ESR-15-11293 - Saxa/Dapa, Safety and Efficacy Study
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      This is a 16-week, single center, randomized, double-blind, active-controlled,
      parallel-group, Phase 3b efficacy and safety study of simultaneous administration of
      saxagliptin 5 mg plus dapagliflozin 10 mg once daily (QD) compared with dapagliflozin plus
      placebo for saxagliptin, and placebo for saxagliptin plus placebo for dapagliflozin in
      patients with Type 2 diabetes who have inadequate glycemic control on metformin or
      metformin/sulfonylurea.
    

Detailed description: 
      The study is intended to demonstrate complimentary action of saxagliptin/dapagliflozin added
      to metformin versus dapagliflozin added to metformin with regard to EGP.

      Many medications are approved for the treatment of T2DM; however, the challenge of achieving
      and maintaining treatment goals within the current sequential therapy approach is linked to
      shortcomings of older classes of drugs. Metformin is in the biguanide drug class that acts to
      decrease hepatic glucose output and subsequently, decreases fasting hyperglycemia. Metformin,
      the oral first-line gold standard agent, is recommended as the initial pharmacological
      therapy because of its glycemic efficacy, weight neutrality, low risk of hypoglycemia, and
      beneficial cardiovascular (CV) profile. Current sequential add-on second and third line oral
      therapy includes oral drugs such as sulfonylureas (SUs) and thiazolidinediones (TZDs). These
      therapies and insulin are associated with increased risks for weight gain and hypoglycemia;
      therefore, caution is recommended when using combination therapy with other agents known to
      cause hypoglycemia. Hypoglycemia is a clinically important issue in optimizing treatment and
      there is emerging evidence that hypoglycemia is associated with negative CV outcomes. Efforts
      by patients to lose weight as part of a therapeutic lifestyle program are undermined by
      therapies that lead to weight gain. The majority of patients with T2DM are overweight or
      obese, and additional weight gain often results in reduced treatment efficacy.

      Over the past few years, it has been widely recognized that the management approach for each
      T2DM patients' needs to be personalized based on his or her clinical characteristics (e.g.,
      the likelihood of weight gain, risk for hypoglycemia, and lifestyle preferences [e.g., many
      patients may be reluctant to use injections]) (Inzucchi et al 2012). Based on data from the
      National Health and Nutrition Examination Survey in 2007 to 2010, HbA1c is not appropriately
      controlled in approximately one-third of patients using even less stringent targets (Ali et
      al 2013).

      Because of the challenge to achieve glycemic control in patients with T2DM, the progressive
      nature of the disease, and the limitations of available oral and non-oral therapies, there is
      a significant medical need for oral combination treatment options and dual add-on therapy in
      patients with high baseline HbA1c. Expert groups have increasingly suggested making use of
      combination therapy early after diagnosis to improve glycemic control (Inzucchi et al 2012,
      Rodbard et al 2009). In a recent study, initiating triple therapy (pathophysiological-based
      approach) in patients with new onset T2DM versus metformin followed by sequential addition of
      SUs and basal insulin (treat-to-fail approach) demonstrated a more durable HbA1c reduction
      over 24 months and less hypoglycemia with initial triple therapy (Abdul-Ghani et al 2014).
      Initial combination therapy with saxagliptin and dapagliflozin added to metformin may have
      similar potential for durable glucose lowering in combination with low risk of hypoglycemia.

      Treatment with saxagliptin and dapagliflozin, both individually and in combination with
      metformin, have demonstrated a favorable safety and tolerability profile. These drugs had a
      low propensity for hypoglycemia, therefore addressing a potential key concern when adding 2
      glucose lowering agents simultaneously. These drugs have demonstrated weight neutrality
      (saxagliptin) or moderate weight reduction (dapagliflozin). Dapagliflozin has also been shown
      to cause a persistent reduction in HbA1c and weight after 2 years of therapy. Dapagliflozin
      was recently shown to increase EGP, which, in part, may be mediated by increased plasma
      glucagon (Merovci et al). In contrast, saxagliptin has been demonstrated to reduce glucagon
      levels, e.g., in response to a meal (Sjöstrand et al 2014) and vildagliptin, also a DPP-4
      inhibitor, has been shown to inhibit EGP (Balas et al 2007).

      A second-line oral dual add-on therapy with saxagliptin co-administered with dapagliflozin
      could be a new option, as part of a triple therapy combination that includes drugs with
      complementary mechanisms of action, opposing effects on plasma glucagon concentration, and
      possibly EGP, low risk of hypoglycemia, and the potential for moderate weight loss, providing
      a more effective and patient-friendly approach to the treatment of T2DM.
    

Intervention name(s): Saxagliptin; Dapagliflozin; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Saxagliptin (Onglyza™) is approved by the US FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. The 5 mg dose will be used for this study as it is the dose that is routinely used in the clinic. In addition, this dose is used in the pivotal studies in the saxagliptin/dapagliflozin clinical program.; Dapagliflozin (Farxiga) is approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Dapagliflozin (Farxiga) is also approved in the EU as an adjunct to diet and exercise to improve glycemic control in patients with T2DM for whom metformin use is considered inappropriate due to intolerance, and in combination with other glucose-lowering medicinal products when these, in combination with diet and exercise do not provide adequate glycemic control. The 10 mg dose was chosen for this study because it has been extensively studied in Phase 3 trials and has demonstrated a favorable benefit-risk profile. In addition, this dose is the most commonly used dose in most countries.; Placebo
Other intervention name(s): Onglyza; Farxiga
Intervention MeSH terms: Dapagliflozin; Saxagliptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment