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

Sponsor

University of Sao Paulo (Other)

Overall Status

Completed

CT.gov ID

NCT04724629

Collaborator

Conselho Nacional de Desenvolvimento Científico e Tecnológico (Other), Science Valley Research Institute (Other)

Enrollment

Locations

Arms

6.8

Actual Duration (Months)

Patients Per Site

4.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Covid19	Biological: Ixekizumab Biological: Aldesleukin Drug: Colchicine Drug: Standard of care (SOC)	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 5, 2021

Actual Primary Completion Date :

Mar 31, 2021

Actual Study Completion Date :

Jul 30, 2021

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

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 [On the 21st day of study, since inclusion.]
proportion of patients with clinical improvement, defined by an increase of two points in the ordinal scale of seven WHO categories

Secondary Outcome Measures

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) [At some point in Day 7, Day 14 and Day 28]
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.
In patients who needed mechanical ventilation, time to indicate mechanical ventilation [Day 0 up to 45 days]
(calculated in days, from entry into the protocol until orotracheal intubation, up to 45 days)
Duration of hospitalization, in survivors [On day 28]
In days
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

Correlation among the inflammatory proteins D-dimer, C- reactive protein (CRP), Lactate Dehydrogenase (LDH) Test, and ferritin with: [During the follow-up period (30 days (+/- 2))]
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
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) [at Day 0, Day 2, Day 4, Day 7, Day 14, Day 21 and Day 28 after randomization;]
Changes from baseline of cytokine storm surrogate markers: white blood counts, lymphocyte counts, neutrophils counts, CRP, ferritin (if applicable), D-dimer (if applicable)
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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;

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Faculdade de Medicina de Ribeirão Preto - USP	Ribeirão Preto	SP	Brazil
2	Hospital e Maternidade Christovão da Gama	Santo André	SP	Brazil	09030-010

Sponsors and Collaborators

University of Sao Paulo
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