Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Diabetic Patients With Established COVID-19

The coronavirus disease 2019 (COVID-19) is an emerging pandemic in 2020 caused by a novel coronavirus named SARS-CoV2. Diabetes confers a significant additional risk for COVID-19 patients. Dipeptidyl peptidase 4 (DPP-4) is a transmembrane glycoprotein expressed ubiquitously in many tissues. In addition to its effect on glucose levels, DPP-4 has various effects on the immune system and several diseases, including lung diseases. This trial aims to assess the safety and efficacy of linagliptin, a DPP-4 inhibitor, in the treatment of COVID-19. The trial will be randomized without blinding, with one are treated by insulin only for glucose balance and the other by insulin and linagliptin. The trial will assess the effects of linagliptin on different measures of COVID-19 recovery.

Study Overview

• Status: Terminated
• Conditions: Glucose Metabolism Disorders; Respiratory Tract Diseases; Diabetes Mellitus, Type 2; Diabetes Mellitus; Endocrine System Diseases; COVID 19; Coronavirus; Metabolic Disease; Severe Acute Respiratory Syndrome Coronavirus 2; Sars-CoV2; Hormones; Hypoglycemic Agents; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Linagliptin
• Intervention / Treatment: Drug: Linagliptin 5 MG

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 3

Contacts and Locations

Study Locations

• Israel
  • Be'er Ya'aqov, Israel
    • Shamir Medical Center
  • Petah tikva, Israel
    • Rabin Medical Center, Beilinson Campus
  • Petah tikva, Israel
    • Rabin Medical Center, Hasharon Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years.
2. History of or type 2 diabetes mellitus or a diagnosis of type 2 diabetes during hospitalization.
3. Confirmation of infection with SARS-CoV-2 by PCR testing.
4. Patients within 10 days from symptom onset or patients within 48 hours after laboratory diagnosis (SARS-CoV-2 PCR).

Exclusion Criteria:

1. WHO COVID-19 Ordinal Scale for Clinical Improvement ≥ 6.
2. Respiratory failure requiring mechanical ventilation prior to randomization.
3. Use of vasopressor or inotropic medications prior to randomization.
4. Intolerance/hypersensitivity to dipeptidyl peptidase-4 inhibitors.
5. Patients expected to require intensive care unit admission or immediate surgical intervention.
6. Participation in another trial assessing any treatment for COVID-19.
7. Current treatment with a DPP-4 inhibitor.
8. Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: DPP-4 inhibition; Participants in the Dipeptidyl Peptidase-4 (DPP-4) inhibition group will receive linagliptin in addition to standard of care insulin regimen as per hospital protocol during their entire hospitalization.	Drug: Linagliptin 5 MG; Linagliptin 5 mg PO once daily; Other Names: Trajenta
NO_INTERVENTION: Control; Participants in the control group will receive only the standard of care insulin regimen as per hospital protocol during their entire hospitalization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to clinical change	Clinical change is defined as 2 points reduction in the World Health Organization (WHO) Ordinal Scale for Clinical Improvement of COVID-19: 0 - No clinical or virological evidence of infection; 1 - No limitation of activities; 2 - Limitation of activities; 3 - Hospitalized, no oxygen therapy; 4 - Oxygen by mask or nasal prongs; 5 - Non-invasive ventilation or high-flow oxygen; 6 - Intubation and mechanical ventilation; 7 - Ventilation + additional organ support - pressors, renal replacement therapy, extracorporeal membrane oxygenation; 8 - Death.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator-free days.		28 days
Percent of serious adverse events and premature discontinuation of treatment.		28 days
Percent of patients with clinical improvement.	Percent of patients with a 2 points reduction in the World Health Organization (WHO) Ordinal Scale for Clinical Improvement of COVID-19.	28 days
Length of hospitalization.		28 days
All-cause mortality.		28 days
Percent of supplemental oxygen use.		28 days
Supplemental oxygen-free days.		28 days
Percent of mechanical ventilation use.		28 days
Percent of ICU admissions.		28 days
ICU-free days.		28 days
Percent of 50% decrease in C-reactive protein (CRP) levels		Up to 28 days
Time to virologic response, defined as no detection of SARS-CoV-2 in a PCR test.		28 days

Collaborators and Investigators

• Sponsor: Rabin Medical Center

Publications and helpful links

General Publications

• Abuhasira R, Ayalon-Dangur I, Zaslavsky N, Koren R, Keller M, Dicker D, Grossman A. A Randomized Clinical Trial of Linagliptin vs. Standard of Care in Patients Hospitalized With Diabetes and COVID-19. Front Endocrinol (Lausanne). 2021 Dec 22;12:794382. doi: 10.3389/fendo.2021.794382. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2020
• Primary Completion (ACTUAL): April 4, 2021
• Study Completion (ACTUAL): May 4, 2021

Study Registration Dates

• First Submitted: April 30, 2020
• First Submitted That Met QC Criteria: April 30, 2020
• First Posted (ACTUAL): May 1, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 2, 2021
• Last Update Submitted That Met QC Criteria: May 28, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Lung Diseases; Severe Acute Respiratory Syndrome; COVID-19; Coronavirus Infections; Diabetes Mellitus; Diabetes Mellitus, Type 2; Endocrine System Diseases; Metabolic Diseases; Respiratory Tract Diseases; Glucose Metabolism Disorders; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Linagliptin
• Other Study ID Numbers: 0303-20-RMC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No