Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes
Condition: Type 2 Diabetes Mellitus; Insulin Resistance
MeSH terms: Diabetes Mellitus, Type 2; Insulin Resistance
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Metformin; saxagliptin; AZD9668; placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): background drug; background drug; study drug; placebo for AZD9668 to be added to background drugs
Other intervention name(s): onglyza
Intervention MeSH terms: Metformin; Saxagliptin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment