Safety and Tolerability Study of Larazotide Acetate in Celiac Disease Subjects

• To demonstrate the safety and tolerability of multiple, oral doses of larazotide acetate in celiac disease subjects that maintain a gluten-free diet. [ Time Frame: Safety measurements were performed at Screening and at Day 0, 7, 14, and 21 ('End of Study'). Any change from baseline value was calculated at each subsequent visit until "End of Study" (Day 21). ]
  Safety endpoints assessed in this study were adverse events, vital signs, hematology, clinical chemistry, urinalysis and ECG
  
  
• To evaluate the efficacy of multiple dose levels of larazotide acetate in preventing intestinal permeability changes induced by gluten challenge [ Time Frame: On Days 0, 6, 13, and 20 subjects drank a solution of lactulose and mannitol. Subject's urine was collected during the day on Day 0 and overnight prior to subsequent visits and analyzed for LAMA recoveries via standardized methodologies. ]
  The primary efficacy outcome was the Day 0-to-Day 14 change in urinary LAMA ratio ( a measure of intestinal permeability) as a response to gluten
  
  

• Changes in daily and weekly reported health outcomes [ Time Frame: Symptom diary - daily; PGWBI - weekly; GSRS - weekly ]
  Health outcomes were assessed using a daily symptom diary; a weekly PGWBI and a weekly GSRS
  
  
• Changes in urinary LAMA ratios between Day 0 to Day 7 [ Time Frame: See Primary Outcome Measure No. 2 ]
  See Primary Outcome Measure No. 2
  
  
• Changes in urinary lactulose fractional excretion between Day 0 to Day 7 to Day 14 [ Time Frame: See Primary Outcome Measure No. 2 ]
  See Primary Outcome Measure No. 2
  
  
• Changes in urinary mannitol fractional excretion between Day 0 to Day 7 to Day 14 [ Time Frame: See Primary Outcome Measure No. 2 ]
  See Primary Outcome Measure No. 2
  
  
• Change in urinary nitrite / nitrate levels from Day 0 to Day 14 [ Time Frame: Day 0 and Day 14 ]
  Nitrite/nitrate levels were assessed for correlation to the measures of intestinal permeability
  
  
• Change in anti-tTG levels from Screening to Day 21 [ Time Frame: Screening and Day 21 ]
  Changes between screening and Day 21 anti-tTG levels were assessed for correlation to the measures of intestinal permeability
  
  
• Change in cell markers and cytokines from PBMCs [ Time Frame: Days 0, 7, 14 and 21 ]
  Serum cytokine and cell surface marker determinations were assessed for correlation to the measures of intestinal permeability
  
  
• Changes in zonulin level [ Time Frame: Days 0, 7, 14 and 21 ]
  Serum zonulin levels were assessed for correlation to the measures of intestinal permeability
  
  

CLIN1001-004 was a randomized, double-blind, placebo controlled, dose-ranging, 7-arm, multicenter study with a gluten challenge. The objects were multiple dose safety and tolerance; efficacy (intestinal permeability [change in urinary LAMA ratio] and disease signs and symptoms) following gluten challenge.

Following a 21-day screening period, subjects were randomized to one of seven treatments groups: four groups received larazotide acetate (0.25 mg, 1 mg, 4 mg or 8 mg TID) along with an 800 mg gluten challenge, one group received placebo with an 800 mg gluten challenge, a safety control arm received the highest dose of larazotide acetate (8 mg TID) and gluten placebo and the last group received drug placebo and gluten placebo. The gluten challenge was administered as capsules (800 mg TID) with each main meal for a total of 2.4 g daily. Drug or drug placebo was administered TID 15 minutes prior to each main meal. Subjects received their assigned treatments for two weeks (Day 0 through Day 14) and came to clinic for a follow-up visit one week later (Day 21). Subjects remained on their gluten-free diet for the duration of the study.