Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes

Type 2 Diabetes Mellitus Clinical Trial

Official title: Neutrophil Elastase Inhibition as Adjunctive Therapy to Improve Glucometabolic Variables in Overweight and Obese, Insulin-Resistant Type 2 Diabetic Patients

Status Completed

Clinical Trial Summary

The role of individual leukocyte populations in type 2 diabetes (T2D) and immunometabolism in general represent important gaps in knowledge to better understand the etiopathogenesis of T2D. Emerging evidence indicates that certain leukocyte populations serve as an important nexus of T2D-associated inflammation. This novel and innovative clinical trial will test the efficacy of a leukocyte-selective anti-inflammatory small drug as adjunctive therapy in improving insulin sensitivity in obese, insulin-resistant type 2 diabetic subjects. This trial also offers a first-in-kind opportunity to better understand the role of specific leukocyte populations in type 2 diabetes. The drug's clinical profile suggests that it will be well-tolerated with few, if any, side effects, and the existence of simple methods that can indirectly measure its activity in vivo

Clinical Trial Description

Type 2 diabetes (T2D) is characterized by concomitant insulin resistance and pancreatic beta cell dysfunction. Disease prevalence continues to increase around the globe and is currently estimated to be at more than 385 million affected people. As many as 1 in 3 people in the United States could have diabetes by the year 2050 with significant economic consequences. In 2014, 1 in 5 health care dollars was spent to support the care of patients at a total estimated cost > $245 billion. Overweight, insulin-resistant (IR) T2D individuals manifest a chronic systemic inflammation which impairs beta cells and peripheral insulin sensitivity. This systemic inflammation is associated with an atherogenic lipid profile and predisposes individuals to higher risk for micro- and macro-vascular disease, irrespective of well-controlled glycemia. Although a variety of pharmacologic approaches maintain daily glycemic control, it is becoming evident that there is an urgent need to identify adjunctive therapies to improve, insulin sensitivity, beta cell function, and HbA1c since they begin deteriorating quite substantially by 5 years following initial treatment. Ideally, such adjunctive therapies should be well-tolerated, easy to administer, should not promote hypoglycemia and should also attenuate the systemic inflammation. The role of neutrophils in T2D and metabolic inflammation represents an important gap in knowledge to better understand inflammation in T2D especially since neutrophils are the most abundant leukocyte population in humans and constitute the bulk of inflammatory leukocytes. Emerging evidence indicates that neutrophils along with neutrophil-derived elastase serve as an important nexus of T2D-associated inflammation. This trial offers a first-in-kind opportunity to better understand the role of neutrophils in T2D diabetics. We hypothesise that inhibition of neutrophil elastase (NE) will attenuate the chronic systemic background inflammation in overweight and obese, IR T2D subjects and that the potential improvement in insulin sensitivity and glucose control could concurrently facilitate functional maintenance and induce the rescue of pancreatic beta cell mass.

To test the hypothesis, we propose a clinical trial that is comprised of the following two aims:

Aim 1: To test whether orally-administered NEI adjunctive therapy in obese, IR T2D subjects improves insulin sensitivity, glucoregulation and glycemic control. The primary endpoint is the improvement of insulin sensitivity at 6 months compared to baseline, assessed by the hyperinsulinemic-euglycemic clamp method. Secondary endpoints will include: i) Safety (rate and severity of adverse events including hypoglycemia); ii) Glycemic and metabolic control variables; iii) Assessment of functional beta cell mass (improvement in baseline oral glucose tolerance test (OGTT) C-peptide levels and AUC, insulin secretion rate (ISR), body mass and body fat-corrected insulin sensitivity; and iv) Changes in inflammatory variables. Exploratory endpoints will include improvement of OGTT C-peptide (and C-peptide AUC) trajectory, ISR trajectory, and decreased dose and dose frequency of background drugs.

Aim 2: To inform the changes in innate and cellular immunity conferred by the trial study agents as a mechanistic approach to understanding the basis of potential efficacy. Evidence of suppression of systemic inflammation will be examined during the trial. Changes in gene expression of PBL and neutrophils may provide a signature of responder versus non-responder status and/or of effect of therapy. ;

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Insulin Resistance
• Type 2 Diabetes Mellitus

• NCT number: NCT02597101
• Study type: Interventional
• Source: Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
• Status: Completed
• Phase: Phase 2
• Start date: November 2015
• Completion date: June 15, 2019