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Antioxidants as Adjuvant Therapy to Standard Therapy in Patients With COVID-19 (ANTIOX-COVID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04570254
Recruitment Status : Completed
First Posted : September 30, 2020
Last Update Posted : May 21, 2021
Sponsor:
Collaborators:
Instituto Nacional de Cardiologia Ignacio Chavez
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Information provided by (Responsible Party):
Adrian Palacios-Chavarria, MD, Unidad Temporal COVID-19 en Centro Citibanamex

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.


Condition or disease Intervention/treatment Phase
Pneumonia, Viral Covid19 ARDS Oxidative Stress Drug: Vitamin C Drug: Vitamin E Drug: Melatonin Drug: N-acetyl cysteine Drug: Pentoxifylline Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 110 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: septic shock and without septic shock will be divided into two groups. An antioxidant will be administered orally or by orogastric tube (vitamin C, melatonin, n-acetylcysteine, vitamin E) plus pentoxifylline. Following a decision tree that the treating physician will follow.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: They will be blinded to the patient's treatment, the patient or participant, the investigator, and the outcome assessor. You will only receive the participant number during the analysis. The care provider will not be blinded; they will know which antioxidant plus pentoxifylline the patient will receive; however, they will not have access to the results until the clinical trial is concluded.
Primary Purpose: Treatment
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
Actual Study Start Date : August 19, 2020
Actual Primary Completion Date : December 1, 2020
Actual Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Patients with septic shock

Only one antioxidant will be administered, which the treating physician will decide following a previously established decision tree plus pentoxifylline via an oral or orogastric tube for five days.

With the following specifications:

  1. Vitamin C. Tablet of 1 gr. A dose of 1 gr every 12 hours.
  2. Vitamin E. 800 mg tablet. 800 mg dose every 24 hours.
  3. Melatonin. Tablet 5 mg. A dose of 50 mg every 24 hours.
  4. N-acetylcysteine. Tablet 600 mg. 600 mg dose every 12 hours.

The dose of pentoxifylline that all patients will receive is as follows:

a) Pentoxifylline. 400 mg tablets. 400 mg dose every 12 hours.

Drug: Vitamin C
Vitamin C. Tablet of 1 gr. A dose of 1 gr every 12 hours. Dissolve one tablet in a volume of 30 ml of water and administer it immediately, then rinse the glass with 10 ml of water and administer it to the patient. Protect from light at all times, as it is photosensitive.
Other Name: Antioxidant option 1

Drug: Vitamin E
Vitamin E. 800 mg tablet. 800 mg dose every 24 hours. Dissolve the capsule in 30 ml of hot water. The administration of vitamin E is recommended during or after meals since its absorption depends on pancreatic enzymes' presence.
Other Name: Antioxidant option 2

Drug: Melatonin
Melatonin Tablet 5 mg. A dose of 50 mg every 24 hours. Grind the 10 5 mg melatonin tablets (50 mg), levitate with 50 mL of Ora-plus (Transferring to a beaker with a magnetic stirrer). Maintain gentle agitation. "Rinse" the mortar with 10 mL of Ora-sweet. Add 30 mL of Ora sweet to the glass where the mixture is being made. Makeup with Ora-sweet cbp 100 mL Place label FL02 with legend Melatonin 50 mg / 20 mL. Protected from light (Dispense in a black bag that covers the transparent bag of the preparation)'s primary packaging) Give after breakfast.
Other Name: Antioxidant option 3

Drug: N-acetyl cysteine
N-acetylcysteine. Tablets, 600 mg. 600 mg dose every 12 hours. Dissolve one tablet in a volume of 30 ml of water and administer it immediately, then rinse the glass with 10 ml of water and administer it to the patient.
Other Name: Antioxidant option 4

Drug: Pentoxifylline
Pentoxifylline. 400 mg tablets. 400 mg dose every 12 hours. The tablet is dissolved in 30 ml of water and is administered orally or nasogastric tube.
Other Name: Pentofifylline ER

Experimental: Patients without septic shock

Only one antioxidant will be administered, which the treating physician will decide following a previously established decision tree plus pentoxifylline via an oral or orogastric tube for five days.

With the following specifications:

  1. Vitamin C. Tablet of 1 gr. A dose of 1 gr every 12 hours.
  2. Vitamin E. 800 mg tablet. 800 mg dose every 24 hours.
  3. Melatonin. Tablet 5 mg. A dose of 50 mg every 24 hours.
  4. N-acetylcysteine. Tablet 600 mg. 600 mg dose every 12 hours.

The dose of pentoxifylline that all patients will receive is as follows:

a) Pentoxifylline. 400 mg tablets. 400 mg dose every 12 hours.

Drug: Vitamin C
Vitamin C. Tablet of 1 gr. A dose of 1 gr every 12 hours. Dissolve one tablet in a volume of 30 ml of water and administer it immediately, then rinse the glass with 10 ml of water and administer it to the patient. Protect from light at all times, as it is photosensitive.
Other Name: Antioxidant option 1

Drug: Vitamin E
Vitamin E. 800 mg tablet. 800 mg dose every 24 hours. Dissolve the capsule in 30 ml of hot water. The administration of vitamin E is recommended during or after meals since its absorption depends on pancreatic enzymes' presence.
Other Name: Antioxidant option 2

Drug: Melatonin
Melatonin Tablet 5 mg. A dose of 50 mg every 24 hours. Grind the 10 5 mg melatonin tablets (50 mg), levitate with 50 mL of Ora-plus (Transferring to a beaker with a magnetic stirrer). Maintain gentle agitation. "Rinse" the mortar with 10 mL of Ora-sweet. Add 30 mL of Ora sweet to the glass where the mixture is being made. Makeup with Ora-sweet cbp 100 mL Place label FL02 with legend Melatonin 50 mg / 20 mL. Protected from light (Dispense in a black bag that covers the transparent bag of the preparation)'s primary packaging) Give after breakfast.
Other Name: Antioxidant option 3

Drug: N-acetyl cysteine
N-acetylcysteine. Tablets, 600 mg. 600 mg dose every 12 hours. Dissolve one tablet in a volume of 30 ml of water and administer it immediately, then rinse the glass with 10 ml of water and administer it to the patient.
Other Name: Antioxidant option 4

Drug: Pentoxifylline
Pentoxifylline. 400 mg tablets. 400 mg dose every 12 hours. The tablet is dissolved in 30 ml of water and is administered orally or nasogastric tube.
Other Name: Pentofifylline ER




Primary Outcome Measures :
  1. Death from any cause [ Time Frame: From admission to discharge, up to 30 days. ]
    It will be evaluated whether secondary to SARS-COV2 pneumonia, the outcome of the patient is dead.

  2. Percentage of patients who required orotracheal intubation [ Time Frame: From admission to discharge, up to 1 week ]
    The percentage of patients with SARS-COV2 pneumonia in whom orotracheal intubation was avoided will be evaluated.

  3. Assisted mechanical ventilation [ Time Frame: From admission to discharge, up to 1 week ]
    It will be evaluated if it is possible to reduce the days of mechanical ventilation

  4. Stay in an intensive care unit [ Time Frame: From admission to discharge, up to 1 week ]
    The number of days of stay in the intensive care unit will be evaluated.


Secondary Outcome Measures :
  1. Measure lipoperoxidation in basal and post-therapy samples [ Time Frame: Baseline and 5 days post-dose ]
    For the measurement of lipid peroxidation, 50 µL of CH3-OH with 4% BHT plus a phosphate buffer pH 7.4 was added to 100 µL of plasma. The mixture was vigorously vortexed for 5 seconds and subsequently incubated in a water bath at 37 ° C for 30 minutes. 1.5 mL of 0.8 M tribarbituric acid was added to the sample, which was incubated in a water bath with boiling temperature for one hour. After this time and to stop the reaction, the sample was placed on ice; 1 mL 5% KCl was added to each sample, as was 4 mL of n-butanol; The sample was vortexed for 30 seconds and centrifuged at 4000 rpm at room temperature for 2 min. Subsequently, the butanol phase was extracted, and the absorbance at 532 nm was measured. The calibration curve was obtained using tetra ethoxy propane as a standard.

  2. Evaluation of the total antioxidant capacity [ Time Frame: Baseline and 5 days post-dose ]
    100 mL of plasma was suspended in 1.5 mL of a reaction mixture prepared as follows: 300 mM of acetate buffer with pH 3.6, 20 mM of ferric chloride hexahydrate, and 10 mM of 2,4,6-Tris-2- Pyridyl-s-triazine dissolved in 40 mM hydrochloric acid in a ratio 10: 1: 1 v / v, respectively. The mixture was vigorously vortexed for 5 seconds. It was incubated at 37 ° C for 15 min in the dark. The absorbance was measured at 593 nm. The calibration curve was obtained using Trolox

  3. Oxidative and antioxidant stress [ Time Frame: Baseline and 5 days post-dose ]
    For the measurement of NO3- / NO2-, 100 µl of plasma were added 100 µL of a 10% solution of ZnSO4, 100 µL of 0.5 N NaOH and 700 µl of tridestated water. It was shaken vigorously and centrifuged at 10,000 rpm for 5 minutes. To the resulting supernatant, Griess reagent (200 µL of 1% sulfanilamide and 200 µL of 1% N- (1-naphthyl) ethylenediamine hydrochloride) was added and incubated for 10 min protected from light at room temperature. The coloration developed after incubation was measured at an analytical wavelength of 540 nm in a double beam UV-Vis spectrometer (DW2000, SLM-Aminco, Urbana, Illinois, USA). The calibration curve was performed with a KNO3 stock solution (Spectrum Quality Products, Inc., Gardena CA) in a concentration range from 0.001 nM to 10 nM.

  4. Effect of antioxidant therapy at the level on organ failure secondary to SARS-COV2 [ Time Frame: From day 0 to day 7 post antioxidant dose. ]
    Measurements will be made using the Sequential Organ Failure Assessment (SOFA) every 24 hours. With a minimum score of 0-1 which translates a mortality in initial score and the highest of 0%. The maximum score of more than 14 translates a mortality of 95.2% in the initial evaluation and 89.7% in the highest evaluation.

  5. Effect of antioxidant therapy at the level on organ failure secondary to SARS-COV2 [ Time Frame: From day 0 to day 7 post antioxidant dose. ]
    Measurements will be made using the Mexico Sequential Organ Failure Assessment (MEXSOFA) every 24 hours. highest evaluation. Patients with an initial MEXSOFA score of 9 points or less calculated during the first 24 hours after admission to the ICU had a mortality rate of 14.8%, while those with an initial MEXSOFA score of 10 points or more had a mortality rate. 40% mortality rate. The MEXSOFA score at 48 h was also associated with mortality: patients with a score of 9 points or less had a mortality rate of 14.1%, while those with a score of 10 points or more had a rate of 50% mortality.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients admitted to the UTC in the Temporary COVID-19 Citibanamex Center with suspected or diagnosed severe pneumonia due to SARS-COV2 with or without septic shock.
  • Patients who accept and sign informed consent. If the patient is clinically unable to authorize, acceptance by a first-degree relative will be requested.
  • Diagnosis of septic shock in the last 24 hours characterized by refractory hypotension and vasopressor requirement despite adequate fluid resuscitation (20 mL/kg of colloids or 40 mL/kg of crystalloids) to maintain a blood pressure ≥ 65 mmHg with lactate> two mmol / L.

Exclusion Criteria:

  • Patients with an advance directive format.
  • Chronic use of steroids in the past six months or recent.
  • Use of statins before admission.
  • Patients who are under some antioxidant treatment.
  • Any contraindication for the use of Vit C, Vit E, NAC, and melatonin.
  • Pregnant women.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04570254


Locations
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Mexico
Unidad Temporal COVID-19 en Centro Citibanamex
Mexico City, Mexico, 11200
Sponsors and Collaborators
Unidad Temporal COVID-19 en Centro Citibanamex
Instituto Nacional de Cardiologia Ignacio Chavez
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Investigators
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Study Director: Maria Elena Soto Lopez, PhD mesoto50@hotmail.com
Principal Investigator: Adrián Palacios Chavarria, MD Unidad Temporal COVID-19 en Centro Citibanamex
Study Chair: José Guillermo Domínguez Cherit, MD Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Publications of Results:

Other Publications:

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Responsible Party: Adrian Palacios-Chavarria, MD, Principal investigator, Unidad Temporal COVID-19 en Centro Citibanamex
ClinicalTrials.gov Identifier: NCT04570254    
Other Study ID Numbers: 09-CEI-011-20160627
First Posted: September 30, 2020    Key Record Dates
Last Update Posted: May 21, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Adrian Palacios-Chavarria, MD, Unidad Temporal COVID-19 en Centro Citibanamex:
SARS-COV2
Pneumonia
ARDS
Antioxidants
Additional relevant MeSH terms:
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COVID-19
Pneumonia
Pneumonia, Viral
Respiratory Tract Infections
Infections
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Vitamins
Vitamin E
Acetylcysteine
Pentoxifylline
Melatonin
Antioxidants
N-monoacetylcystine
Micronutrients
Physiological Effects of Drugs
Molecular Mechanisms of Pharmacological Action
Protective Agents
Central Nervous System Depressants
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Platelet Aggregation Inhibitors
Radiation-Protective Agents
Vasodilator Agents
Free Radical Scavengers