Ignite Creation Date:
2024-05-06 @ 3:16 PM
Last Modification Date:
2024-10-26 @ 1:46 PM
Study NCT ID:
NCT04570254
Status:
COMPLETED
Last Update Posted:
2021-05-21
First Post:
2020-09-26
Brief Title:
Antioxidants as Adjuvant Therapy to Standard Therapy in Patients With COVID-19
Sponsor:
Unidad Temporal COVID-19 en Centro Citibanamex
Organization:
Unidad Temporal COVID-19 en Centro Citibanamex
Study Overview
Official Title:
Open Clinical Trial of the Use of Antioxidants and Pentoxifylline as Adjuvant Therapy to Standard Therapy in Patients With and Without Septic Shock Secondary to COVID-19 Severe Pneumonia
Status:
COMPLETED
Status Verified Date:
2021-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ANTIOX-COVID
Brief Summary:
Introduction SARS-CoV2 infection produces severe pneumonia with pulmonary alveolar collapse There is no specific treatment to date In experimental models and humans with septic shock there is a high production of nitric oxide NO and reactive nitrogen species RNS and can cause multiple organ failure The administration of antioxidants such as n-acetylcysteine NAC vitamin C melatonin and vitamin E participate in increasing the intracellular content of GSH ROS sequestration protection of the lipids of cell membranes cytosol proteins nuclear DNA mitochondrial and decrease LPO
Justification as there is no specific antiviral therapy the therapeutic options are limited complications and mortality are high It is intended to evaluate the effect of antioxidants on the storm outcome of the dysregulation of oxidative stress
Hypothesis It is postulated that adjuvant therapy with antioxidants and Pentoxifylline reduces the use of ventilators in patients with or without septic shock secondary to severe SARS-COV2 pneumonia as decreases lipoperoxidation and corrects dysregulation of oxidative stress by increasing the antioxidant capacity
Objectives To evaluate whether it is possible to avoid intubation or decrease assisted mechanical ventilation days improve oxidative stress dysregulation in patients with SARS-COV2 infection with severe pneumonia with or without septic shock
Methodology Quasi-experimental open analytical prospective and longitudinal study before-after In patients over 18 years of age who are admitted to the CITIBANAMEX Center with or without septic shock secondary to severe SARS-COV2 pneumonia There will be two groups 1 patients without septic shock and 2 patients with septic shock secondary to severe pneumonia due to SARS-COV2 A single antioxidant will be applied following the clinical decision tree NAC Vit C Vit E melatonin more Pentoxifylline orally or by orogastric tube for a total of 5 days from the start of the protocol APACHE II will calculate the risk SOFA MEXSOFA measurements of IL-8 vitamin C NO3 NO2 LOP total antioxidant capacity will be carried out at baseline and 48 hours SOFA will be calculated for seven days in addition to days of hospitalization days of mechanical ventilation It was evaluated 28 days after discharge by telephone
Justification as there is no specific antiviral therapy the therapeutic options are limited complications and mortality are high It is intended to evaluate the effect of antioxidants on the storm outcome of the dysregulation of oxidative stress
Hypothesis It is postulated that adjuvant therapy with antioxidants and Pentoxifylline reduces the use of ventilators in patients with or without septic shock secondary to severe SARS-COV2 pneumonia as decreases lipoperoxidation and corrects dysregulation of oxidative stress by increasing the antioxidant capacity
Objectives To evaluate whether it is possible to avoid intubation or decrease assisted mechanical ventilation days improve oxidative stress dysregulation in patients with SARS-COV2 infection with severe pneumonia with or without septic shock
Methodology Quasi-experimental open analytical prospective and longitudinal study before-after In patients over 18 years of age who are admitted to the CITIBANAMEX Center with or without septic shock secondary to severe SARS-COV2 pneumonia There will be two groups 1 patients without septic shock and 2 patients with septic shock secondary to severe pneumonia due to SARS-COV2 A single antioxidant will be applied following the clinical decision tree NAC Vit C Vit E melatonin more Pentoxifylline orally or by orogastric tube for a total of 5 days from the start of the protocol APACHE II will calculate the risk SOFA MEXSOFA measurements of IL-8 vitamin C NO3 NO2 LOP total antioxidant capacity will be carried out at baseline and 48 hours SOFA will be calculated for seven days in addition to days of hospitalization days of mechanical ventilation It was evaluated 28 days after discharge by telephone
