A Clinical Trial to Assess the Safety of Oral SRT2104 and Its Effects on Vascular Dysfunction in Otherwise Healthy Cigarette Smokers and Subjects With Type 2 Diabetes Mellitus
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 1

Summary: 
      The primary purpose of this study is to evaluate the safety and tolerability of SRT2104 (2.0
      g administered once daily for 28 days) and to examine the effects of SRT2104 (2.0 g
      administered once daily for 28 days) on reversing vasomotor and fibrinolytic dysfunction in
      both type 2 diabetes mellitus patients and otherwise healthy cigarette smokers in a fed
      state.

      This study will investigate the effects of SRT2104 on the reduction of platelet activation
      markers (platelet-monocyte aggregates), and to evaluate the effects of SRT2104 on platelet
      and monocyte surface markers (P-selectin, CD11b), inflammatory markers (high sensitivity CRP,
      IL-6, SAA, TNF-α and sCD40L), and markers of oxidative stress (urinary and plasma
      F2-isoprostanes and nitrotyrosine).

      Further goals of this study is to characterize the pharmacokinetic profile of SRT2104 after a
      single dose and multiple administrations in both type 2 diabetes mellitus patients and
      otherwise healthy cigarette smokers in a fed state, and to explore the effects of SRT2104 on
      potential biomarkers of activity for glucose control (HbA1c, glycated albumin and
      fructosamine) and/or Sirt1 activation.
    

Detailed description: 
      Single-center, randomized, double-blind, placebo-controlled, crossover, safety, activity, and
      pharmacokinetic (PK) study of 2.0 g of SRT2104 administered orally once daily for 28
      consecutive days to two different populations: type 2 diabetic (T2D) subjects on an existing,
      stable, hypoglycemic regimen and otherwise healthy cigarette smokers (≥ 10cigarettes/day for
      at least 1 year). Approximately 24 subjects with T2D and 24 otherwise healthy cigarette
      smokers, aged 18-60 years, who fulfill the inclusion/exclusion criteria, will be enrolled in
      this study to ensure at least 20 evaluable subjects per population are enrolled. Subjects
      will be evenly stratified and randomized to receive SRT2104 2.0 g/day or placebo once daily
      for 28 days. After 28 days, subjects will cross over to receive the other test article for
      another 28 days of dosing, bringing the total dosing period to 56 days.

      Subjects will sign the informed consent form at the screening visit (to occur within 21 days
      of first dose of test article), and will undergo screening assessments to verify eligibility
      for the study. If eligible and willing to participate, subjects will return to the clinic on
      Days -1 and 1 for safety assessments, hematology and biochemistry measurements, platelet
      monocyte aggregation (PMA) assessment, forearm venous occlusion plethysmography, pulse wave
      analysis (PWA), pulse wave velocity (PWV) and PK sampling. The first dose of test article
      will occur on Day 1 after eligibility has been confirmed. After each 28 day dosing period,
      subjects will return on Day 28 and Day 56 for safety assessments, hematology and biochemistry
      measurements, forearm plethysmography, PWA, PWV, and PK sampling. Subjects will return to the
      clinic on Days 2, 15, 29, 43, and 57 for safety assessments and additional PK sampling.
      Subjects will be asked to complete a study drug diary on a daily basis for compliance and
      adverse event (AE) monitoring (diabetic subjects will be required to monitor and record their
      fasting blood glucose in the diary also). An End of Study visit will occur 14 days following
      the final dose of SRT2104 or placebo on Day 70. A followup safety call will be made to each
      subject 30 days following their final dose of SRT2104 or placebo (Day 86).
    

Intervention name(s): Placebo; SRT2104
Intervention type(s): Drug; Drug
Intervention description(s): For the placebo product, SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product.
Eight placebo capsules are stored in a dosing bottle and provided to all participating subjects for oral ingestion.; SRT2104 investigational product is a size 00 Swedish Orange opaque hard gelatin capsule containing 0.25 g of SRT2104, a new chemical entity which is supplied as a micronized, yellowish/amber powder. Eight SRT2104 capsules are stored in a dosing bottle and provided to all participating subjects for oral ingestion.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science