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Effects of COVID-19 Infection on Beta-cell Function in Euglycemic Patients (COBETOX)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04463849
Recruitment Status : Recruiting
First Posted : July 9, 2020
Last Update Posted : July 9, 2020
Sponsor:
Collaborator:
Luigi Sacco University Hospital
Information provided by (Responsible Party):
Paolo Fiorina, MD, University of Milan

Brief Summary:

In recent months, a new coronavirus, SARS-CoV-2, has been identified as the cause of a serious lung infection named COVID-19 by the World Health Organization. This virus has spread rapidly among the nations of the world and it is the cause of a pandemic and a global health emergency. There is still very little scientific evidence on the virus, however epidemiological data suggest that one of the most frequent comorbidities is diabetes, along with hypertension and heart disease. There is no scientific evidence on the possible effects of this infection on the function of the β cell and on glycemic control. Clinical evidence seems to suggest that COVID-19 infection mostly affects the respiratory system, and an acute worsening of glycemic compensation is not described as generally observed in bacterial pneumonia. However, previous work on acute respiratory syndromes (SARS) caused by similar coronaviruses, had described that the infection has multi-organ involvement related to the expression of the SARS coronavirus receptor, the angiotensin 2 converting enzyme, in different organs, especially at the level of endocrine pancreatic tissue. In the population of this previous work, glucose intolerance and fasting hyperglycaemia have been described and in 37 of 39 diabetic patients examined, a remission of diabetes was observed three years after the infection. It is possible that the coronaviruses responsible for SARS may enter the pancreatic islets using the angiotensin 2 converting enzyme receptor, expressed at the level of the endocrine pancreas, thus causing diabetes. Additionally, previous literature on coronavirus infections (SARS and MERS or Middle-East Respiratory Syndrome) suggested that diabetes could worsen the evolution of the disease. In particular, in case of Middle-East Respiratory Syndrome-CoV infection, diabetic mice had a more prolonged serious illness and a delay in recovery regardless of the viremic titer. This could probably be due to a dysregulation of the immune response, which results in more serious and prolonged lung disease.

There are currently no data on pancreatic beta cell function in patients with COVID-19.


Condition or disease Intervention/treatment Phase
COVID19 BETA-CELL FUNCTION Diagnostic Test: Stimulation test with arginine infusion in order to verify the possible existence of damage to the beta cell function induced by COVID-19 infection Not Applicable

Detailed Description:

The project is monocentric, interventional, non-pharmacological, non-profit. Patients will be enrolled in hospital for confirmed COVID-19 infection (with reverse transcriptase-polymerase chain reaction on the airway swab) but with normal basal blood glucose and no previous history of diabetes or impaired fasting glucose or impaired glucose tolerance. Patients will be compared to a control group of healthy volunteers, not affected by COVID-19 and with no previous history of diabetes or impaired fasting glucose or impaired glucose tolerance. Once the informed consent has been signed, the clinical parameters and biochemical parameters will be collected according to the time points provided by the protocol both in positive COVID-19 patients and in healthy volunteers.

COVID-19 positive patients and healthy controls will undergo a stimulation test of β-cell function (evaluation of the secretive response of insulin to the stimulation test with arginine infusion) and the monitoring of glycemic values through a professional retrospective continuous glucose monitoring. For the test, an infusion solution containing 25% arginine hydrochloride will be used, arginine is an insulinogenic amino acid, useful to verify the possible existence of damage to the cellular beta function induced by COVID-19 infection, clinically observable with changes in insulin secretory response. Given the usefulness of the test, performed for diagnostic purposes, this protocol is identified as "non-pharmacological". The test is contraindicated only in patients with severe hepatic and renal insufficiency, in all other subjects the side effects are minimal and spontaneous resolution before the end of the test (flushing 33%, oral paraesthesia 46%, nausea 12%, dizziness 14%). For the stimulation test with arginine infusion, after the basal sampling at (0 minutes), an intravenous injection of arginine 5 grams will be practiced in 60 seconds followed by serial withdrawals at +2, +5, +10 and +30 minutes. The following analytes will be assayed on the basal sample: glycosylated hemoglobin, glycaemia, insulin, pro-insulin, C-peptide, glucagon, serum inflammatory cytokines (Il1β, IL-2, IL-6, IL-7, IL-10, TNF- α, IFN-γ, MIP-1β, MCP-1, GM-CSF, G-CSF Insulin, C-peptide and glucagon will be dosed on all points of the curve.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Effects of SARS-CoV-2 Infection on Beta-cell Function in Euglycemic Patients
Actual Study Start Date : June 30, 2020
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Arginine

Arm Intervention/treatment
Experimental: COVID-19 positive patients
Patients will be enrolled in hospital for confirmed COVID-19 infection (with reverse transcriptase-polymerase chain reaction on the airway swab) but with normal basal glucose and no previous history of diabetes or impaired fasting glucose or impaired tolerance glucose. Patients will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.
Diagnostic Test: Stimulation test with arginine infusion in order to verify the possible existence of damage to the beta cell function induced by COVID-19 infection

All participants will be subjected to the collection of glycemic data through continuous professional retrospective monitoring of blood glucose for seven days, positioned on the day the test will be performed. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.

The evaluation of insulin secretion will be evaluated by performing the stimulus test with arginine infusion according to validated protocols.

Other Name: Positioning of the device for glycemic monitoring

Healthy volunteers
Healthy volunteers, not affected by COVID-19 and with no previous history of diabetes or impaired fasting glucose or impaired glucose tolerance will be enrolled. Healthy volunteers will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.
Diagnostic Test: Stimulation test with arginine infusion in order to verify the possible existence of damage to the beta cell function induced by COVID-19 infection

All participants will be subjected to the collection of glycemic data through continuous professional retrospective monitoring of blood glucose for seven days, positioned on the day the test will be performed. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.

The evaluation of insulin secretion will be evaluated by performing the stimulus test with arginine infusion according to validated protocols.

Other Name: Positioning of the device for glycemic monitoring




Primary Outcome Measures :
  1. Serum β - cellular function index insulin levels [ Time Frame: 12 months ]
    Difference in insulin levels during and after COVID-19 infection and compared to patients in the control group

  2. Serum β - cellular function index C-peptide levels [ Time Frame: 12 months ]
    Difference in C-peptide levels during and after COVID-19 infection and compared to patients in the control group

  3. Serum β - cellular function HOMA-β index [ Time Frame: 12 months ]
    Difference in HOMA-β index during and after COVID-19 infection and compared to patients in the control group

  4. Serum β - cellular function pro-insulin/insulin ratio [ Time Frame: 12 months ]
    Difference in pro-insulin/insulin ratio during and after COVID-19 infection and compared to patients in the control group

  5. Evaluation of the secretory response of insulin to the arginine stimulation test [ Time Frame: 12 months ]
    Check for the existence of damage to the beta cell function induced by COVID-19 infection, clinically observable with changes in the secretory response of insulin

  6. Viral SARS-CoV-2 particles in β cells [ Time Frame: 12 months ]
    Presence of SARS-CoV-2 viral particles in β cells in COVID-19 patient samples

  7. Percentage of patients with preserved β cells function [ Time Frame: 12 months ]
    Evidence of impairment of β cell function in the serum of COVID-19 patients


Secondary Outcome Measures :
  1. Glucose values [ Time Frame: 12 months ]
    Changes in glucose values in COVID-19 patients and healthy volunteers

  2. Values of continuous glucose monitoring [ Time Frame: 12 months ]
    Changes in the values of continuous glucose monitoring in both COVID-19 patients and healthy volunteers

  3. Changes in the inflammatory marker interleukin 1-β [ Time Frame: 12 months ]
    Comparison of interleukin 1-β levels in COVID-19 patients compared with healthy subjects

  4. Changes in the inflammatory marker interleukin IL-2 [ Time Frame: 12 months ]
    Comparison of interleukin IL-2 levels in COVID-19 patients compared with healthy subjects

  5. Changes in the inflammatory marker interleukin IL-6 [ Time Frame: 12 months ]
    Comparison of interleukin IL-6 levels in COVID-19 patients compared with healthy subjects

  6. Changes in the inflammatory marker interleukin IL-7 [ Time Frame: 12 months ]
    Comparison of interleukin IL-7 levels in COVID-19 patients compared with healthy subjects

  7. Changes in the inflammatory marker interleukin IL-10 [ Time Frame: 12 months ]
    Comparison of interleukin IL-10 levels in COVID-19 patients compared with healthy subjects

  8. Changes in the inflammatory marker tumor necrosis factor-α [ Time Frame: 12 months ]
    Comparison of interleukin tumor necrosis factor-α levels in COVID-19 patients compared with healthy subjects

  9. Changes in the inflammatory marker interferon gamma [ Time Frame: 12 months ]
    Comparison of interferon gamma levels in COVID-19 patients compared with healthy subjects

  10. Changes in the inflammatory marker macrophage inflammatory protein-1β [ Time Frame: 12 months ]
    Comparison of macrophage inflammatory protein-1β levels in COVID-19 patients compared with healthy subjects

  11. Changes in the inflammatory marker monocyte chemoattractant protein-1 [ Time Frame: 12 months ]
    Comparison of macrophage inflammatory monocyte chemoattractant protein-1 in COVID-19 patients compared with healthy subjects

  12. Changes in the inflammatory marker granulocyte-macrophage colony-stimulating factor [ Time Frame: 12 months ]
    Comparison of macrophage inflammatory granulocyte-macrophage colony-stimulating factor in COVID-19 patients compared with healthy subjects

  13. Changes in the inflammatory marker granulocyte colony-stimulating factor [ Time Frame: 12 months ]
    Comparison of macrophage inflammatory granulocyte colony-stimulating factor in COVID-19 patients compared with healthy subjects



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria for COVID-19 positive patients

  • Male and female patients with COVID19 and normal basal blood sugar, unprecedented in diabetes or impaired fasting glucose or impaired glucose tolerance
  • Age> 18 years and <80 years
  • Availability to informed consent and corporate privacy

Inclusion criteria for healthy subjects

  • Male and female patients not affected by COVID19, unprecedented in diabetes or impaired fasting glucose or impaired glucose tolerance
  • Age> 18 years and <80 years
  • Availability to informed consent and corporate privacy

Exclusion criteria for COVID-19 positive patients

  • Age <18 years
  • Previous history of diabetes or impaired fasting glucose or impaired glucose tolerance
  • Severe liver failure
  • Severe kidney failure

Exclusion criteria for healthy subjects

  • Age <18 years
  • Previous history of diabetes or impaired fasting glucose or impaired glucose tolerance
  • Positivity to the nasopharyngeal swab for SARS-CoV-2
  • Severe liver failure
  • Severe kidney failure

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): NCT04463849


Contacts
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Contact: Paolo Fiorina, MD, PhD 0239042648 paolo.fiorina@unimi.it
Contact: Teresa Letizia, Dr. 0239042648 teresa.letizia@unimi.it

Locations
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Italy
Sacco University Hospital Recruiting
Milan, MI, Italy, 20157
Contact: Paolo Fiorina, MD, PhD    0239042648    paolo.fiorina@unimi.it   
Contact: Teresa Letizia, Dr.    0239042648    teresa.letizia@unimi.it   
Principal Investigator: Paolo Fiorina, MD, PhD         
Sponsors and Collaborators
University of Milan
Luigi Sacco University Hospital
Publications:

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Responsible Party: Paolo Fiorina, MD, Clinical Professor, University of Milan
ClinicalTrials.gov Identifier: NCT04463849    
Other Study ID Numbers: 6/2020
First Posted: July 9, 2020    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
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
Additional relevant MeSH terms:
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Infection