Trial Outcomes & Findings for Use of Pyridostigmine for Constipation in Diabetics (NCT NCT00276406)

NCT ID: NCT00276406

Last Updated: 2012-11-30

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 30 participants
• Primary outcome timeframe: Baseline period (days 7-9 ), Treatment period (days 14-17)
• Results posted on: 2012-11-30

Participant Flow

Participants were recruited from Mayo Clinic in Rochester, Minnesota and the study was conducted at between May 2006 and October 2010.

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 One patient consented but was withdrawn because of severe hyperglycemia during the baseline period. 30 were enrolled and completed all study procedures.

Participant milestones

Measure	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.	Placebo Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Overall Study STARTED	16	14
Overall Study COMPLETED	16	14
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Use of Pyridostigmine for Constipation in Diabetics

Baseline characteristics by cohort

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.	Total n=30 Participants Total of all reporting groups
Age Continuous	48.5 years STANDARD_DEVIATION 11.4 • n=5 Participants	52.1 years STANDARD_DEVIATION 11.3 • n=7 Participants	50.2 years STANDARD_DEVIATION 11.3 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment United States	16 participants n=5 Participants	14 participants n=7 Participants	30 participants n=5 Participants
Body Mass Index	27.9 kilograms/meter^2 STANDARD_DEVIATION 4.4 • n=5 Participants	31.6 kilograms/meter^2 STANDARD_DEVIATION 6.0 • n=7 Participants	29.7 kilograms/meter^2 STANDARD_DEVIATION 5.5 • n=5 Participants
Hemoglobin A1c	8.1 Percentage STANDARD_DEVIATION 1.7 • n=5 Participants	7.7 Percentage STANDARD_DEVIATION 1.2 • n=7 Participants	7.9 Percentage STANDARD_DEVIATION 0.3 • n=5 Participants
Subjects with diabetic retinopathy	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Geometric Center (GC) of Colonic transit Geometric Center of Colonic Transit at 24 hr (GC24	1.96 Units on a scale STANDARD_DEVIATION 0.71 • n=5 Participants	1.98 Units on a scale STANDARD_DEVIATION 0.62 • n=7 Participants	1.97 Units on a scale STANDARD_DEVIATION 0.66 • n=5 Participants
Geometric Center (GC) of Colonic transit Geometric Center of Colonic Transit at 48 hr (GC48	2.92 Units on a scale STANDARD_DEVIATION 0.89 • n=5 Participants	2.97 Units on a scale STANDARD_DEVIATION 1.00 • n=7 Participants	2.94 Units on a scale STANDARD_DEVIATION 0.93 • n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy Baseline	1.96 units on a scale Standard Error 0.18	1.98 units on a scale Standard Error 0.17
Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy Treatment	2.45 units on a scale Standard Error 0.20	1.84 units on a scale Standard Error 0.16

PRIMARY outcome

Timeframe: Baseline period (days 7-9 ), Treatment period (days 14-17)

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

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours Baseline	16.73 hours Standard Error 2.30	20.59 hours Standard Error 3.29
Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours Treatment	10.44 hours Standard Error 1.40	18.77 hours Standard Error 3.23

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Gastric Emptying Half-time (GE t1/2) Baseline	142 minutes Standard Error 19	141 minutes Standard Error 12
Gastric Emptying Half-time (GE t1/2) Treatment	122 minutes Standard Error 13	121 minutes Standard Error 13.42

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Colonic Filling at 6 Hours Baseline	37 percentage of meal Standard Error 9	41 percentage of meal Standard Error 10
Colonic Filling at 6 Hours Treatment	53 percentage of meal Standard Error 7	48 percentage of meal Standard Error 9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy Baseline	2.92 units on a scale Standard Error 0.22	2.97 units on a scale Standard Error 0.27
Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy Treatment	3.59 units on a scale Standard Error 0.25	3.26 units on a scale Standard Error 0.27

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Stool Frequency Per Day Baseline	0.95 Number of bowel movements Standard Error 0.2	1.2 Number of bowel movements Standard Error 0.2
Stool Frequency Per Day Treatment	1.5 Number of bowel movements Standard Error 0.2	1.4 Number of bowel movements Standard Error 0.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Stool Form/Consistency Baseline	2.5 units on a scale Standard Error 0.3	2.8 units on a scale Standard Error 0.5
Stool Form/Consistency Treatment	3.4 units on a scale Standard Error 0.2	2.6 units on a scale Standard Error 0.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Stool Ease of Passage Baseline	3.5 units on a scale Standard Error 0.2	3.6 units on a scale Standard Error 0.2
Stool Ease of Passage Treatment	3.8 units on a scale Standard Error 0.5	3.5 units on a scale Standard Error 0.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Sense of Completely Emptying Bowels Treatment	73 percentage of bowel movements Standard Error 8	66 percentage of bowel movements Standard Error 8
Sense of Completely Emptying Bowels Baseline	86 percentage of bowel movements Standard Error 6	74 percentage of bowel movements Standard Error 8

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Stool Frequency Per Week Baseline	2.1 Number complete bowel movements per week Standard Error 0.9	2.1 Number complete bowel movements per week Standard Error 0.8
Stool Frequency Per Week Treatment	4.0 Number complete bowel movements per week Standard Error 1.2	3.1 Number complete bowel movements per week Standard Error 0.9

SECONDARY outcome

Timeframe: Baseline period (9 days), Treatment period (7 days)

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

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
Heart Rate Before and After Treatment Baseline	74 beats per minute Standard Error 3	76 beats per minute Standard Error 4
Heart Rate Before and After Treatment Treatment	66 beats per minute Standard Error 2	75 beats per minute Standard Error 3

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Pyridostigmine n=16 Participants 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 n=14 Participants Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
QTc Interval Before and After Treatment Baseline	428 Milliseconds Standard Error 6	420 Milliseconds Standard Error 8
QTc Interval Before and After Treatment Treatment	415 Milliseconds Standard Error 18	421 Milliseconds Standard Error 4

Adverse Events

Pyridostigmine

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Pyridostigmine n=16 participants at risk 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 n=14 participants at risk Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.
General disorders Increased salivation and/or sweating	18.8% 3/16 • Number of events 3 • 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.	14.3% 2/14 • Number of events 2 • 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.
Nervous system disorders Muscle twitching	18.8% 3/16 • Number of events 3 • 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.	7.1% 1/14 • Number of events 1 • 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.
Gastrointestinal disorders Abdominal discomfort, nausea	25.0% 4/16 • Number of events 4 • 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.	14.3% 2/14 • Number of events 2 • 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.
General disorders Fatigue, lightheadedness	12.5% 2/16 • Number of events 2 • 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.	0.00% 0/14 • 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.
Skin and subcutaneous tissue disorders Pruritis	6.2% 1/16 • Number of events 1 • 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.	0.00% 0/14 • 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.
Renal and urinary disorders Bluish discoloration of urine	6.2% 1/16 • Number of events 1 • 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.	0.00% 0/14 • 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.
Skin and subcutaneous tissue disorders Cellulitis	6.2% 1/16 • Number of events 1 • 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.	0.00% 0/14 • 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.

Additional Information

Adil E. Bharucha, MD

Mayo Clinic

Phone: 507-284-6439

Email: bharucha.adil@mayo.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place