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

Effect of Stress and a Alpha-1 Antagonist on Anorectal Functions

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.

Study Overview

• Status: Completed
• Conditions: Constipation
• Intervention / Treatment: Drug: Alfuzosin; Other: Placebo

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 Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weekly Rate of Spontaneous Bowel Movements at 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.	4 weeks
Weekly Rate of Complete Spontaneous Bowel Movements at 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).	4 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Adil Bharucha, MBBS, MD, Mayo Clinic

Publications and helpful links

General Publications

• Chakraborty S, Feuerhak K, Muthyala A, Harmsen WS, Bailey KR, Bharucha AE. Effects of Alfuzosin, an alpha1-Adrenergic Antagonist, on Anal Pressures and Bowel Habits in Women With and Without Defecatory Disorders. Clin Gastroenterol Hepatol. 2019 May;17(6):1138-1147.e3. doi: 10.1016/j.cgh.2018.08.036. Epub 2018 Aug 18.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2013
• Primary Completion (Actual): September 6, 2017
• Study Completion (Actual): September 6, 2017

Study Registration Dates

• First Submitted: April 15, 2013
• First Submitted That Met QC Criteria: April 17, 2013
• First Posted (Estimate): April 18, 2013

Study Record Updates

• Last Update Posted (Actual): January 29, 2019
• Last Update Submitted That Met QC Criteria: January 10, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Alfuzosin
• Other Study ID Numbers: 12-006090; 1UL1RR024150 (U.S. NIH Grant/Contract); R01DK078924 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No