Detailed Description:
I Background
The SARS-CoV-2 virus has a positive-sense RNA with a genome of approximately 27-32 kb in length COVID-2019 infection causes severe pneumonia that turns into a pulmonary alveolar collapse within a few hours and leads to the cessation of oxygen exchange The incubation period for the virus is 2 to 10 days and the clinical spectrum of the disease ranges from asymptomatic infection to severe respiratory failure There is elevated lymphopenia lactate creatinine and kinase dehydrogenase and higher concentrations of interleukins such as IL-1β IL-5 IL-7 IL-8 IL-9 IL-10 IL-15 IL-12p70 FGF GCSF GMCSF IFNγ IP10 MCP1 MIP1A MIP1B PDGF TNF-α and VEGF
There is no treatment for the definitive cure of COVID-19 and there is no vaccine that allows prevention Considering that the best management choice is to reestablish hemodynamic status stop organ failure improve anti-inflammatory conditions and improve redox status management strategies could not be randomized since individual conditions change and patients may have comorbidities at first The studies that support antioxidant therapy in septic management range from those carried out in vitro in vivo in an animal model and humans so the evidence makes it necessary that patients treated with specific antiviral drugs or antibiotics receive at the same time nutritional supplement and antioxidants
The data that support each of the antioxidants as therapy in septic shock are mentioned below
1 N-ACETYL CYSTEINE
The administration of N-acetylcysteine NAC a glutathione GSH precursor as a strategy to limit oxidative lung injury has been proposed since it increases the intracellular content of GSH Alterations in GSH metabolism in alveoli and lung tissue are a central feature in many lung diseases NAC increases the synthesis of GSH increases glutathione-S-transferase GST activity and has a direct action on free radicals ROS The application of NAC reduces levels of IL-8 IL-6 ICAM NAC in patients with septic shock is associated with a shorter time on mechanical ventilation and fewer days of stay in the ICU
The application of NAC reduces levels of IL-8 IL-6 ICAM NAC in patients with septic shock is associated with a shorter time on mechanical ventilation and fewer days of stay in the ICU NAC uptake and intracellular concentration can be increased through the use of liposomes L-NAC NAC supplementation in animals exposed to lipopolysaccharides LPS reduced lung edema lipoperoxidation OLP ACE damage chloramine concentration and concentrations of the eicosanoids thromboxane and leukotrienes LTB2 and LTB4 in the lung In clinical trials supplementation with a bolus of 150 mgkg NAC followed by 50 mgkgday of NAC for four days in patients with acute lung injury ALI or ARDS improved the oxygenation rate from day 1 to 4 and reduced mortality
2 MELATONIN
Melatonin MT has been shown to possess ROS-sequestering properties protects lipids in cell membranes cytosol proteins and nuclear and mitochondrial DNA
Furthermore in another study MT demonstrated anti-apoptotic antioxidant and pleiotropic anti-inflammatory effects in vitro and in vivo as direct elimination activity against ROS and stimulation of antioxidant enzymes such as CAT SOD GPx GR and gamma-glutamylcysteine synthase MT can accumulate within the mitochondria and thus reduce the local excess production of ROS which is typical in dysfunctional mitochondria during sepsis Based on these favorable preliminary data randomized control trials are warranted to assess TMs efficacy and safety as an add-on treatment in COVID-19 sepsis The previously mentioned studies have recommended its use in sepsis which should be considered in COVID-19 since it is also accessible and its cost is low making it possible to weigh the riskbenefit in the event of a pandemic
3 VITAMIN C
Ascorbic acid or vitamin C is a water-soluble antioxidant that functions as a cofactor for multiple enzymes It is absorbed at the intestinal level through the sodium-dependent transporter of vitamin C filtered freely in the glomerulus and reabsorbed at the proximal tubule level through the same transporter Ascorbic acid inhibits the production of superoxide O2- and peroxynitrite OONO- by inhibiting superoxide-producing NADPH oxidase O2- and inducible nitric oxide iNOS mRNA expression which prevents the abundant production of nitric oxide NO that generates peroxynitrite OONO- in the presence of O2-
4 PENTOXIFILINA
