Safety and Tolerability Study of Larazotide Acetate in Celiac Disease Subjects

Study Overview
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Brief Summary
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This study was run to determine the safety, tolerance, and efficacy of multiple doses of larazotide acetate in subjects with celiac disease following a gluten challenge.

Detailed Description
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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.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo Controlled, Dose Ranging, Multicenter Study to Determine the Safety, Tolerance, and Efficacy of Larazotide Acetate (AT-1001) in Celiac Disease Subjects During Gluten Challenge.

Conditions
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Celiac Disease

Intervention / Treatment
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* Drug: larazotide acetate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have been diagnosed with celiac disease by biopsy for ≥ 6 months. Have a Anti-Tissue Transglutaminase (tTG) ≤ 10 EU as measured by serology. Must be on a gluten-free diet for at least the past 6 months. Exclusion Criteria: Have any chronic active GI disease other than celiac disease (e.g., IBS, Crohn's, Colitis). Have diabetes (Type 1 or Type 2). Chronically consumes non-steroidal anti-inflammatory agents (NSAIDs) or takes proton-pump inhibitors. Consuming oral corticosteroids or immune suppressants.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, double-blind, placebo controlled, dose ranging, multicenter
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + Gluten<br>placebo TID + gluten 800 mg TID administered orally in capsules | Drug: Placebo<br>* capsule<br>|
| Placebo Comparator: Placebo + Gluten placebo<br>placebo TID + gluten placebo TID administered orally in capsules | Drug: Placebo<br>* capsule<br>|
| Other: Larazotide acetate 8 mg + Gluten placebo<br>Safety Control Arm. Larazotide acetate 8 mg TID + gluten placebo TID administered orally in capsules | Drug: larazotide acetate<br>* capsule<br>* Other names: INN-202;|
| Active Comparator: Larazotide acetate 0.25 mg + Gluten<br>Larazotide acetate 0.25 mg TID + gluten 800 mg TID administered orally in capsules | Drug: larazotide acetate<br>* capsule<br>* Other names: INN-202;|
| Active Comparator: Larazotide acetate 1 mg + Gluten<br>Larazotide acetate 1 mg TID + gluten 800 mg TID administered orally in capsules | Drug: larazotide acetate<br>* capsule<br>* Other names: INN-202;|
| Active Comparator: Larazotide acetate 4 mg + Gluten<br>Larazotide acetate 4 mg TID + gluten 800 mg TID administered orally in capsules | Drug: larazotide acetate<br>* capsule<br>* Other names: INN-202;|
| Active Comparator: Larazotide acetate 8 mg + Gluten<br>Larazotide acetate 8 mg TID + gluten 800 mg TID administered orally in capsules | Drug: larazotide acetate<br>* capsule<br>* Other names: INN-202;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate the safety and tolerability of multiple, oral doses of larazotide acetate in celiac disease subjects that maintain a gluten-free diet. | Safety endpoints assessed in this study were adverse events, vital signs, hematology, clinical chemistry, urinalysis and ECG | 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). | 
| To evaluate the efficacy of multiple dose levels of larazotide acetate in preventing intestinal permeability changes induced by gluten challenge | 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 | 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. | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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larazotide acetate