In a clinical trial sponsored by Alba Therapeutics, researchers from 10 clinical sites in the U.S. conducted a study to determine if the investigational medication, larazotide acetate, is safe and effective in preventing gluten-induced intestinal permeability and alleviating gastrointestinal symptoms in people with celiac disease.
Immune system responses are triggered in those with celiac disease when incompletely digested gluten peptides go between the cells of lamina propria of the small intestine and/or pass through the space between the epithelial cells. When this intestinal permeability occurs, an immune system response is triggered and the response results in the disassembly of the tight junction in the intestine and creates an opening. The goal of this study was to determine if larazotide acetate works, as it is believed to by preventing this opening of the tight junctions in the intestine.
The study involved 80 adults with biopsy-proven celiac disease. Some were asked to take on a gluten-challenge, which consisted of taking two pills containing 400 mg of gluten per day. All participants were divided into one of seven different treatment groups within the study; four groups underwent the gluten challenge along with .25, 1, 4, or 8 mg of larazotide acetate. The study drug larazotide acetate was taken three times a day. The remaining groups were used as the safety control group and were given one of the following: 8 mg of the study drug and no gluten challenge; a placebo drug and placebo gluten (also known as the “gluten-free control arm”); or a placebo drug and the gluten challenge. All participants were asked to maintain their typical gluten-free diet throughout the duration of the study.
The primary effectiveness of the drug was evaluated through the urinary lactose-to-mannitol (LAMA) ratio, a measure of intestinal permeability, while the secondary efficacy was determined through the Gastrointestinal Symptom Rating Scale (GSRS). In people with celiac disease, intestinal damage leads to the simultaneous reduction of the absorption of monosaccharides and an increase in the absorption of disaccharides, which are both carbohydrates. As a result, an increase in the LAMA ratio is observed. This LAMA ratio varied greatly across all control groups and while some increases were reported, the data gathered was not statistically significant. In addition, no statistically significant changes were observed between the larazotide acetate groups and the placebo group. A decrease in the LAMA ratio would show a reduction in intestinal permeability.
The GSRS is a self-evaluation questionnaire used to determine the severity of gastrointestinal symptoms. Participants receiving the larazotide acetate placebo who underwent the gluten challenge reported severe gastrointestinal symptoms, especially in comparison to those receiving the placebo gluten. The participants who received the active larazotide acetate while on the gluten challenge reported less severe symptoms than those receiving the placebo study medication while on the gluten challenge. Study authors noted that those receiving the lower doses of .25 and 1 mg doses of larazotide acetate showed statistically significant prevention of gastrointestinal symptoms while the larger doses did not present any statistically significant differences.
Since the LAMA ratios did not meet statistical significance, the researchers concluded the primary efficacy goal of this study was not met. However, one of the secondary efficacy goals was met in that the drug limited the gastrointestinal symptoms brought on by gluten ingestion. The most common side effects of the investigational drug were urinary tract infection and headache, but the researchers concluded the drug to be generally well-tolerated.
“As this is the first published clinical trial detailing results of a clinical trial for a medication designed to prevent toxicity related to gluten exposure, this is a landmark in celiac disease research,” said Daniel Leffler, MD, MS, Director of Clinical Research at the Celiac Center at Beth Israel Deaconess Medical Center. “The primary outcome of LAMA is one that many of us question the significance of, and this test is not being used in any clinical trials going forward. It was also shown not to be predictive of intestinal damage in a subsequent study. Given that the side effects of the medication were similar to placebo and that there was significant protection against symptoms related to gluten exposure, this shows that rigorous clinical trials in celiac disease are possible and that this particular agent warrants further study.”
The full study results are published in the American Journal of Gastroenterology.
Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Leffler D, Schuppan D, Pallav K, Najarian R, Goldsmith JD, Hansen J, Kabbani T, Dennis M, Kelly CP.Gut. 2012 May 22