Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes

Phase 2

Completed

Conditions: Insulin Resistance
Type 2 Diabetes Mellitus

Interventions: Drug: Metformin
Drug: saxagliptin
Drug: placebo
Drug: AZD9668

Registration Number: NCT02597101

Lead Sponsor: Nick Giannoukakis, PhD

Brief 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

Detailed 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	placebo	5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day) and 60 mg placebo tablet twice daily
AZD9668	AZD9668	60 mg AZD9668 twice daily in addition to 5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day)
Placebo	saxagliptin	5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day) and 60 mg placebo tablet twice daily
Placebo	Metformin	5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day) and 60 mg placebo tablet twice daily
AZD9668	Metformin	60 mg AZD9668 twice daily in addition to 5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day)
AZD9668	saxagliptin	60 mg AZD9668 twice daily in addition to 5 mg saxagliptin, once a day, together with optimised (after titration) metformin (500-2000 mg/day)

Primary Outcome Measures

Name	Time	Method
Insulin Sensitivity at 6 Months From Baseline	6 months	The primary outcome measure is the insulin sensitivity at 6 months from baseline, assessed by the hyperinsulinemic-euglycemic clamp method. This is calculated as the M/LBM. M/LBM = whole-body insulin sensitivity adjusted for lean body mass. M/LBM is calculated as the steady-state glucose disposal (in mL) per kilogram lean body mass divided by steady-state insulin concentrations (micro IU/mL).

Secondary Outcome Measures

Name	Time	Method
Severity of All Adverse Events Including Hypoglycemia	12 months	Severity of all adverse events including hypoglycemia based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 severity grade score (0-4). Higher scores indicate a worse severity.
Severity of Known AEs of AZD9668	12 months	Attribution score of AE to known AEs of AZD9668 in terms of an atribution scale of 0-4. The scale is defined as: Score 0=Unrelated; Score 1=The AE is unlikely related; Score 2=The AE has a reasonable possibility to be related; Score 3=The AE is likely related; Score 4=The AE is clearly related
Severity of Known AEs of Saxagliptin	12 months	Attribution score of AE to known AEs of saxagliptin in terms of an atribution scale of 0-4. The scale is defined as: Score 0=Unrelated; Score 1=The AE is unlikely related; Score 2=The AE has a reasonable possibility to be related; Score 3=The AE is likely related; Score 4=The AE is clearly related
Severity of Known AEs of Metformin	12 months	Attribution score of AE to known AEs of metformin in terms of an atribution scale of 0-4. The scale is defined as: Score 0=Unrelated; Score 1=The AE is unlikely related; Score 2=The AE has a reasonable possibility to be related; Score 3=The AE is likely related; Score 4=The AE is clearly related
Change in Glycated HbA1c Levels Compared to Baseline	12 months	Difference in the value of HbA1c study end (12 months) compared to baseline value (time 0)
Change in OGTT From Baseline	12 months	The difference of the calculated area under the curve of the 2 hour OGTT test (AUC is the value of the area under the glucose concentration time curve) at 12 months minus the AUC at baseline (time zero). This AUC is calculated as the concentration of glucose versus time curve and the reporting units are mcg\*dL/hour. The trapezoid rule was applied to the curve to obtain the AUC.
Change in OGTT-derived Insulinogenic Index Using C-peptide	12 months	The change from baseline at 12 months where the insulinogenic index = ratio of fasting C-peptide concentration (ng/mL)/fasting glucose (ng/mL) at the time of the OGTT test.
Change From Baseline in the Serum Levels of Inflammatory Markers	12 months	Serum levels refers to the concentration in serum of each of the analytes in the multi-analyte assay (Luminex) in terms of pg/mL depending on the analyte measured. We are reporting the difference in these values between 12 months and baseline.