Pentoxifylline is a xanthine drug indicated in some severe alcoholic hepatitis it also acts on the plasma membrane of red blood cells and makes it more malleable thus improving blood perfusion Pentoxifylline exerts several antioxidant and anti-inflammatory activities such as reducing the restoration of GSH levels maintaining mitochondrial viability inhibiting the production of TNF-α preserving vascular endothelial functions and also supplementation with antioxidants has been reported better oxygenation rates higher GSH and more robust immune response Also there was a reduction in hospital stay length the time of mechanical ventilation the length of the ICU stays the multiple organ dysfunction rate and the mortality rate in patients with ALI ARDS
II Research question
Will the administration of adjuvant therapy with specific antioxidant and pentoxifylline in patients with or without septic shock secondary to severe pneumonia due to COVID-19 will it avoid the use of mechanical ventilation reduce the time of use of a mechanical ventilator days of hospital stay decrease the lipoperoxidation and will it increase the antioxidant capacity in patients admitted to intensive care
III Justification
In this COVID-19 pandemic severe pneumonia and septic shock are the leading cause of morbidity and mortality in intensive care units worldwide In this sense and based on the discoveries of recent years in the field of oxidative stress including those recently found in our group it is necessary to report results on new treatments capable of reducing the deleterious inflammatory response and the redox state In patients with pneumonia and septic shock The situation that currently occurs in patients who progress to severity due to infection with COVID-19
Septic shock has been presented in other viral diseases such as Middle East Respiratory Syndrome Coronavirus MERS-CoV detected for the first time in Saudi Arabia in which it exhibited a wide range of presentations at the time of diagnosis similar to SARS-COv2 from patients without symptoms subtle signs of pneumonia or multiorgan failure with the capacity to cause the death of which the possible therapeutic interventions with antioxidants have been proposed since then that have been proposed for the new virus through the conclusions based on systematic reviews
Many viral diseases such as SARS-CoV although clinical data are limited can develop moderate and severe septic shock and increase ROS and RNS production which is associated with overexpression of iNOS NADP oxidases cyclooxygenase two and xanthine oxidase which activates transcription factors such as NF-B resulting in an exacerbated pro-inflammatory host response Also O2 and ONOO participate as an essential mediator of pro-inflammatory interleukin production These will continue to stimulate the production and release of more ROS and RNS that can interfere with mitochondrial respiration since mitochondrial dysfunction is commonly induced in an environment of septic shock Therefore antioxidant treatment may be a way to avoid excessive inflammation associated with a history of high oxidation in COVID-19 patients
With this study we intend to evaluate the effect of the use of antioxidants on outcomes in storm regulation due to dysregulation of oxidative stress shortening of ventilator use days of stay and clinical repercussion through the measurement of organ dysfunction in six different systems using the SOFA score before and after the intervention in critically ill patients due to SARS-Cov2 infection
IV Hypothesis
It is hypothesized that adjuvant therapy with antioxidants and pentoxifylline reduces ventilator use in patients with or without septic shock secondary to severe COVID-19 pneumonia and decreases lipoperoxidation and corrects dysregulation of oxidative stress through the increase of antioxidant capacity
V Primary objective
Provide combined antioxidant therapy as an adjunct to standard therapy for patients with or without septic shock secondary to severe SARS-COV2 pneumonia to evaluate whether it is possible to avoid intubation reduce days of assisted mechanical ventilation and improve stress dysregulation oxidant leading to multiple organ failure
VI Secondary objective
1 Evaluate the prevalence of comorbidity in patients with or without septic shock and severe SARS-CoV2 pneumonia in the ICU
2 To evaluate the effect of adjuvant antioxidant therapy in reducing days with the ventilator and days of hospital stay in patients
3 Analyze the effect on organ failure in five devices and systems neurological respiratory hemodynamic hepatic hematological of each of the therapies implemented in the different systems evaluated with the SOFA score
4 Measure lipoperoxidation in basal and post-therapy samples
5 Measure the antioxidant capacity in basal and post-therapy samples
6 Measure IL-6 in basal and post-therapy samples
7 Measure procalcitonin CRP troponin pro-BNP ferritin and D-dimer
8 Determine the status of outcomes by comorbidity strata
9 Document the use of ARA ACE SGLT2 inhibitors in patients with COVID-19
10 Analyze the previous use of steroids and those who did not have it in a stratified way
VII Methodology
Study design
It is a quasi-experimental open analytical prospective and longitudinal before-after study
Sample size
The sample size calculation was based on studies that currently have mortality using Vitamin C because there is no history of antioxidants in the clinical context The sample size was calculated using X2 to compare two independent proportions
Therefore it will be necessary to include 11 patients in each group if desired to obtain 80 possibility 80 power or 32 if the power is 99 to detect a mean difference of 3 in SOFA between the groups On the other hand treatment will be possible in these patients it will be possible to measure the basal state of oxidative stress and state three after the therapy allows the use of small samples as the patient is his control
Statistic analysis
Continuous variables will be expressed as mean standard deviation or median with minimum and maximum depending on their distribution Categorical variables will be expressed as frequencies and percentages The normality of the variables will be evaluated using the Shapiro-Wilk or Shapiro-France test depending on the sample size Variables with normal distribution will be analyzed with parametric tests Students t-test for independent measurements or paired t-test for before-after measurements While various non-parametric tests were used Mann-Whitney test Kruskal-Wallis or Wilcoxon signed rank test depending on the particular case to contrast variables without Gaussian distribution Analysis of paired samples before-after will be performed with Friedman or Wilcoxon and paired t-test depending on the distribution of the data For multivariate analysis a binary logistic regression analysis will be performed Also an analysis of repeated samples and panel data testing different models grouped model model for longitudinal data marginal approximation model and multilevel model
The SARS-CoV-2 virus has a positive-sense RNA with a genome of approximately 27-32 kb in length COVID-2019 infection causes severe pneumonia that turns into a pulmonary alveolar collapse within a few hours and leads to the cessation of oxygen exchange The incubation period for the virus is 2 to 10 days and the clinical spectrum of the disease ranges from asymptomatic infection to severe respiratory failure There is elevated lymphopenia lactate creatinine and kinase dehydrogenase and higher concentrations of interleukins such as IL-1β IL-5 IL-7 IL-8 IL-9 IL-10 IL-15 IL-12p70 FGF GCSF GMCSF IFNγ IP10 MCP1 MIP1A MIP1B PDGF TNF-α and VEGF
There is no treatment for the definitive cure of COVID-19 and there is no vaccine that allows prevention Considering that the best management choice is to reestablish hemodynamic status stop organ failure improve anti-inflammatory conditions and improve redox status management strategies could not be randomized since individual conditions change and patients may have comorbidities at first The studies that support antioxidant therapy in septic management range from those carried out in vitro in vivo in an animal model and humans so the evidence makes it necessary that patients treated with specific antiviral drugs or antibiotics receive at the same time nutritional supplement and antioxidants
The data that support each of the antioxidants as therapy in septic shock are mentioned below
1 N-ACETYL CYSTEINE
The administration of N-acetylcysteine NAC a glutathione GSH precursor as a strategy to limit oxidative lung injury has been proposed since it increases the intracellular content of GSH Alterations in GSH metabolism in alveoli and lung tissue are a central feature in many lung diseases NAC increases the synthesis of GSH increases glutathione-S-transferase GST activity and has a direct action on free radicals ROS The application of NAC reduces levels of IL-8 IL-6 ICAM NAC in patients with septic shock is associated with a shorter time on mechanical ventilation and fewer days of stay in the ICU
