Clinical trial NCT00276406: Use of Pyridostigmine for Constipation in Diabetics
Official title: Pyridostigmine in Diabetics With Constipation: Randomized, Placebo-controlled, Double-blind Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Constipation
Diabetes Mellitus
Colonic Transit
Gastric Emptying
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National Center for Research Resources (NCRR)
First posted: 2006-01-13
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy
timeFrame: Baseline period (days 7-9 ), Treatment period (days 14-17)
measure: Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours
timeFrame: Baseline period (days 7-9 ), Treatment period (days 14-17)
Secondary outcomes:
measure: Gastric Emptying Half-time (GE t1/2)
timeFrame: Baseline period (9 days), Treatment period (7 days)
measure: Colonic Filling at 6 Hours
timeFrame: Baseline period (9 days), Treatment period (7 days)
measure: Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy
timeFrame: Baseline period (days 7-9 ), Treatment period (days 14-17)
measure: Stool Frequency Per Day
timeFrame: Daily during baseline period (9 days), Treatment period (7 days)
measure: Stool Form/Consistency
timeFrame: Daily during baseline period (9 days), Treatment period (7 days)
measure: Stool Ease of Passage
timeFrame: Daily during baseline period (9 days), Treatment period (7 days)
measure: Sense of Completely Emptying Bowels
timeFrame: Daily during baseline period (9 days), Treatment period (7 days)
measure: Stool Frequency Per Week
timeFrame: Daily during baseline period (9 days), Treatment period (7 days)
measure: Heart Rate Before and After Treatment
timeFrame: Baseline period (9 days), Treatment period (7 days)
measure: QTc Interval Before and After Treatment
timeFrame: Baseline period (9 days), Treatment period (7 days)
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Adil E. Bharucha, MBBS, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bharucha AE, Low P, Camilleri M, Veil E, Burton D, Kudva Y, Shah P, Gehrking T, Zinsmeister AR. A randomised controlled study of the effect of cholinesterase inhibition on colon function in patients with diabetes mellitus and constipation. Gut. 2013 May;62(5):708-15. doi: 10.1136/gutjnl-2012-302483. Epub 2012 Jun 7.