Use of Pyridostigmine for Constipation in Diabetics

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00276406
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 53
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Constipation; Diabetes Mellitus; Colonic Transit; Gastric Emptying	Drug: Pyridostigmine; Drug: Placebo	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pyridostigmine in Diabetics With Constipation: Randomized, Placebo-controlled, Double-blind Trial
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pyridostigmine 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; Pyridostigmine will be started at (60mg) tid, increased over 10 days to 120 mg tid, and maintained at that dose for 7 days.; Other Names: Mestinon
Placebo Comparator: Placebo Placebo (sham) capsules, matching the appearance of the active drug comparator and taken TID.	Drug: Placebo; 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.

Outcome Measures

Primary Outcome Measures

1. Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy [Baseline period (days 7-9 ), Treatment period (days 14-17)]

   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.

2. Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours [Baseline period (days 7-9 ), Treatment period (days 14-17)]

   Calculated by linear interpolation of values on the AC emptying curve.

Secondary Outcome Measures

1. Gastric Emptying Half-time (GE t1/2) [Baseline period (9 days), Treatment period (7 days)]

   The measure of time for 50 percent of a radio-labeled meal to empty from the stomach.

2. Colonic Filling at 6 Hours [Baseline period (9 days), Treatment period (7 days)]

   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.

3. Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy [Baseline period (days 7-9 ), Treatment period (days 14-17)]

   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.

4. Stool Frequency Per Day [Daily during baseline period (9 days), Treatment period (7 days)]

   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.

5. Stool Form/Consistency [Daily during baseline period (9 days), Treatment period (7 days)]

   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.

6. Stool Ease of Passage [Daily during baseline period (9 days), Treatment period (7 days)]

   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.

7. Sense of Completely Emptying Bowels [Daily during baseline period (9 days), Treatment period (7 days)]

   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.

8. Stool Frequency Per Week [Daily during baseline period (9 days), Treatment period (7 days)]

   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.

9. Heart Rate Before and After Treatment [Baseline period (9 days), Treatment period (7 days)]

   Heart rate is the number of beats per minute, as recording on an Electrocardiogram (ECG).

10. QTc Interval Before and After Treatment [Baseline period (9 days), Treatment period (7 days)]

    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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Adil E. Bharucha, MBBS, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Adil Bharucha, MD, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00276406
• Other Study ID Numbers: 05-004037; UL1RR024150-01; P01DK068055
• First Posted: Jan 13, 2006
• Last Update Posted: Nov 30, 2012
• Last Verified: Nov 1, 2012

• Additional relevant MeSH terms: Constipation; Pyridostigmine Bromide

Study Results

Participant Flow

Recruitment Details	Participants were recruited from Mayo Clinic in Rochester, Minnesota and the study was conducted at between May 2006 and October 2010.
Pre-assignment Detail	68 patients were assessed for eligibility. 24 were ineligible. 13 were eligible but declined to participate in the study. One patient consented but was withdrawn because of severe hyperglycemia during the baseline period. 30 were enrolled and completed all study procedures.

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Period Title: Overall Study
STARTED	16	14
COMPLETED	16	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Pyridostigmine	Placebo	Total
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.	Total of all reporting groups
Overall Participants	16	14	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.5 (11.4)	52.1 (11.3)	50.2 (11.3)
Sex: Female, Male (Count of Participants)
Female	13 81.3%	9 64.3%	22 73.3%
Male	3 18.8%	5 35.7%	8 26.7%
Region of Enrollment (participants) [Number]
United States	16 100%	14 100%	30 100%
Body Mass Index (kilograms/meter^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms/meter^2]	27.9 (4.4)	31.6 (6.0)	29.7 (5.5)
Hemoglobin A1c (Percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage]	8.1 (1.7)	7.7 (1.2)	7.9 (0.3)
Subjects with diabetic retinopathy (Number) [Number]
Number [Participants]	9 56.3%	7 50%	16 53.3%
Geometric Center (GC) of Colonic transit (Units on a scale) [Mean (Standard Deviation) ]
Geometric Center of Colonic Transit at 24 hr (GC24	1.96 (0.71)	1.98 (0.62)	1.97 (0.66)
Geometric Center of Colonic Transit at 48 hr (GC48	2.92 (0.89)	2.97 (1.00)	2.94 (0.93)

Outcome Measures

1. Primary Outcome

Title	Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy
Description	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.
Time Frame	Baseline period (days 7-9 ), Treatment period (days 14-17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	1.96 (0.18)	1.98 (0.17)
Treatment	2.45 (0.20)	1.84 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyridostigmine, Placebo
	Comments	Analysis was adjusted for BMI and baseline values and incorporated Bonferroni corrections.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	ANCOVA
	Comments

2. Primary Outcome

Title	Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours
Description	Calculated by linear interpolation of values on the AC emptying curve.
Time Frame	Baseline period (days 7-9 ), Treatment period (days 14-17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	16.73 (2.30)	20.59 (3.29)
Treatment	10.44 (1.40)	18.77 (3.23)

3. Secondary Outcome

Title	Gastric Emptying Half-time (GE t1/2)
Description	The measure of time for 50 percent of a radio-labeled meal to empty from the stomach.
Time Frame	Baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	142 (19)	141 (12)
Treatment	122 (13)	121 (13.42)

4. Secondary Outcome

Title	Colonic Filling at 6 Hours
Description	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.
Time Frame	Baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	37 (9)	41 (10)
Treatment	53 (7)	48 (9)

5. Secondary Outcome

Title	Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy
Description	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.
Time Frame	Baseline period (days 7-9 ), Treatment period (days 14-17)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	2.92 (0.22)	2.97 (0.27)
Treatment	3.59 (0.25)	3.26 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyridostigmine, Placebo
	Comments	Analysis was adjusted for BMI and baseline values and incorporated Bonferroni corrections.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Stool Frequency Per Day
Description	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.
Time Frame	Daily during baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	0.95 (0.2)	1.2 (0.2)
Treatment	1.5 (0.2)	1.4 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyridostigmine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Stool Form/Consistency
Description	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.
Time Frame	Daily during baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	2.5 (0.3)	2.8 (0.5)
Treatment	3.4 (0.2)	2.6 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyridostigmine, Placebo
	Comments	Bowel diaries were analyzed by computing the mean scores for the 9-day baseline period and separately for the last 7 days of the treatment period (i.e., when the pyridostigmine dose was stable in each subject.) Individual subject treatment period mean bowel function scores were then compared using a similar ANCOVA model, with the corresponding individual subject baseline mean bowel function score and gender as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	Stool Ease of Passage
Description	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.
Time Frame	Daily during baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	3.5 (0.2)	3.6 (0.2)
Treatment	3.8 (0.5)	3.5 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyridostigmine, Placebo
	Comments	Bowel diaries were analyzed by computing the mean scores for the 9-day baseline period and separately for the last 7 days of the treatment period (i.e., when the pyridostigmine dose was stable in each subject.) Individual subject treatment period mean bowel function scores were then compared using a similar ANCOVA model, with the corresponding individual subject baseline mean bowel function score and gender as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.04
	Comments
	Method	ANCOVA
	Comments

9. Secondary Outcome

Title	Sense of Completely Emptying Bowels
Description	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.
Time Frame	Daily during baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	86 (6)	74 (8)
Treatment	73 (8)	66 (8)

10. Secondary Outcome

Title	Stool Frequency Per Week
Description	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.
Time Frame	Daily during baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	2.1 (0.9)	2.1 (0.8)
Treatment	4.0 (1.2)	3.1 (0.9)

11. Secondary Outcome

Title	Heart Rate Before and After Treatment
Description	Heart rate is the number of beats per minute, as recording on an Electrocardiogram (ECG).
Time Frame	Baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	74 (3)	76 (4)
Treatment	66 (2)	75 (3)

12. Secondary Outcome

Title	QTc Interval Before and After Treatment
Description	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).
Time Frame	Baseline period (9 days), Treatment period (7 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridostigmine	Placebo
Arm/Group Description	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.	Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Measure Participants	16	14
Baseline	428 (6)	420 (8)
Treatment	415 (18)	421 (4)

Adverse Events

Time Frame	Adverse events were collected for the baseline (9 days) and treatment (7 days) periods. Events occuring in more than one subject are tabulated by treatment arm.
Arm/Group Title	Pyridostigmine		Placebo
Arm/Group Description	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.		Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
All Cause Mortality
	Pyridostigmine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pyridostigmine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Pyridostigmine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/16 (68.8%)		5/14 (35.7%)
Gastrointestinal disorders
Abdominal discomfort, nausea	4/16 (25%)	4	2/14 (14.3%)	2
General disorders
Increased salivation and/or sweating	3/16 (18.8%)	3	2/14 (14.3%)	2
Fatigue, lightheadedness	2/16 (12.5%)	2	0/14 (0%)	0
Nervous system disorders
Muscle twitching	3/16 (18.8%)	3	1/14 (7.1%)	1
Renal and urinary disorders
Bluish discoloration of urine	1/16 (6.3%)	1	0/14 (0%)	0
Skin and subcutaneous tissue disorders
Pruritis	1/16 (6.3%)	1	0/14 (0%)	0
Cellulitis	1/16 (6.3%)	1	0/14 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.