Use of Pyridostigmine for Constipation in Diabetics

Study Overview
=================
Brief Summary
-----------------
Doctors at Mayo Clinic are doing this study to learn if pyridostigmine, a drug, affects the speed at which food travels through the stomach, intestines and colon, and if pyridostigmine improves constipation symptoms in patients with diabetes. Pyridostigmine has been approved by the Food and Drug Administration (FDA) for routine clinical use, however, its use as proposed in this study is considered investigational.

Detailed Description
-----------------
Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. The study evaluated the effects of a cholinesterase inhibitor (pyridostigmine vs. placebo) on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. After a 9-day baseline period, patients with diabetes mellitus and chronic constipation without defecatory disorder will be randomized to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose of 120 mg three times a day; this dose will be maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function will be evaluated at baseline and the final 3 and 7 days of treatment, respectively.

Official Title
-----------------
Pyridostigmine in Diabetics With Constipation: Randomized, Placebo-controlled, Double-blind Trial

Conditions
-----------------
Constipation, Diabetes Mellitus, Colonic Transit, Gastric Emptying

Intervention / Treatment
-----------------
* Drug: Pyridostigmine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with diabetes mellitus (Type I or type II), diagnosed by a physician. On medical treatment for diabetes (oral medication or injected insulin) for at least one year Symptomatic constipation at least 25% of the time in the past year (Rome II criteria for functional constipation) 18-70 years of age Colonoscopy negative for obstructive lesions, cancer, or inflammatory bowel disease (IBS) within the last 8 years if 50 years of age or older Able to provide written informed consent before participating in trial Able to communicate adequately with the Investigator and to comply with the requirements for the entire study Exclusion Criteria: History of pelvic floor dysfunction (other functional GI disorders, eg IBS, non-ulcer dyspepsia are acceptable); Specifically, patients will be excluded if they have at least 2 of the following 3 criteria: History of digital evacuation of the rectum or pressure on the posterior aspect of the vagina or perineum to facilitate defecation Examination findings suggestive of puborectalis spasm or anismus, on assessment by an experienced gastroenterologist with expertise in this field; i.e. high anal sphincter tone at rest, failure of perineal descent by >1cm on straining, and tenderness or paradoxical contraction of the puborectalis on digital examination Requirement of > 200g to expel a rectal balloon during voluntary straining Abdominal surgery other than appendectomy, cholecystectomy, hysterectomy, tubal ligation, or inguinal hernia repair Suspected or known gastrointestinal or genitourinary obstruction Uncontrolled hypertension (defined as > 150/90 at rest) Known cardiac arrhythmia or ECG abnormalities, i.e. cardiac conduction disturbances (2nd or 3rd degree atrioventricular (AV) block, prolonged corrected QT interval (QTc)(> 460 msec) or bradycardia (< 45 beats/minute)) Renal insufficiency with serum creatinine greater than 2 mg/dl based on a reading from the previous 6 months Asthma or chronic obstructive pulmonary disease requiring systemic steroids in the previous 3 years (inhaled steroids acceptable) Current use of narcotics, gut prokinetic drugs (eg metoclopramide, domperidone, tegaserod, senekot), anticholinergic medication (eg. Hyoscyamine, belladonna), antidiarrheals (Imodium, Lomotil), or laxatives other than fiber supplements, docusate, or glycerin suppositories. Patients on any of these restricted medications must cease use at least 48 hours before starting and for the duration of both study phases. No rescue laxatives will be permitted within 7 days of transit testing Patients who have taken any investigational medications within the past 30 days Known intolerance or allergy to eggs Pregnant or breast-feeding females

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pyridostigmine<br>Oral pyridostigmine, starting with 60 mg capsules three times per day (TID), increasing by 60 mg every third day (i.e., over 10 days) up to the maximum tolerated dose or 120 mg TID (a total of 360 mg per day). This dose was maintained for 7 days. | Drug: Pyridostigmine<br>* Pyridostigmine will be started at (60mg) tid, increased over 10 days to 120 mg tid, and maintained at that dose for 7 days.<br>* Other names: Mestinon;|
| Placebo Comparator: Placebo<br>Placebo (sham) capsules, matching the appearance of the active drug comparator and taken TID. | Drug: Placebo<br>* If subject is randomized to placebo, placebo pills will be started at (60mg) tid, increased over 10 days to 120 mg tid, and maintained at that dose for 7 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images of the abdomen are taken hourly for the first 6 hours after the radio-labeled meal, then at 8, 24 and 48 hours. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. GC24 is the measurement taken at 24 hours after the radio-labeled meal. | Baseline period (days 7-9 ), Treatment period (days 14-17) | 
| Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours | Calculated by linear interpolation of values on the AC emptying curve. | Baseline period (days 7-9 ), Treatment period (days 14-17) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastric Emptying Half-time (GE t1/2) | The measure of time for 50 percent of a radio-labeled meal to empty from the stomach. | Baseline period (9 days), Treatment period (7 days) | 
| Colonic Filling at 6 Hours | The proportion of a radio-labeled meal in the colon at 6 hours (identifiable by radio-labelled tracer to capsule eaten with meal), measured by scintigraphy. This is an indirect measurement of small-bowel transit time. | Baseline period (9 days), Treatment period (7 days) | 
| Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly for the first 6 hours after the radio-labeled meal, then at 8, 24 and 48 hours. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. GC48 is the measurement taken at 48 hours after the radio-labeled meal. | Baseline period (days 7-9 ), Treatment period (days 14-17) | 
| Stool Frequency Per Day | During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record the number of times per day they had a bowel movement. Only the 7 days of highest treatment dose will be used for comparison purposes. | Daily during baseline period (9 days), Treatment period (7 days) | 
| Stool Form/Consistency | During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record a description of stool consistency according to the Bristol Stool Form Scale (ranging from 1 (hard lumps) to 7 (watery)). The Bristol Stool Scale is a medical aid designed to classify the form of human feces into seven categories or types. Types 1 and 2 indicate constipation with 3 and 4 being the ideal stools especially the latter, as they are the easiest to defecate, and 5-7 tending towards diarrhea. | Daily during baseline period (9 days), Treatment period (7 days) | 
| Stool Ease of Passage | During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record a description of stool ease of passage of stool, according to the Bristol Stool Form Scale (ranging from 1 (manual disimpaction) to 7 (incontinence)). Only the 7 days at highest treatment dose will be used for comparison purposes. | Daily during baseline period (9 days), Treatment period (7 days) | 
| Sense of Completely Emptying Bowels | During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record whether or not they felt they had completely emptied their bowels(1= Yes; 0= No). Only the 7 days of highest treatment dose will be used for comparison purposes. | Daily during baseline period (9 days), Treatment period (7 days) | 
| Stool Frequency Per Week | During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record the number of times per day they had a bowel movement. Complete spontaneous bowel movements per week are reported. Only the 7 days of highest treatment dose will be used for comparison purposes. | Daily during baseline period (9 days), Treatment period (7 days) | 
| Heart Rate Before and After Treatment | Heart rate is the number of beats per minute, as recording on an Electrocardiogram (ECG). | Baseline period (9 days), Treatment period (7 days) | 
| QTc Interval Before and After Treatment | The corrected QT interval (QTc) is a measurement of time (seconds) between the Q and T waves of an heart beat as recorded during an Electrocardiogram (ECG). | Baseline period (9 days), Treatment period (7 days) |