Clinical Trial of Pioglitazone Treatment in Patients With Type 2 Diabetes Mellitus and Covid-19

Study Overview
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Brief Summary
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The treatment with pioglitazone added to the standard treatment of patients with DM2 hospitalized for COVID-19 may produce a decrease in the number of patients who progress to a second phase of severe systemic inflammation.

Detailed Description
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According to the latest studies, the evolution of the SARS-CoV-2 (COVID-19) infection shows two clinically different phases: The first phase of viral and clinical infection of viriasis (fever, myalgia, etc.) affects all patients and it is resolved in asymptomatic patients or with clinically moderate-mild affectations. However, towards the end of the first week of illness, a not inconsiderable number of patients progress towards a second phase of rapid and abrupt deterioration of their respiratory and cardiac function. More and more data indicate an important role of overactivated macrophages, interleukin 6 (IL6) and an excessive inflammatory response in the genesis of this second phase of aggravation. Linking with this hypothesis, the adipose tissue densely infiltrated by macrophages is the source of one third of the body's IL6, its production being even greater in the fat of central disposition of male distribution. All of this could explain the worse prognosis observed in men, obese and with type 2 diabetes (DM2). Regarding the possible effect of pioglitazone on the expression of ACE2, there is little literature, and less evidence, about the response of this receptor to treatment with pioglitazone, and what is more important, its effect on COVID-19 infection. Two studies have analyzed the expression of this receptor after administration of pioglitazone in different murine models of liver and kidney disease. The conclusions of these studies were that the administration of pioglitazone in rats with hepatic steatosis increased the expression of ACE2. It is known that the increased expression of ACE2 facilitates the entry of SARS-CoV-2 into the cell, in animal models it has been seen that ACE2 protects against the development of respiratory distress syndrome and that severe cases of COVID-19 and SARS 2003 have been linked to the possible inhibition of ACE2 by the virus and the increase in angiotensin II. In conclusion, it is a safe and proven drug in patients with DM2, cheap, with years of clinical experience. The use of pioglitazone added to the conventional treatment of patients at high risk, such as patients with COVID-19 and DM2, could be accompanied by a better evolution of the patients, avoiding or mitigating the inflammatory process that already occurs before its onset. seems to trigger the second accelerated phase of the disease.

Official Title
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Non-blinded, Randomized and Controlled Clinical Trial of Pioglitazone Treatment in Patients With Type 2 Diabetes Mellitus and Covid-19

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Pioglitazone 30 mg
* Other: standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients > 18 years Confirmed diagnosis of COVID-19 or high clinical suspicion according to current criteria. Diagnosis prior to admission of DM2. Patients who provide their informed consent to participate in the study Exclusion Criteria: Under 18 years Known hypersensitivity to the active ingredient or any of the drug's excipients. Known history of heart failure or situation at the time of initiation of the heart failure study. Hepatic failure. Dialysis Situation of diabetic ketoacidosis at the start of the study. Diabetes mellitus different from type 2. Active bladder cancer or a history of bladder cancer Hematuria Patients included in another experimental study with another drug. Admission to the Intensive Care Unit. Patients requiring mechanical ventilation at the time of inclusion Pregnancy Lactation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pioglitazone<br> | Drug: Pioglitazone 30 mg<br>* Patients receive 30 mg/day of pioglitazone for the entire period they remain in hospital<br>|
| Other: Standard of care treatment<br> | Other: standard of care<br>* Patients receive the standard of care, according to the hospital protocol for patients with type 2 diabetes mellitus hospitalized.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients treated with pioglitazone, together with conventional treatment for COVID-19 infection, who during their admission evolve towards the need to receive support with mechanical ventilation, enter the ICU and / or die. | Number of patients receive pioglitazone treatment during their hospital stay who receive support with mechanical ventilation, enter the ICU and / or die. | Through hospitalization period, an average of 10-20 days until hospital discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of pioglitazone treatment-Emergent Adverse Events in patients with DM2 and symptomatic SARS-CoV-2 infection. | Proportion of patients who develop heart failure or adverse reaction associated with treatment. | Everyday through hospitalization period, an average of 10-20 days until hospital discharge | 
| Biomarker analysis: systemic inflammation parameters during the administration of pioglitazone treatment. | Changes in this inflammation parameter: C-reactive protein (in mg/dl) | Each 48 hours through hospitalization period, an average of 10-20 days until hospital discharge | 
| Biomarker analysis: systemic inflammation parameters during the administration of pioglitazone treatment. | Changes in this inflammation parameter: D-dimer (in μg/mL) | Each 48 hours through hospitalization period, an average of 10-20 days until hospital discharge | 
| Biomarker analysis: systemic inflammation parameters during the administration of pioglitazone treatment. | Changes in this inflammation parameter: ferritin (in ng/mL) | Each 48 hours through hospitalization period, an average of 10-20 days until hospital discharge | 
| Biomarker analysis: systemic inflammation parameters during the administration of pioglitazone treatment. | Changes in this inflammation parameter: creatine kinase (CK) (in mg/dL) | Each 48 hours through hospitalization period, an average of 10-20 days until hospital discharge | 
| Biomarker analysis: systemic inflammation parameters during the administration of pioglitazone treatment. | Changes in this inflammation parameter: number of lymphocytes (in μL) | Each 48 hours through hospitalization period, an average of 10-20 days until hospital discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pioglitazone, Covid19