Clinical trial NCT04724629: Survival TRial Using CytoKines in COVID-19 (STRUCK Trial)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Keywords: Colchicine
Ixekizumab
Cytokine storm
Lung vasculitis
Recombinant Human Interleukin-2
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
Collaborators: name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
name: Science Valley Research Institute
First posted: 2021-01-26
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


Eligibility 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;

Primary outcomes:
measure: 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
timeFrame: On the 21st day of study, since inclusion.
Secondary outcomes:
measure: Time until independence from oxygen therapy in days
timeFrame: During the follow-up period (30 days (+/- 2))
measure: Ventilator free days (in days)
timeFrame: During the follow-up period (30 days (+/- 2))
measure: Assessment of worsening pulmonary involvement, defined as the presence of one of these criteria (absence or presence)
timeFrame: At some point in Day 7, Day 14 and Day 28
measure: In patients who needed mechanical ventilation, time to indicate mechanical ventilation
timeFrame: Day 0 up to 45 days
measure: Duration of hospitalization, in survivors
timeFrame: On day 28
measure: Analysis of in-hospital mortality
timeFrame: Day 0 up to 45 days
measure: Analysis of general mortality
timeFrame: During the follow-up period (30 days (+/- 2))
Other outcomes:
measure: Correlation among the inflammatory proteins D-dimer, C- reactive protein (CRP), Lactate Dehydrogenase (LDH) Test, and ferritin with:
timeFrame: During the follow-up period (30 days (+/- 2))
measure: 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)
timeFrame: at Day 0, Day 2, Day 4, Day 7, Day 14, Day 21 and Day 28 after randomization;
measure: Change in Score for Sepsis (SOFA score)
timeFrame: On days 7 and 14 of randomization
measure: Analysis of secondary infections
timeFrame: During the follow-up period (30 days (+/- 2))
measure: Qualitative and quantitative assessment of treatment- related adverse effects assessed by the Common Terminology Criteria for Adverse Event (CTCAE) version 5.0.
timeFrame: Within the first month
Locations:
city: Ribeirão Preto
country: Brazil
facility: Faculdade de Medicina de Ribeirão Preto - USP
state: SP
city: Santo André
country: Brazil
facility: Hospital e Maternidade Christovão da Gama
state: SP
Study officials:
affiliation: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, USP, SP, Brazil
name: Fernando Rodrigues, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital e Maternidade Dr. Christóvão da Gama, Grupo Leforte, Santo André, SP, Brazil
name: Eduardo Ramacciotti, MD, PhD
role: STUDY_CHAIR
affiliation: Hospital Leforte Liberdade, SP, Brazil
name: Leandro B Agati, PhD
role: STUDY_DIRECTOR
affiliation: Hospital das Clinicas de Sao Paulo (USP)
name: Esper Kallas, MD, PhD
role: STUDY_CHAIR
affiliation: Duke University
name: Renato D Lopes, MD, PhD
role: STUDY_CHAIR
References: