Larazotide acetate continues to be the best medication under study at the current time to help people with celiac disease. It appears that it will not ever replace the gluten-free diet, but it can help prevent responses to the kind of accidental gluten ingestion people with CD encounter because of contaminated food or low levels of gluten in food thought to be gluten free.
While research slowed temporarily due to economic factors affecting the drug’s owner, Alba Therapeutics Corporation, results of a study done in 2007 were finally published in a medical journal in July 2012. Useful information from this study is now generally available. While the study was not a complete success, it did document some benefits of the drug, give some idea about how much gluten patients with CD can tolerate, as well as demonstrate some problems with studying celiac disease treatments in an outpatient setting.
This study, in the American Journal of Gastroenterology used urinary LAMA ratios (read article) to evaluate the effectiveness of larazotide acetate, as well as patients’ reported symptoms using standard questionnaires. The study was able to show that the larazotide improved symptoms. However, it also pointed out the weakness of using urinary LAMA levels in an outpatient setting.
This was a dose-ranging exploratory study. There were 86 patients with celiac disease in 7 study arms. There were 4 groups given larazotide, in the following amounts: 0.25 mg, 1 mg, 4 mg, and 8 mg, all 3 times a day. The smaller doses were significantly lower than those used in the few other studies available. The very first study of this drug, for example, used a 12 mg daily dose.
All of the patients in these 4 study arms got gluten challenges. The gluten was placed in 400 mg capsules, 2 of which were taken 3 times a day by the these 4 groups as well as a group getting placebo medication. The group getting placebo medication plus a gluten challenge was the fifth arm. The total gluten challenge was a total of 2.4 grams a day.
There were 2 more arms. One got 8 mg of larazotide 3 times a day and no gluten. The final arm got placebo medication and a placebo challenge.
Medications and gluten (or placebos) were taken for 14 days. All the participants had been controlled on a gluten-free diet beforehand. Anyone not getting active medication or gluten was given a similar-appearing substitute.
The primary object of this study was to see if larazotide use would prevent an increase in the LAMA results in patients challenged with gluten. LAMA stands for lactulose-to-mannitol ratio, and is measured in urine after a person drinks a solution made with these 2 sugars.
LAMA testing was done on days 0, 7, 14, and 21. On day 0, participants were told not to eat or drink anything except water for 4 hours before the test. They then drank the lactulose and mannitol solution, and all urine was collected for the next 6 hours, during which time they could only drink more water.
The other test days, they were told to stop eating after a normal dinner at around 6 PM, followed by not eating or drinking anything but water until 10 PM. At that time, they were to completely empty their bladders and then drink the sugar solution. Nothing but water was allowed after that. Any urine produced during the night plus all the morning sugar was collected.
Patients filled out a questionnaire called the Gastrointestinal Symptom Rating Scale (GSRS) which includes 15 standard questions about symptoms in 5 areas: diarrhea, abdominal pain, indigestion, constipation and acid reflux. An abbreviated version, called the Celiac Disease GSRS (CeD-GSRS) focused on the symptoms most reported by patients with CD in the areas of abdominal pain, diarrhea, and indigestion.
Patients’ general health was monitored with screenings of blood chemistries, blood cell counts, and urine. EKGs were done. Levels of larazotide in the blood were measured. Celiac disease autoantibodies were followed.
All side effects were noted. Those that were known to be associated with celiac disease itself were not considered to be caused by the medication.
Results – LAMA
LAMA ratios did not differ significantly after the gluten challenges in the larazotide-treated participants as compared to those who got placebo. This was discouraging for the researchers.
They did learn, however, that LAMA ratios may not be a good way to study this in an outpatient setting. The ratios varied widely. LAMA values decreased between days 0 and 7 in the gluten-free group as well as the gluten-challenged group that did not take any larazotide. This was not a problem in a previous study conducted on people in the hospital. Patients in the hospital study had lowered LAMA ratios as well as less symptoms when taking larazotide.
According to the GSRS, most doses of larazotide did decrease symptoms in response to the gluten challenge. The 0.25 mg dose and the 4 mg dose three times a day led to a statistically significant decrease in symptoms.
Pooling all the results from patients who got any larazotide and a gluten challenge, the symptoms most decreased were abdominal pain, indigestion and reflux. These improvements could be observed in both the GSRS and the CeD-GSRS.
Patients also kept diaries of their symptoms. Total weekly numbers of episodes of diarrhea, severity of abdominal discomfort, as well as stool consistency were all better in the patients who got the 0.25 mg dose and the 1 mg dose of larazotide.
Additionally, symptoms usually associated with CD were much more pronounced in all patients who got gluten without larazotide (50% had symptoms) as compared with those who got larazotide or did not get gluten (20.8% had symptoms).
There were no significant differences in the levels of antibodies to tTG in any of the groups.
The 2.4 gram daily dose of gluten was clearly enough to cause symptoms in patients who did not take any larazotide.
Fifteen out of 60 patients who got larazotide had side effects, as did 7 out of the 26 who got placebo. The most commonly reported symptom in both groups was headache. There were no serious adverse effects reported, and no laboratory indicators of toxicity.
5.8 percent of those who received larazotide reported urinary tract infections, although only 1 was confirmed by a culture of the urine for bacteria, and only 1 person took antibiotics. All of the symptoms resolved, and they were not believed to be related to the larazotide.
In this study, changes in urinary LAMA ratios did not correlate well with symptoms or expected results, but rather varied quite a lot between different people in each study group. Most groups had a lower LAMA on day 7, even those who got placebo treatment and placebo gluten.
The investigators surmised that the people in the study may have been more compliant with their own gluten-free diets during the two weeks, so that the LAMA results at day 0 may have represented people who were not yet completely gluten free. They suggested that future trials have a longer period of LAMA or other testing before the study drug is started.
While the LAMA results did not confirm anything, the study did show that some doses of larazotide decreased symptoms in patients with CD given gluten. It also showed that 2.4 grams of gluten a day was enough to produce symptoms. That is one answer to the question of how much gluten someone can take in without having their CD worsened. The answer would have to be less than 2.4 grams.
The authors of the study suggested that addition to a longer lead-in time, studies of larazotide should involve more people. They also suggested that small bowel biopsies may be needed to actually confirm or disprove the effects of the drug.
What Comes Next?
Larazotide is still under study. There is a trial actively recruiting patients as of October 2013, designated NCT01396213. This is its description:
“A randomized, double-blind, placebo-controlled Phase 2B study to evaluate the efficacy and safety of Larazotide Acetate in the treatment of patients with celiac disease who have persistent symptoms despite being on a gluten-free diet.”
Information about this study can be found at: http://clinicaltrials.gov/ct2/show/NCT01396213?term=larazotide+acetate+and+celiac+disease&rank=1
If you or a family member might be interested in participating in this study, you can look at the information to see if you qualify or talk to your gastroenterologist.
It does seem likely that larazotide acetate will find a place in the management of celiac disease.
Paterson BM , Lammers KM , Arrieta MC et al. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study . Aliment Pharmacol Ther 2007; 26:757-66.
Leffler D.A., Kelly C. P., Abdallah H. Z., et al. A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease During Gluten Challenge. Am J Gastroenterol advance online publication, 24 July 2012.