Investigation of Eluxadoline for Diabetic Diarrhea

Overview

Diabetes is a chronic disease that affects a large part of the United States population. The majority of patients with diabetes will experience gastrointestinal symptoms. One of the most troublesome gastrointestinal symptoms that diabetes can cause is diarrhea, otherwise known as "Diabetic Diarrhea." This occurs because diabetes does damage to nerves that control the gut and prevent it from functioning normally. Currently, there are only several medications used to treat the symptoms of Diabetic Diarrhea, but many of these medications have serious side effects or do not work well. We are investigating the drug eluxadoline for the treatment of Diabetic Diarrhea. Eluxadoline is a gut-specific medication that is FDA approved to treat diarrhea related to irritable bowel syndrome (IBS-D). Our hypothesis is eluxadoline will safely and successfully reduce diarrhea symptoms (number of stools and less liquid stools) and improve the quality of life in patients with Diabetic Diarrhea when compared with placebo. Each patient with Diabetic Diarrhea who participates will take both eluxadoline and a placebo drug at separate times over a period of several months as part of a crossover study design. While on each medication, eluxadoline or placebo, the participants will keep a diary of symptoms and will be followed by the medical team through a combination of office visits and questionnaires. There will be five planned office visits and intermittent phone calls (questionnaires, surveys) over the 140-day study period. Participants will not be permitted to use any other anti-diarrhea medication during the study period and will continue on medication for management of their diabetes.

Over 30 million Americans have been diagnosed with diabetes and the related complications account for the 7th most common cause of death in the United States. Within the gastrointestinal system, diabetic enteropathy can manifest in a variety of ways of which diarrhea (DD) may be amongst the most debilitating. The prevalence of DD has been estimated to approach 20%. Autonomic neuropathy, loss of nitrergic neurons and loss of stimulation of alpha adrenergic neurons have all been postulated to have an effect on gut motility and water reabsorption. New research may indicate that chronic hyperglycemia damages Interstitial Cells of Cajal and other enteric nerves through oxidative stress to cause symptoms. Other areas of emerging research have explored the role of enteric hormones, smooth muscle cell abnormalities, inflammatory mediators, enteric glial cells, and the patients' microbiome as factors in the pathogenesis of DD Globally, symptoms of DD are inversely correlated with glycemic control. DD is a diagnosis of exclusion and its associated voluminous, watery stools are often unresponsive to conventional therapy. Eluxadoline has emerged as an FDA approved drug for the treatment of IBS-D. It is an agonist of mu and kappa opioid receptors while also an antagonist at delta receptors in the gut. Through these mechanisms, eluxadoline acts to slow peristalsis while at the same time prevents constipation and provides pain relief to patients with IBS-D. Given its success in the treatment of IBS-D, we hypothesize that eluxadoline will safely bring significant symptom relief and improve quality of life for patients with DD. Our study is a double blind, placebo controlled cross over design to investigate the safety and effectiveness of eluxadoline in relieving the symptoms of DD. Diabetic patients over the age of 18 with diarrhea for which an alternative underlying etiology has not been identified will be eligible to participate in a pre-randomization phase lasting four weeks to document baseline symptoms. At the conclusion of the pre-randomization period, patients will be randomized to either Experimental Group A or Experimental Group B. Randomization will be performed by a statistician and only the Temple Pharmacist will be aware of the group assignment to distribute study drug or placebo. Participants will receive either eluxadoline 100mg by mouth twice daily or matching placebo for 42 days, complete a washout period of 28 days when neither placebo or eluxadoline will be given, and then continue on by taking either eluxadoline or placebo for an additional 42 days based on which experimental group they have been assigned. Throughout the study period, patients will keep a daily stool diary, participate in questionnaires administered by a study coordinator and have pre-determined follow up office visits with study physicians. The primary endpoint compared between eluxadoline and placebo will be proportion of days in which all bowel movements for that day have a consistency on the Bristol Stool Scale \<5. Secondary endpoints will be improvement on the subject's Likert scores for global satisfaction, score on the Diabetes-39 and Facit-D questionnaires as well as proportion of days with fecal incontinence and nights with nocturnal diarrhea. We hypothesize that compared to placebo, eluxadoline will significantly improve the primary and secondary endpoints described above.