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

• ClinicalTrials.gov Identifier: NCT04724629
• Recruitment Status: Recruiting
• First Posted: January 26, 2021
• Last Update Posted: January 26, 2021
• Sponsor: University of Sao Paulo
• Collaborators: Conselho Nacional de Desenvolvimento Científico e Tecnológico; Science Valley Research Institute
• Information provided by (Responsible Party): Fernando Bellissimo Rodrigues, University of Sao Paulo

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 (Clinical Trial)
• Estimated 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.
• 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: January 5, 2021
• Estimated Primary Completion Date: March 31, 2021
• Estimated Study Completion Date: July 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 Name: 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 Name: 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 :

1. 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 [ Time Frame: 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 :

1. Time until independence from oxygen therapy in days [ Time Frame: During the follow-up period (30 days (+/- 2)) ]
2. Ventilator free days (in days) [ Time Frame: During the follow-up period (30 days (+/- 2)) ]
3. Assessment of worsening pulmonary involvement, defined as the presence of one of these criteria (absence or presence) [ Time Frame: 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.
4. In patients who needed mechanical ventilation, time to indicate mechanical ventilation [ Time Frame: Day 0 up to 45 days ]
   (calculated in days, from entry into the protocol until orotracheal intubation, up to 45 days)
5. Duration of hospitalization, in survivors [ Time Frame: On day 28 ]
   In days
6. Analysis of in-hospital mortality [ Time Frame: Day 0 up to 45 days ]
7. Analysis of general mortality [ Time Frame: During the follow-up period (30 days (+/- 2)) ]

Other Outcome Measures:

1. Correlation among the inflammatory proteins D-dimer, C- reactive protein (CRP), Lactate Dehydrogenase (LDH) Test, and ferritin with: [ Time Frame: 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
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) [ Time Frame: 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)
3. Change in Score for Sepsis (SOFA score) [ Time Frame: On days 7 and 14 of randomization ]
4. Analysis of secondary infections [ Time Frame: During the follow-up period (30 days (+/- 2)) ]
5. Qualitative and quantitative assessment of treatment- related adverse effects assessed by the Common Terminology Criteria for Adverse Event (CTCAE) version 5.0. [ Time Frame: Within the first month ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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;

Contacts and Locations

Contacts

Contact: Poliana Goulart; +551144688183; qualidade@svriglobal.com

Locations

Brazil

Faculdade de Medicina de Ribeirão Preto - USP; Recruiting

Ribeirão Preto, SP, Brazil

Contact: Livia A Bonifacio, PhD livia_pb@usp.br

Hospital e Maternidade Christovão da Gama; Recruiting

Santo André, SP, Brazil, 09030-010

Contact: Poliana Goulart +551144688183 qualidade@svriglobal.com

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

More Information

• Responsible Party: Fernando Bellissimo Rodrigues, Associated Professor - Dept of Social Medicine, University of Sao Paulo
• ClinicalTrials.gov Identifier: NCT04724629
• Other Study ID Numbers: 402422/2020-1
• First Posted: January 26, 2021
• Last Update Posted: January 26, 2021
• Last Verified: January 2021

• 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

Keywords provided by Fernando Bellissimo Rodrigues, University of Sao Paulo:

Colchicine; Ixekizumab; Cytokine storm; Lung vasculitis; Recombinant Human Interleukin-2

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Aldesleukin; Colchicine; Ixekizumab; Antineoplastic Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Gout Suppressants; Antirheumatic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents