The Effect of Sitagliptin Treatment in COVID-19 Positive Diabetic Patients

NCT ID: NCT04365517

Last Updated: 2021-09-28

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 170 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-29
• Study Completion Date: 2022-12-30

Brief Summary

The COVID-19 pathology is frequently associated with diabetes mellitus and metabolic syndrome. In the epidemic outbreak that exploded at the beginning of 2020 in the Lombardy Region, about two thirds of the patients who died from COVID-19 were affected by diabetes mellitus. COVID-19 occurs in 70% of cases with an inflammatory pathology of the airways that can be fed by a cytokine storm and result in severe respiratory failure (10% cases) and death (5%). The pathophysiological molecular mechanisms are currently not clearly defined. It is hypothesized that the transmembrane glycoprotein type II CD26, known for the enzyme activity Dipeptilpeptidase 4 of the extracellular domain, may play a main role in this condition. It is in fact considerably expressed at the level of parenchyma and pulmonary interstitium and carries out both systemic and paracrine enzymatic activity, modulating the function of various proinflammatory cytokines, growth factors and vasoactive peptides in the deep respiratory tract. Of particular interest is the fact that Dipeptilpeptidase 4 has been identified as a cellular receptor for S glycoprotein of MERS-COV. In the case of the SARS-COV 2 virus, the main receptor is the Angiotensin-Converting Enzyme 2 protein, but a possible interaction with Dipeptilpeptidase 4 also cannot be excluded. The selective blockade of Dipeptilpeptidase 4 could therefore favorably modulate the pulmonary inflammatory response in the subject affected by COVID-19. This protein is also known for the enzymatic degradation function of the native glucagon-like peptide 1, one of the main regulators of insulin secretion. This is why it is a molecular target in the treatment of diabetes (drugs that selectively inhibit Dipeptilpeptidase 4 are marketed with an indication for the treatment of type 2 diabetes). It is believed that the use of a Dipeptilpeptidase 4 inhibitor in people with diabetes and hospitalized for Covid-19 may be safe and of particular interest for an evaluation of the effects on laboratory and instrumental indicators of inflammatory lung disease. Among the drugs that selectively block Dipeptilpeptidase 4, the one with the greatest affinity is Sitagliptin.

Detailed Description

The investigators propose a randomized controlled open label intervention study. Patients hospitalized for COVID-19 and affected by type 2 diabetes mellitus will be included in the study and divided into two groups by randomization: sitagliptin add-on standard of care therapy with nutritional therapy with or without insulin treatment (study group) vs nutritional therapy with or without insulin treatment (group of control, standard therapy). The design of the study provides an open randomization to allow its feasibility in times compatible with the achievement of adequate cases during the epidemic. The presence of placebo and a double-blind study, would lead to longer planning and enrollment times.

Patients with type 2 diabetes mellitus hospitalized for COVID-19 and randomized to the study group will be treated with sitagliptin at an adjusted dosage for estimated glomerular filtrate: 100 mg once daily (estimated glomerular filtration rate less than or equal to 45 mL / min / 1.73 m2) or 50 mg (estimated glomerular filtration rate 30-45 mL / min / 1.73 m2) in combination or not with insulin treatment. Patients with stage IV and V renal impairment (estimated glomerular filtration rate less than or equal to 30 mL / min / 1.73 m2) will be excluded. Enrolled patients will be followed according to the following scheme:

Time points:

• T0: The doctor explains the protocol to the patient and he gives to him the informed consent and the letter to the general practitioner.
• T1: The patient gives the signed and dated consent and officially enters the study. Basic assessments will be made. At the baseline, the clinical response, the main laboratory and instrumental tests will be taken into consideration. Biological samples will be taken for immunological study. Diabetic patients will begin treatment with Sitagliptin 100 or 50 mg add-on to nutritional therapy and, eventually, insulin treatment. Any other hypoglycemic agents taken before admission will be suspended.
• T2: 7 days after T1, for both groups of patients, evaluation of the clinical response, of the average daily blood glucose levels, of the main laboratory and instrumental tests.
• T3: 10 days after T2, for both groups of patients, evaluation of clinical response, average daily blood glucose levels, of the main laboratory and instrumental tests. Collection of biological samples for immunological study. End of the study.

Conditions

Covid19; Diabetes Mellitus, Type 2; CKD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment group

patients will be treated with sitagliptin add on to nutritional therapy with o without insulin treatment. The dose of sitagliptin will be established on the basis of the estimated glomerular filtrate: 100 mg in single daily administration (estimated glomerular filtration rate less than or equal to 45 mL / min / 1.73 m2) or 50 mg (estimated glomerular filtration rate 30-45 mL / min / 1.73 m2) in combination or not with insulin. Patients with stage IV and V renal failure (estimated glomerular filtration rate less than or equal to 30 mL / min / 1.73 m2) will be excluded

Group Type: ACTIVE_COMPARATOR

Sitagliptin

Intervention Type: DRUG

We propose a randomized controlled open label intervention study. Patients with type 2 diabetes admitted to COVID-19 and randomized to the study group will be treated with sitagliptin at an adjusted dosage for estimated glomerular filtrate: 100 mg once daily (estimated glomerular filtration rate less than or equal to 45 mL / min / 1.73 m2 ) or 50 mg (estimated glomerular filtration rate 30-45 mL / min / 1.73 m2) in combination or not with insulin. Patients with stage IV and V renal failure (estimated glomerular filtration rate less than or equal to 30 mL / min / 1.73 m2) will be excluded

Control group

Patients who will be prescribed nutritional therapy with or without insulin treatment

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Sitagliptin

We propose a randomized controlled open label intervention study. Patients with type 2 diabetes admitted to COVID-19 and randomized to the study group will be treated with sitagliptin at an adjusted dosage for estimated glomerular filtrate: 100 mg once daily (estimated glomerular filtration rate less than or equal to 45 mL / min / 1.73 m2 ) or 50 mg (estimated glomerular filtration rate 30-45 mL / min / 1.73 m2) in combination or not with insulin. Patients with stage IV and V renal failure (estimated glomerular filtration rate less than or equal to 30 mL / min / 1.73 m2) will be excluded

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Diagnosis of type 2 diabetes, according to ADA 2020 criteria
• HbA1c levels at the entrance or in the two previous months <9%
• Diagnosis of Covid-19 (swab for positive SARS-COV2 RNA) with pneumonia, with or without increase in inflammation indexes, with or without respiratory failure
• No indication for tocilizumab therapy (BCRSS, Brescia Covid Respiratory Severity Scale, <3).
• Written and dated informed consent from the patient or his legally valid representative

Exclusion Criteria

• Pregnancy
• Type 1 diabetes
• Stage IV and V renal failure (stimated glomerular filtration rate <30 ml / min)
• Treatment with Dipeptidyl peptidase-4 inhibitors or GLP-1 Receptor Agonists in the month prior to hospitalization
• Pioglitazone treatment in the month prior to hospitalization
• Treatment in the month preceding or in the course of hospitalization with "biological" drugs for immuno-rheumatological diseases (in particular tocilizumab)
• Presence of other acute or chronic ongoing infections
• Neurological or psychiatric diseases, diagnosis of hemoglobinopathy, diagnosis of liver disease, cancer, cystic fibrosis or malabsorption syndrome
• Dysphagia with need for artificial nutrition
• Positive history of acute and chronic pancreatitis
• Unstable cardiovascular disease or known atherosclerotic disease
• A history of alcohol or drug abuse
• Known human immunodeficiency virus (HIV) or hepatitis
• Presence of serious diseases or conditions that make the patient unsuitable for the study
• Surgery in the previous two weeks

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Milan

OTHER

Sponsor Role: lead

Responsible Party

Paolo Fiorina, MD

Director of Endocrinology and Diabetology ASST FBF Sacco

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Paolo Fiorina, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Milan

Locations

ASST FBF Sacco

Milan, , Italy

Countries

Italy

Central Contacts

Teresa Letizia, Dr.

Role: CONTACT

letizia.teresa@asst-fbf-sacco.it

02 39042648

Facility Contacts

Teresa Letizia, Dr.

Role: primary

letizia.teresa@asst-fbf-sacco.it

02 39042648

References

Yang JK, Feng Y, Yuan MY, Yuan SY, Fu HJ, Wu BY, Sun GZ, Yang GR, Zhang XL, Wang L, Xu X, Xu XP, Chan JC. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet Med. 2006 Jun;23(6):623-8. doi: 10.1111/j.1464-5491.2006.01861.x.

Reference Type: BACKGROUND

PMID: 16759303 (View on PubMed)

Perlman S, Azhar EI, Memish ZA, Hui DS, Zumla A. Confronting the persisting threat of the Middle East respiratory syndrome to global health security. Lancet Infect Dis. 2020 Feb;20(2):158-160. doi: 10.1016/S1473-3099(19)30347-0. Epub 2019 Jul 3. No abstract available.

Reference Type: BACKGROUND

PMID: 31279728 (View on PubMed)

Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? Lancet. 2020 Apr 11;395(10231):1225-1228. doi: 10.1016/S0140-6736(20)30627-9. Epub 2020 Mar 13.

Reference Type: BACKGROUND

PMID: 32178769 (View on PubMed)

Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-481. doi: 10.1016/S2213-2600(20)30079-5. Epub 2020 Feb 24.

Reference Type: BACKGROUND

PMID: 32105632 (View on PubMed)

Zou H, Zhu N, Li S. The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease. Expert Opin Ther Targets. 2020 Feb;24(2):147-153. doi: 10.1080/14728222.2020.1721468. Epub 2020 Jan 31.

Reference Type: BACKGROUND

PMID: 31971463 (View on PubMed)

Meyerholz DK, Lambertz AM, McCray PB Jr. Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome. Am J Pathol. 2016 Jan;186(1):78-86. doi: 10.1016/j.ajpath.2015.09.014. Epub 2015 Nov 18.

Reference Type: BACKGROUND

PMID: 26597880 (View on PubMed)

Ikeda T, Kumagai E, Iwata S, Yamakawa A. Soluble CD26/Dipeptidyl Peptidase IV Enhances the Transcription of IL-6 and TNF-alpha in THP-1 Cells and Monocytes. PLoS One. 2013 Jun 21;8(6):e66520. doi: 10.1371/journal.pone.0066520. Print 2013.

Reference Type: BACKGROUND

PMID: 23805228 (View on PubMed)

Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013 Mar 14;495(7440):251-4. doi: 10.1038/nature12005.

Reference Type: BACKGROUND

PMID: 23486063 (View on PubMed)

Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 Apr;46(4):586-590. doi: 10.1007/s00134-020-05985-9. Epub 2020 Mar 3. No abstract available.

Reference Type: BACKGROUND

PMID: 32125455 (View on PubMed)

Vankadari N, Wilce JA. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect. 2020 Mar 17;9(1):601-604. doi: 10.1080/22221751.2020.1739565. eCollection 2020.

Reference Type: BACKGROUND

PMID: 32178593 (View on PubMed)

Kulcsar KA, Coleman CM, Beck SE, Frieman MB. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 2019 Oct 17;4(20):e131774. doi: 10.1172/jci.insight.131774.

Reference Type: BACKGROUND

PMID: 31550243 (View on PubMed)

Li K, Wohlford-Lenane CL, Channappanavar R, Park JE, Earnest JT, Bair TB, Bates AM, Brogden KA, Flaherty HA, Gallagher T, Meyerholz DK, Perlman S, McCray PB Jr. Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):E3119-E3128. doi: 10.1073/pnas.1619109114. Epub 2017 Mar 27.

Reference Type: BACKGROUND

PMID: 28348219 (View on PubMed)

Other Identifiers

Sacco FBF

Identifier Type: -

Identifier Source: org_study_id