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| ID | Type | Description | Link |
|---|---|---|---|
| UL1RR024150-01 | U.S. NIH Grant/Contract | View source | |
| P01DK068055 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
| National Center for Research Resources (NCRR) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pyridostigmine | Experimental | 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 Comparator | Placebo (sham) capsules, matching the appearance of the active drug comparator and taken TID. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pyridostigmine | Drug | Pyridostigmine will be started at (60mg) tid, increased over 10 days to 120 mg tid, and maintained at that dose for 7 days. |
|
| 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) |
| 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 |
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Inclusion Criteria:
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:
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
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| Name | Affiliation | Role |
|---|---|---|
| Adil E. Bharucha, MBBS, MD | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22677718 | Result | 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. |
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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.
Participants were recruited from Mayo Clinic in Rochester, Minnesota and the study was conducted at between May 2006 and October 2010.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Placebo | Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Error | units on a scale | Baseline period (days 7-9 ), Treatment period (days 14-17) |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Increased salivation and/or sweating | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Adil E. Bharucha, MD | Mayo Clinic | 507-284-6439 | bharucha.adil@mayo.edu |
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| ID | Term |
|---|---|
| D003248 | Constipation |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D044882 | Glucose Metabolism Disorders |
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| ID | Term |
|---|---|
| D011729 | Pyridostigmine Bromide |
| ID | Term |
|---|---|
| D011726 | Pyridinium Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Placebo | Drug | 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. |
|
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) |
Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Body Mass Index (BMI) is a health index for comparing weight to height. BMI is a person's weight in kilograms (kg) divided by his or her height in meters squared. The body mass index is an indication if a person is at a suitable weight for his height on an approximation of body fat. A body mass index of under 20 is considered to be underweight, while a body mass index between 20 to 25 is considered healthy. A body mass index in the range of 25 to 30 is regarded as overweight. A body mass index over 30 is regarded as obese. | Mean | Standard Deviation | kilograms/meter^2 |
|
| Hemoglobin A1c | Hemoglobin A1c (HgA1c) or glycolated hemoglobin is a laboratory test of blood which provides a measure the average blood glucose (sugar) levels for the prior 3 month period. | Mean | Standard Deviation | Percentage |
|
| Subjects with diabetic retinopathy | Diabetic retinopathy is a condition of the eye caused by diabetes, caused by abnormal blood vessel growth, which invades the retina and can cause reduced vision and blindness. Note: because not all subjects had retinopathy, the number of subjects with retinopathy in each arm will not match the overall number of subjects enrolled in each arm. | Number | Participants |
|
| Geometric Center (GC) of Colonic transit | The scintigraphic method is used to measure movement of large intestine contents. A radio-labeled isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule taken by mouth with a meal. Abdominal anterior and posterior gamma images are taken hourly. 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. | Mean | Standard Deviation | Units on a scale |
|
| OG001 | Placebo | Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid. |
|
|
|
| Primary | Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours | Calculated by linear interpolation of values on the AC emptying curve. | Posted | Mean | Standard Error | hours | Baseline period (days 7-9 ), Treatment period (days 14-17) |
|
|
|
| Secondary | Gastric Emptying Half-time (GE t1/2) | The measure of time for 50 percent of a radio-labeled meal to empty from the stomach. | Posted | Mean | Standard Error | minutes | Baseline period (9 days), Treatment period (7 days) |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | percentage of meal | Baseline period (9 days), Treatment period (7 days) |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | units on a scale | Baseline period (days 7-9 ), Treatment period (days 14-17) |
|
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | Number of bowel movements | Daily during baseline period (9 days), Treatment period (7 days) |
|
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | units on a scale | Daily during baseline period (9 days), Treatment period (7 days) |
|
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | units on a scale | Daily during baseline period (9 days), Treatment period (7 days) |
|
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | percentage of bowel movements | Daily during baseline period (9 days), Treatment period (7 days) |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Error | Number complete bowel movements per week | Daily during baseline period (9 days), Treatment period (7 days) |
|
|
|
| Secondary | Heart Rate Before and After Treatment | Heart rate is the number of beats per minute, as recording on an Electrocardiogram (ECG). | Posted | Mean | Standard Error | beats per minute | Baseline period (9 days), Treatment period (7 days) |
|
|
|
| Secondary | 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). | Posted | Mean | Standard Error | Milliseconds | Baseline period (9 days), Treatment period (7 days) |
|
|
|
| 0 |
| 16 |
| 11 |
| 16 |
| EG001 | Placebo | Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid. | 0 | 14 | 5 | 14 |
| Muscle twitching | Nervous system disorders | Systematic Assessment |
|
| Abdominal discomfort, nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue, lightheadedness | General disorders | Systematic Assessment |
|
| Pruritis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Bluish discoloration of urine | Renal and urinary disorders | Systematic Assessment |
|
| Cellulitis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
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| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |