Effects of Alpha-1 Antagonist, Stress and Relaxation on Anorectal Functions

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01834729
• Collaborator: National Center for Research Resources (NCRR) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 74
• Location: 1
• Arms: 2
• Actual Duration (Months): 54.2
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This study is designed to better understand the effects of effects of stress, relaxation, and a medication alfuzosin on bowel control and emptying in healthy people and patients with bowel problems.

Condition or Disease	Intervention/Treatment	Phase
Constipation	Drug: Alfuzosin; Other: Placebo	Phase 2

Detailed Description

Normally, bowel emptying requires relaxation of the anal sphincter (i.e., lowermost end of intestinal tract) and pelvic muscles. Some people cannot relax these muscles normally and experience constipation. Alfuzosin is a medication which is approved to treat bladder but not bowel problems.

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Stress and a Alpha-1 Antagonist on Anorectal Functions
• Actual Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Sep 6, 2017
• Actual Study Completion Date: Sep 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alfuzosin In Part A, subjects randomized to this arm will receive a single dose of oral alfuzosin immediate release (IR) 2.5 mg. In Part B, only constipated patients will receive oral alfuzosin (10 mg extended release (ER)) capsules.	Drug: Alfuzosin; oral alfuzosin immediate release (IR) 2.5 mg (Part A) or oral alfuzosin extended release (ER) 10 mg (Part B); Other Names: Xatral (immediate release 2.5 mg) Uroxatral (extended release 10 mg)
Placebo Comparator: Placebo Subjects randomized to this arm will receive a single placebo capsule identical to the study drug.	Other: Placebo; placebo capsule identical to the study drug

Outcome Measures

Primary Outcome Measures

1. Weekly Rate of Spontaneous Bowel Movements at 4 Weeks [4 weeks]

   A bowel movement is considered a spontaneous bowel movement (SBM) if no laxative, enema, or suppository was taken in the preceding 24 hours.

2. Weekly Rate of Complete Spontaneous Bowel Movements at 4 Weeks [4 weeks]

   If the subject indicates that the spontaneous bowel movement (SBM) was associated with a sensation of complete bowel emptying, the SBM will be counted as a complete spontaneous bowel movement (CSBM).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion criteria for controls (Part A only):

• Healthy

• Able to provide written informed consent before participating in the study

• Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

Inclusion criteria for patients (Parts A and B):

• Women with chronic constipation for 1 year with any 2 or more of the following symptoms for 3 months or longer, i.e. <3 bowel motions/week, straining ≥ 25% of time, hard or lumpy stools ≥ 25% of time, incomplete evacuation ≥ 25% of time, feeling of anorectal blockage ≥ 25% of time.

• Able to provide written informed consent before participating in the study

• Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

Exclusion criteria for controls (Part A); Items indicated with an asterisk (*) are also exclusion criteria for patients (Parts A and B):

• Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study and/or pose safety concerns.*

• Current symptomatic orthostatic hypotension or history of hypotensive response as defined by a reduction of ≥ 30 mmHg in systolic or ≥ 20 mmHg in diastolic blood pressure.*

• Current symptoms of a functional gastrointestinal disorder assessed by questionnaire.

• Putative risk factors for pelvic floor trauma, i.e. six or more vaginal deliveries, birthweight >4500gms (macrosomia), or known 4th degree perineal tear.

• Inability to withdraw medications prior to the baseline period and throughout the study (except as protocol defined rescue medications):

1. Medications that substantially alter GI transit* including laxatives, magnesium and aluminum containing antacids, prokinetics, erythromycin, narcotics, anti-cholinergics, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRI) and newer antidepressants

2. Selective serotonin reuptake inhibitor (SSRI) antidepressants are permissible at low, stable doses. All medications shall be reviewed and dis/approved by the principal investigator on a case by case basis.*

3. Potent Cytochrome P450 3A4 (Cyp3A4) inhibitors such as ketoconazole, itraconazole and ritonavir, nitrates and phosphodiesterase inhibitors.* Note: stable doses of thyroid replacement, estrogen replacement, low dose aspirin for cardioprotection, and birth control (but with adequate backup contraception as drug-interactions with birth control have not been conducted) are permissible.*

• Stable dose of thyroxine will be permitted*

• Prolonged Q-Tc interval > 500 msec on ECG within the last three months*

• Estimated glomerular filtration rate (eGFR) < 60 mL/minute. * Based on guidelines and recommendations from the National Kidney Disease Education Program (NKDEP) of the National Institutes of Health (NIH) and the Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation, the an eGFR using the Modification of Diet in Renal Disease (MDRD) Study equation is more accurate than a creatinine clearance calculated from serum and urine measurements. The formula is eGFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American). Based on our extensive experience in clinical practice and research studies, it is anticipated that all potentially eligible participants will have normal serum creatinine.

• History of allergies to alpha-1 adrenoreceptor antagonist*

• Active rectal inflammation, cancer; perianal sepsis; history of pelvic radiation, rectosigmoid surgery or inflammatory bowel disease*

• Pregnant women, prisoners and institutionalized individuals*

• Persons with a latex allergy.

Contacts and Locations

Locations

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

Sponsors and Collaborators

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

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 20, 2016

More Information

Publications

None provided.

• Responsible Party: Adil Bharucha, PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01834729
• Other Study ID Numbers: 12-006090; 1UL1RR024150; R01DK078924
• First Posted: Apr 18, 2013
• Last Update Posted: Jan 29, 2019
• Last Verified: Jan 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Constipation; Alfuzosin

Study Results

Participant Flow

Pre-assignment Detail	A total of 38 healthy subjects and 36 subjects with constipation for 1 year or longer participated in the study. Both the healthy subjects and constipation subjects participated in Part A. Only the constipation subjects participated in Part B.

Arm/Group Title	Control Placebo	Control Alfuzosin	Constipation Placebo	Constipation Alfuzosin
Arm/Group Description	Healthy subjects defined as not having a functional bowel disorder randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug.	Healthy subjects defined as not having a functional bowel disorder randomized to this arm will receive a receive a single dose of oral alfuzosin immediate release (IR) 2.5 mg.	Subjects with constipation for 1 year or longer randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug	Subjects with constipation for 1 year or longer randomized to this arm will receive a single dose of oral alfuzosin immediate release (IR) 2.5 mg.
Period Title: Overall Study
STARTED	18	20	18	18
COMPLETED	17	19	15	16
NOT COMPLETED	1	1	3	2

Baseline Characteristics

Arm/Group Title	Control Placebo	Control Alfuzosin	Constipation Placebo	Constipation Alfuzosin	Total
Arm/Group Description	Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug	Subjects randomized to this arm will receive a single dose of oral alfuzosin immediate release (IR) 2.5 mg.	Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug	In this arm, only constipated patients will receive oral alfuzosin (10 mg extended release (ER)) capsules. Alfuzosin: oral alfuzosin immediate release (IR) 2.5 mg (Part A) or oral alfuzosin extended release (ER) 10 mg (Part B)	Total of all reporting groups
Overall Participants	18	20	18	18	74
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	32	45	36	40	40
Sex: Female, Male (Count of Participants)
Female	18 100%	20 100%	18 100%	18 100%	74 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%	20 100%	18 100%	18 100%	74 100%
Body mass index (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	24	27	25	25	26

Outcome Measures

1. Primary Outcome

Title	Weekly Rate of Spontaneous Bowel Movements at 4 Weeks
Description	A bowel movement is considered a spontaneous bowel movement (SBM) if no laxative, enema, or suppository was taken in the preceding 24 hours.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Placebo	Control Alfuzosin	Constipation Placebo	Constipation Alfuzosin
Arm/Group Description	Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug	Subjects randomized to this arm will receive a single dose of oral alfuzosin immediate release (IR) 2.5 mg.	Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug	Constipated patients will receive oral alfuzosin (10 mg extended release (ER) capsules.
Measure Participants	18	20	18	18
Mean (Standard Error) [spontaneous bowel movements per week]	1.6 (0.3)	1.3 (0.1)	1.6 (0.4)	1.3 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Constipation Placebo, Constipation Alfuzosin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Least squares means
	Comments

2. Primary Outcome

Title	Weekly Rate of Complete Spontaneous Bowel Movements at 4 Weeks
Description	If the subject indicates that the spontaneous bowel movement (SBM) was associated with a sensation of complete bowel emptying, the SBM will be counted as a complete spontaneous bowel movement (CSBM).
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Placebo	Control Alfuzosin	Constipation Placebo	Constipation Alfuzosin
Arm/Group Description	Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug	Subjects randomized to this arm will receive a single dose of oral alfuzosin immediate release (IR) 2.5 mg.	Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug	Constipated patients will receive oral alfuzosin (10 mg extended release (ER)) capsules.
Measure Participants	18	20	18	18
Mean (Standard Error) [complete SBM per week]	0.6 (0.1)	0.7 (0.05)	0.7 (0.1)	0.7 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Constipation Placebo, Constipation Alfuzosin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Least squares means
	Comments

Adverse Events

Time Frame	Subject safety monitoring was performed for six hours after treatment in healthy patients and two weeks in constipated patients.
Arm/Group Title	Control Placebo		Control Alfuzosin		Constipation Placebo		Constipation Afluzosin
Arm/Group Description	Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug		Subjects randomized to this arm will receive a single dose of oral alfuzosin immediate release (IR) 2.5 mg.		Subjects randomized to this arm will receive a placebo capsule identical to the study drug. Placebo: placebo capsule identical to the study drug		Constipated patients will receive oral alfuzosin (10 mg extended release (ER)) capsules.
All Cause Mortality
	Control Placebo		Control Alfuzosin		Constipation Placebo		Constipation Afluzosin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/20 (0%)		0/18 (0%)		0/18 (0%)
Serious Adverse Events
	Control Placebo		Control Alfuzosin		Constipation Placebo		Constipation Afluzosin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/20 (0%)		0/18 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Control Placebo		Control Alfuzosin		Constipation Placebo		Constipation Afluzosin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		1/20 (5%)		1/18 (5.6%)		1/18 (5.6%)
Cardiac disorders
Hypotension	0/18 (0%)	0	1/20 (5%)	1	0/18 (0%)	0	0/18 (0%)	0
Gastrointestinal disorders
Abdominal cramps	0/18 (0%)	0	0/20 (0%)	0	1/18 (5.6%)	1	0/18 (0%)	0
General disorders
Headache	0/18 (0%)	0	0/20 (0%)	0	0/18 (0%)	0	1/18 (5.6%)	1
Fatigue	0/18 (0%)	0	0/20 (0%)	0	0/18 (0%)	0	1/18 (5.6%)	1

Limitations/Caveats

Men were not studied; baseline bowel diary was not preceded by a run-in period; treatment phase only lasted 2 weeks.

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.