The application of NAC reduces levels of IL-8 IL-6 ICAM NAC in patients with septic shock is associated with a shorter time on mechanical ventilation and fewer days of stay in the ICU NAC uptake and intracellular concentration can be increased through the use of liposomes L-NAC NAC supplementation in animals exposed to lipopolysaccharides LPS reduced lung edema lipoperoxidation OLP ACE damage chloramine concentration and concentrations of the eicosanoids thromboxane and leukotrienes LTB2 and LTB4 in the lung In clinical trials supplementation with a bolus of 150 mgkg NAC followed by 50 mgkgday of NAC for four days in patients with acute lung injury ALI or ARDS improved the oxygenation rate from day 1 to 4 and reduced mortality
2 MELATONIN
Melatonin MT has been shown to possess ROS-sequestering properties protects lipids in cell membranes cytosol proteins and nuclear and mitochondrial DNA
Furthermore in another study MT demonstrated anti-apoptotic antioxidant and pleiotropic anti-inflammatory effects in vitro and in vivo as direct elimination activity against ROS and stimulation of antioxidant enzymes such as CAT SOD GPx GR and gamma-glutamylcysteine synthase MT can accumulate within the mitochondria and thus reduce the local excess production of ROS which is typical in dysfunctional mitochondria during sepsis Based on these favorable preliminary data randomized control trials are warranted to assess TMs efficacy and safety as an add-on treatment in COVID-19 sepsis The previously mentioned studies have recommended its use in sepsis which should be considered in COVID-19 since it is also accessible and its cost is low making it possible to weigh the riskbenefit in the event of a pandemic
3 VITAMIN C
Ascorbic acid or vitamin C is a water-soluble antioxidant that functions as a cofactor for multiple enzymes It is absorbed at the intestinal level through the sodium-dependent transporter of vitamin C filtered freely in the glomerulus and reabsorbed at the proximal tubule level through the same transporter Ascorbic acid inhibits the production of superoxide O2- and peroxynitrite OONO- by inhibiting superoxide-producing NADPH oxidase O2- and inducible nitric oxide iNOS mRNA expression which prevents the abundant production of nitric oxide NO that generates peroxynitrite OONO- in the presence of O2-
4 PENTOXIFILINA
Pentoxifylline is a xanthine drug indicated in some severe alcoholic hepatitis it also acts on the plasma membrane of red blood cells and makes it more malleable thus improving blood perfusion Pentoxifylline exerts several antioxidant and anti-inflammatory activities such as reducing the restoration of GSH levels maintaining mitochondrial viability inhibiting the production of TNF-α preserving vascular endothelial functions and also supplementation with antioxidants has been reported better oxygenation rates higher GSH and more robust immune response Also there was a reduction in hospital stay length the time of mechanical ventilation the length of the ICU stays the multiple organ dysfunction rate and the mortality rate in patients with ALI ARDS
II Research question
Will the administration of adjuvant therapy with specific antioxidant and pentoxifylline in patients with or without septic shock secondary to severe pneumonia due to COVID-19 will it avoid the use of mechanical ventilation reduce the time of use of a mechanical ventilator days of hospital stay decrease the lipoperoxidation and will it increase the antioxidant capacity in patients admitted to intensive care
III Justification
In this COVID-19 pandemic severe pneumonia and septic shock are the leading cause of morbidity and mortality in intensive care units worldwide In this sense and based on the discoveries of recent years in the field of oxidative stress including those recently found in our group it is necessary to report results on new treatments capable of reducing the deleterious inflammatory response and the redox state In patients with pneumonia and septic shock The situation that currently occurs in patients who progress to severity due to infection with COVID-19
Septic shock has been presented in other viral diseases such as Middle East Respiratory Syndrome Coronavirus MERS-CoV detected for the first time in Saudi Arabia in which it exhibited a wide range of presentations at the time of diagnosis similar to SARS-COv2 from patients without symptoms subtle signs of pneumonia or multiorgan failure with the capacity to cause the death of which the possible therapeutic interventions with antioxidants have been proposed since then that have been proposed for the new virus through the conclusions based on systematic reviews
Many viral diseases such as SARS-CoV although clinical data are limited can develop moderate and severe septic shock and increase ROS and RNS production which is associated with overexpression of iNOS NADP oxidases cyclooxygenase two and xanthine oxidase which activates transcription factors such as NF-B resulting in an exacerbated pro-inflammatory host response Also O2 and ONOO participate as an essential mediator of pro-inflammatory interleukin production These will continue to stimulate the production and release of more ROS and RNS that can interfere with mitochondrial respiration since mitochondrial dysfunction is commonly induced in an environment of septic shock Therefore antioxidant treatment may be a way to avoid excessive inflammation associated with a history of high oxidation in COVID-19 patients
With this study we intend to evaluate the effect of the use of antioxidants on outcomes in storm regulation due to dysregulation of oxidative stress shortening of ventilator use days of stay and clinical repercussion through the measurement of organ dysfunction in six different systems using the SOFA score before and after the intervention in critically ill patients due to SARS-Cov2 infection
IV Hypothesis
It is hypothesized that adjuvant therapy with antioxidants and pentoxifylline reduces ventilator use in patients with or without septic shock secondary to severe COVID-19 pneumonia and decreases lipoperoxidation and corrects dysregulation of oxidative stress through the increase of antioxidant capacity
V Primary objective
Provide combined antioxidant therapy as an adjunct to standard therapy for patients with or without septic shock secondary to severe SARS-COV2 pneumonia to evaluate whether it is possible to avoid intubation reduce days of assisted mechanical ventilation and improve stress dysregulation oxidant leading to multiple organ failure
VI Secondary objective
1 Evaluate the prevalence of comorbidity in patients with or without septic shock and severe SARS-CoV2 pneumonia in the ICU
2 To evaluate the effect of adjuvant antioxidant therapy in reducing days with the ventilator and days of hospital stay in patients
3 Analyze the effect on organ failure in five devices and systems neurological respiratory hemodynamic hepatic hematological of each of the therapies implemented in the different systems evaluated with the SOFA score
4 Measure lipoperoxidation in basal and post-therapy samples
5 Measure the antioxidant capacity in basal and post-therapy samples
6 Measure IL-6 in basal and post-therapy samples
7 Measure procalcitonin CRP troponin pro-BNP ferritin and D-dimer
8 Determine the status of outcomes by comorbidity strata
9 Document the use of ARA ACE SGLT2 inhibitors in patients with COVID-19
10 Analyze the previous use of steroids and those who did not have it in a stratified way
VII Methodology
Study design
It is a quasi-experimental open analytical prospective and longitudinal before-after study
Sample size
The sample size calculation was based on studies that currently have mortality using Vitamin C because there is no history of antioxidants in the clinical context The sample size was calculated using X2 to compare two independent proportions
Therefore it will be necessary to include 11 patients in each group if desired to obtain 80 possibility 80 power or 32 if the power is 99 to detect a mean difference of 3 in SOFA between the groups On the other hand treatment will be possible in these patients it will be possible to measure the basal state of oxidative stress and state three after the therapy allows the use of small samples as the patient is his control
Statistic analysis
Continuous variables will be expressed as mean standard deviation or median with minimum and maximum depending on their distribution Categorical variables will be expressed as frequencies and percentages The normality of the variables will be evaluated using the Shapiro-Wilk or Shapiro-France test depending on the sample size Variables with normal distribution will be analyzed with parametric tests Students t-test for independent measurements or paired t-test for before-after measurements While various non-parametric tests were used Mann-Whitney test Kruskal-Wallis or Wilcoxon signed rank test depending on the particular case to contrast variables without Gaussian distribution Analysis of paired samples before-after will be performed with Friedman or Wilcoxon and paired t-test depending on the distribution of the data For multivariate analysis a binary logistic regression analysis will be performed Also an analysis of repeated samples and panel data testing different models grouped model model for longitudinal data marginal approximation model and multilevel model
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None