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STS Administration on Coronavirus Disease (COVID-19) Patients in Critical Care (H4COVID)

Primary Purpose

COVID-19, Virus Diseases, Corona Virus Infection

Status
Recruiting
Phase
Phase 2
Locations
Greece
Study Type
Interventional
Intervention
Sodium Thiosulfate 25% Solution for Injection
Sponsored by
Hellenic Institute for the Study of Sepsis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring COVID-19, SARS-CoV-2, Hydrogen Sulfide, Sodium Thiosulfate, Hydrogen Sulfide donor

Eligibility Criteria

18 Years - 110 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age equal to or older than 18 years
  2. Both genders
  3. For women of childbearing potential, they must use or be willing to use a dual contraceptive method during the study.
  4. Written consent statement provided by the patient or his / her legal representative in case patients are unable to consent.
  5. Confirmed COVID-19 disease
  6. WHO-CPS 7 to 9
  7. Hospitalization in Intensive Care Unit
  8. Serum H2S levels less than 140 μM

Exclusion Criteria:

  1. Age less than 18 years
  2. Denial of written consent
  3. Decision not to resuscitate

Sites / Locations

  • General Hospitan of Athens KAT 2nd Department of ICURecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

No Intervention

Experimental

Experimental

Arm Label

Standard Treatment

One intravenous 12.5 gr STS - Treatment Group 1

Three intravenous doses of 12.5 gr STS - Treatment Group 2

Arm Description

The standard treatment includes the application of mechanical ventilation and / or support with the administration of inotropes and / or extracorporeal oxygenation (ECMO) and the intravenous administration of fluids and dexamethasone. The administration of any other immunosuppressive therapy, including tocilizumab and / or antimicrobials at the discretion of the therapists, is permitted.

Patients will receive standard treatment and one intravenous (iv)12.5 gr STS in 60 minutes continuous intravenous infusion. STS is dissolved in a final volume of 100ml N/S 0.9% w/v,

Patients will receive standard treatment and three intravenous doses of 12.5 g STS. STS is dissolved in a final volume of 100ml N/S 0.9% w/v. Each dose will be given in 60 minutes of continuous intravenous infusion with 48 hours intervals between each dose.

Outcomes

Primary Outcome Measures

Comparison of treatment-emergent serious and non-serious adverse events between treatment groups.
Change in the number of adverse events (AEs) and serious adverse events (SAEs) among treatment groups

Secondary Outcome Measures

World Health Organization clinical progression scale (WHO-CPS) on day 7 from inclusion in the study
Change in the WHO-CPS score on day 7 from inclusion in the study. The minimum WHO-CPS score is 0 for uninfected patients (no viral RNA detected) and the maximum is 10 for patients who are dead. Higher scores equals worse outcome
WHO-CPS on day 14 from inclusion in the study
Change in the WHO-CPS score on day 14 from inclusion in the study. The minimum WHO-CPS score is 0 for uninfected patients (no viral RNA detected) and the maximum is 10 for patients who are dead. Higher scores equals worse outcome
WHO-CPS on day 28 from inclusion in the study
Change in the WHO-CPS score on day 28 from inclusion in the study. The minimum WHO-CPS score is 0 for uninfected patients (no viral RNA detected) and the maximum is 10 for patients who are dead. Higher scores equal worse outcome
Average value of the total sequential organ failure assessment (SOFA) score on day 7
change between baseline sequential organ failure assessment (SOFA) score and measured sequential organ failure assessment SOFA score at Study Day 7. The minimum score is 0 points if the patient has PaO2/FiO2 (fraction of inspired oxygen) ≥400 mmHg, ≥150 Platelets (per mm3), hypotension (MAP ≥ 70mmHg), 15 on the Glasgow Scale, <1.2 bilirubin and creatinine or urine output (mg/dl). Maximum SOFA score is 24. if the patient has PaO2/FiO2 <100 mmHg, <20 Platelets (per mm3), Adrenaline >0.1 or Noradrenaline >0.1μg/kg/min , <6 on the Glasgow Scale, ≥12 bilirubin and ≥5.0 or <200ml/day creatinine or urine output (mg/dl).
Hydrogen sulfide concentrations daily until day 7 in patient's blood serum.
Change in patients blood serum concentrations of hydrogen sulfide levels from day 1 until day 7.
IL-6 cytokine concentrations daily until day 7 in patient's blood serum.
Change in patients blood serum concentrations of cytokine IL-6 levels from visit study day 1 until visit study day 7
Tumor Necrosis Factor (TNF) cytokine concentrations daily until day 7 in patient's blood serum.
Change in patients blood serum concentrations of cytokine TNF levels from visit study day 1 until visit study day 7
Change in the production of Th1, Th2, and T17 cytokines from mononuclear cells of patient's blood on days 1,4 and 7
Comparison of cytokine production on patients' blood serum by stimulation of monocytes, Th1, Th2, and T17 cells on visit study day 1, visit study day 4, and visit study day 7.
Ferritin concentrations on days 1,4 and 7
Changes in patients blood serum concentrations of ferritin levels on visit study day 1, visit study day 4 and visit study day 7
C-reactive protein concentrations on days 1,4 and 7
Changes in patients blood serum concentrations of C-reactive protein levels on visit study day 1, visit study day 4 and visit study day 7
D-dimers concentrations on days 1,4 and 7
Changes in patients blood serum concentrations of d-dimers levels on visit study day 1, visit study day 4 and visit study day 7
Cytokine IL-6 concentrations on days 1,4 and 7
Changes in patients blood serum concentrations of IL-6 levels on visit study day 1, visit study day 4 and visit study day 7

Full Information

First Posted
March 10, 2022
Last Updated
January 11, 2023
Sponsor
Hellenic Institute for the Study of Sepsis
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1. Study Identification

Unique Protocol Identification Number
NCT05277285
Brief Title
STS Administration on Coronavirus Disease (COVID-19) Patients in Critical Care
Acronym
H4COVID
Official Title
Hydrogen Sulfate Guided Therapy With STS for COVID-19 Patients in Need of Critical Care: The H4COVID Open-label, Randomized, Triple-arm Trial
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 1, 2022 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hellenic Institute for the Study of Sepsis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The primary purpose is to describe the safety of administration of three doses of STS to critically ill patients with confirmed COVID-19. A secondary purpose is to describe data on the clinical efficacy of administration of up to three doses of STS in critically ill patients with confirmed COVID-19.
Detailed Description
With the appearance of the COVID-19 pandemic, a race for the discovery of effective treatments to combat SARS-CoV-2 infection and its sequelae commenced. Some patients with COVID-19 develop severe acute respiratory syndrome which is the main reason for death. The aim of this study is to spearhead pharmacotherapeutic solutions for COVID-19 patients in the intensive care which have proven to be the hardest to treat due to the high death rate, the long-term allocation of patients in ICU, and the slow recovery that oftentimes leads to residual symptoms and signs. The ever-increasing pressure on the health care system requires finding an effective treatment that can benefit even advanced-stage patients such as those in the intensive care unit. It was not until recently that the published literature about hydrogen sulfide shifted from revolving around its toxicity to its recognition as an endogenous gaseous signaling molecule and its biological roles. Hydrogen Sulfide (H2S) is a novel gaseous signaling molecule (gasotransmitter) that regulates a variety of physiological functions and provides protection against organ damage (anti-inflammatory, prolonged survival, cardioprotection, antioxidant, and more). H2S also displays beneficial roles in preventing lung disorders such as pneumonia, lung injury (acute/ chronic), and chronic obstructive pulmonary disease and limits viral replication. H2S has been shown to be effective in reversing lung inflammation and improving pulmonary function in various animal models. Based on preclinical data, cystathionine-γ-lyase (CSE)-derived H2S or exogenously applied H2S may block Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) entry into the host cells by interrupting Angiotensin-Converting Enzyme-2 (ACE2) and transmembrane protease serine-2 (TMPRSS2), inhibiting viral replication by attenuating syncytium formation and virus assembly/release, and thus may protect SARS-CoV-2-induced lung damage by suppressing the immune response and the development of inflammation. Lymphopenia is a key characteristic of COVID-19 patients. Serum H2S was positively correlated with the lymphocyte count and is considered a predictor of mortality. Additionally reduced H2S bioavailability has been suggested as an indicator of enhanced pro-inflammatory responses and endothelial dysfunction. Both these conditions often accompany severe COVID-19. Interleukin-6 (IL-6) has been proposed as the principle pro-inflammatory cytokine involved in the cytokine storm that leads to severe lung injury, respiratory failure, and death by COVID-19. A negative association between IL-6 and serum H2S has been shown to exist. The above-mentioned results led to further evaluation of admission H2S levels as a marker of survival in a recent study. Results showed that serum levels of H2S on day 1 lower than 150.44 micromolars (μM) had the best tradeoff for sensitivity and specificity for death. Thus, administration of a H2S-donor could be a potential remedy for COVID-19 by relieving the damage in lungs and other organs. Sodium thiosulfate (STS) is a H2S-donor with known safety and efficacy profile in humans for other diseases, including calciphylaxis and cyanide poisoning. STS can be metabolized to H2S and acts as a precursor for H2S signaling. Moreover, in patients presenting with acute coronary syndrome, a phase 1 study was conducted, showing that STS was well tolerated, even with concomitant use of blood pressure lowering drugs. Additionally, the Groningen Intervention study for Preservation of cardiac function with Sodium thiosulfate in ST-elevation myocardial infarction (GIPS-IV trial) is the first trial in humans designed to test the hypothesis that STS provides protection against I/R injury in patients presenting with ST-segment elevation myocardial infarction

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19, Virus Diseases, Corona Virus Infection
Keywords
COVID-19, SARS-CoV-2, Hydrogen Sulfide, Sodium Thiosulfate, Hydrogen Sulfide donor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard Treatment
Arm Type
No Intervention
Arm Description
The standard treatment includes the application of mechanical ventilation and / or support with the administration of inotropes and / or extracorporeal oxygenation (ECMO) and the intravenous administration of fluids and dexamethasone. The administration of any other immunosuppressive therapy, including tocilizumab and / or antimicrobials at the discretion of the therapists, is permitted.
Arm Title
One intravenous 12.5 gr STS - Treatment Group 1
Arm Type
Experimental
Arm Description
Patients will receive standard treatment and one intravenous (iv)12.5 gr STS in 60 minutes continuous intravenous infusion. STS is dissolved in a final volume of 100ml N/S 0.9% w/v,
Arm Title
Three intravenous doses of 12.5 gr STS - Treatment Group 2
Arm Type
Experimental
Arm Description
Patients will receive standard treatment and three intravenous doses of 12.5 g STS. STS is dissolved in a final volume of 100ml N/S 0.9% w/v. Each dose will be given in 60 minutes of continuous intravenous infusion with 48 hours intervals between each dose.
Intervention Type
Drug
Intervention Name(s)
Sodium Thiosulfate 25% Solution for Injection
Other Intervention Name(s)
NATRIUMTHIOSULFAT 25%
Intervention Description
The drug will be administered via continuous infusion after being diluted to a concentration 12.5 gr/100ml
Primary Outcome Measure Information:
Title
Comparison of treatment-emergent serious and non-serious adverse events between treatment groups.
Description
Change in the number of adverse events (AEs) and serious adverse events (SAEs) among treatment groups
Time Frame
Visit study day 28
Secondary Outcome Measure Information:
Title
World Health Organization clinical progression scale (WHO-CPS) on day 7 from inclusion in the study
Description
Change in the WHO-CPS score on day 7 from inclusion in the study. The minimum WHO-CPS score is 0 for uninfected patients (no viral RNA detected) and the maximum is 10 for patients who are dead. Higher scores equals worse outcome
Time Frame
Visit study day 7
Title
WHO-CPS on day 14 from inclusion in the study
Description
Change in the WHO-CPS score on day 14 from inclusion in the study. The minimum WHO-CPS score is 0 for uninfected patients (no viral RNA detected) and the maximum is 10 for patients who are dead. Higher scores equals worse outcome
Time Frame
Visit study day 14
Title
WHO-CPS on day 28 from inclusion in the study
Description
Change in the WHO-CPS score on day 28 from inclusion in the study. The minimum WHO-CPS score is 0 for uninfected patients (no viral RNA detected) and the maximum is 10 for patients who are dead. Higher scores equal worse outcome
Time Frame
Visit study day 28
Title
Average value of the total sequential organ failure assessment (SOFA) score on day 7
Description
change between baseline sequential organ failure assessment (SOFA) score and measured sequential organ failure assessment SOFA score at Study Day 7. The minimum score is 0 points if the patient has PaO2/FiO2 (fraction of inspired oxygen) ≥400 mmHg, ≥150 Platelets (per mm3), hypotension (MAP ≥ 70mmHg), 15 on the Glasgow Scale, <1.2 bilirubin and creatinine or urine output (mg/dl). Maximum SOFA score is 24. if the patient has PaO2/FiO2 <100 mmHg, <20 Platelets (per mm3), Adrenaline >0.1 or Noradrenaline >0.1μg/kg/min , <6 on the Glasgow Scale, ≥12 bilirubin and ≥5.0 or <200ml/day creatinine or urine output (mg/dl).
Time Frame
Visit study day 7
Title
Hydrogen sulfide concentrations daily until day 7 in patient's blood serum.
Description
Change in patients blood serum concentrations of hydrogen sulfide levels from day 1 until day 7.
Time Frame
Visit study day 1 until visit day 7
Title
IL-6 cytokine concentrations daily until day 7 in patient's blood serum.
Description
Change in patients blood serum concentrations of cytokine IL-6 levels from visit study day 1 until visit study day 7
Time Frame
Visit study day 1 until visit day 7
Title
Tumor Necrosis Factor (TNF) cytokine concentrations daily until day 7 in patient's blood serum.
Description
Change in patients blood serum concentrations of cytokine TNF levels from visit study day 1 until visit study day 7
Time Frame
Visit study day 1 until visit day 7
Title
Change in the production of Th1, Th2, and T17 cytokines from mononuclear cells of patient's blood on days 1,4 and 7
Description
Comparison of cytokine production on patients' blood serum by stimulation of monocytes, Th1, Th2, and T17 cells on visit study day 1, visit study day 4, and visit study day 7.
Time Frame
Visit study day 1, Visit study day 4, Visit study day 7
Title
Ferritin concentrations on days 1,4 and 7
Description
Changes in patients blood serum concentrations of ferritin levels on visit study day 1, visit study day 4 and visit study day 7
Time Frame
Visit study day 1, Visit study day 4, Visit study day 7
Title
C-reactive protein concentrations on days 1,4 and 7
Description
Changes in patients blood serum concentrations of C-reactive protein levels on visit study day 1, visit study day 4 and visit study day 7
Time Frame
Visit study day 1, Visit study day 4, Visit study day 7
Title
D-dimers concentrations on days 1,4 and 7
Description
Changes in patients blood serum concentrations of d-dimers levels on visit study day 1, visit study day 4 and visit study day 7
Time Frame
Visit study day 1, Visit study day 4, Visit study day 7
Title
Cytokine IL-6 concentrations on days 1,4 and 7
Description
Changes in patients blood serum concentrations of IL-6 levels on visit study day 1, visit study day 4 and visit study day 7
Time Frame
Visit study day 1, Visit study day 4, Visit study day 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
110 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age equal to or older than 18 years Both genders For women of childbearing potential, they must use or be willing to use a dual contraceptive method during the study. Written consent statement provided by the patient or his / her legal representative in case patients are unable to consent. Confirmed COVID-19 disease WHO-CPS 7 to 9 Hospitalization in Intensive Care Unit Serum H2S levels less than 140 μM Exclusion Criteria: Age less than 18 years Denial of written consent Decision not to resuscitate
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Evangelos Giamarellos-Bourboulis, MD, PhD
Phone
+302107480662
Email
egiamarel@med.uoa.gr
First Name & Middle Initial & Last Name or Official Title & Degree
Antigoni Kotsaki, MD, PhD
Phone
+306946637164
Email
scra@sepsis.gr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ioannis Alamanos, MD
Organizational Affiliation
General Hospital of Athens KAT
Official's Role
Principal Investigator
Facility Information:
Facility Name
General Hospitan of Athens KAT 2nd Department of ICU
City
Athens
State/Province
Kifisia
ZIP/Postal Code
14561
Country
Greece
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ioannis Alamanos, MD
Phone
6932300372
Email
icualamanos@yahoo.gr
First Name & Middle Initial & Last Name & Degree
Vasilios Kaldis, MD
Phone
6947520344
Email
vkaldis@yahoo.gr

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

STS Administration on Coronavirus Disease (COVID-19) Patients in Critical Care

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