrovirals)

What is the study measuring?

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))

Other Outcome Measures

Outcome Measure	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))
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

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Conselho Nacional de Desenvolvimento Científico e Tecnológico; Science Valley Research Institute
• Investigators: Principal Investigator: Fernando Rodrigues, MD, PhD, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, USP, SP, Brazil; Study Chair: Eduardo Ramacciotti, MD, PhD, Hospital e Maternidade Dr. Christóvão da Gama, Grupo Leforte, Santo André, SP, Brazil; Study Director: Leandro B Agati, PhD, Hospital Leforte Liberdade, SP, Brazil; Study Chair: Esper Kallas, MD, PhD, Hospital das Clinicas de Sao Paulo (USP); Study Chair: Renato D Lopes, MD, PhD, Duke University

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 5, 2021
• Primary Completion (ACTUAL): March 31, 2021
• Study Completion (ACTUAL): July 30, 2021

Study Registration Dates

• First Submitted: October 5, 2020
• First Submitted That Met QC Criteria: January 23, 2021
• First Posted (ACTUAL): January 26, 2021

Study Record Updates

• Last Update Posted (ACTUAL): July 28, 2022
• Last Update Submitted That Met QC Criteria: July 26, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Colchicine; Cytokine storm; Ixekizumab; Lung vasculitis; Recombinant Human Interleukin-2
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Dermatologic Agents; Gout Suppressants; Aldesleukin; Colchicine; Ixekizumab
• Other Study ID Numbers: 402422/2020-1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes