Transdermal Administration of a Prokinetic Agent for Bowel Evacuation in Persons With SCI

A Novel Application of Iontophoresis in the Transcutaneous Delivery of a Prokinetic Agent for the Promotion of Bowel Evacuation

Bowel care (BC) is a time-consuming and cumbersome activity of daily living for most individuals with SCI. Previous studies have reported that the average time to complete a BC routine is 45 minutes; 10-20% of SCI individuals report BC routines lasting for more than 1 hour. In past studies, the investigators have shown that a medication called neostigmine (NEO) combined with a medication called glycopyrrolate (GLY) can increase bowel activity and thus, promote bowel movement. The investigators have successfully used this medication with traditional and novel methods of colonoscopic preparations, and have shown that it improves the quality of these preparations. In this Phase I, proof of concept pilot study, the investigators propose to study the effectiveness of this medicine when it is delivered through the skin. In order to make delivery more efficient, the investigators will be using a technique called iontophoresis, which uses a mild electric current to drive the drug through the surface of the skin. The instrument includes an electrode containing the active agent (delivers charge) and an oppositely charged electrode (receives charge) which will be placed on the surface of the skin. The study design will consist of a screening visit to determine each individual's response to a previously established IV dose of NEO and GLY, followed by a dose titration study (two visits) of iontophoresed NEO and GLY. Study visits will be separated by no less than 2 days and no more than 14 days.

If this delivery method is shown to be effective, it may represent a way to vastly improve the clinical utility of this medication by allowing for needle-free self administration, and expanding the clinical indication to routine, at home bowel care.

Study Overview

• Status: Completed
• Conditions: Neurogenic Bowel; Spinal Cord Injury
• Intervention / Treatment: Drug: Neostigmine and Glycopyrrolate

Detailed Description

In this Phase I, proof of concept pilot study, we propose to study the safety and efficacy of transcutaneous neostigmine and glycopyrrolate facilitated by iontophoresis. The study design will consist of a screening visit to determine each individual's response to a previously established IV dose of NEO and GLY, followed by a dose titration study (two visits) of iontophoresed NEO and GLY. Study visits will be separated by no less than 2 days and no more than 14 days.

Screening Bowel Evacuation Study, Part 1: Visit 1 (30 Subjects with SCI):

A previously determined efficacious dose of IV neostigmine (0.03 mg/kg IV NEO) with glycopyrrolate (0.006 mg/kg GLY) will be administered during the first study visit to determine subject responsiveness to the known effective mode of administration. Irregardless of excess weight, the maximum dose of neostigmine and glycopyrrolate (NG) is limited to 10.0 mg and GLY to 2.0 mg. If the subject responds to the IV NEO, subsequent study visits to determine the effective dose of transcutaneous NEO and GLY will be performed. Subjects will be asked to arrive at the Spinal Cord Research Center at the James J. Peters Veteran Affairs Medical Center (JJP VAMC) (Room 7A-13) on the day of their scheduled study visits. Heart rate (continuous ecg), blood pressure, airway resistance (Impulse Oscillometry, IOS), signs and symptoms, and artificial bowel evacuation will be monitored throughout the study visit. Subjects will remain in this position until a bowel movement occurs, or for the next 60 minutes of the study. Subjects will be monitored for a minimum of 1.5 hours post drug, and until they reach ± 10% of their baseline heart rate (continuous 3 lead ECG) and airway caliber as measured by IOS.

Transcutaneous Bowel Evacuation Study, Part 2: Visits 2-3 (up to 25Subjects with SCI):

The same subjects who participated in Visit 1 who demonstrated a response to the IV NEO and GLY will participate in visits 2-3. Due to probable inter-subject variability of drug response to the doses of neostigmine being administered, subjects will receive increasing doses of iontophoresed neostigmine on separate days over 2 study visits to determine the most effective average dose. We will administer the transcutaneous NEO and GLY facilitated by iontophoresis. The dosages for Visits 2-3 are as follows: Visit 2: 0.05 mg/kg NEO and 0.01 mg/kg GLY, Visit 3: 0.07 mg/kg NEO and 0.14 mg/kg GLY. Irregardless of excess weight, the maximum dose of NG is limited to 10.0 mg and GLY to 2.0 mg. Heart rate (continuous ecg), blood pressure, airway resistance (Impulse Oscillometry, IOS) signs and symptoms, and artificial bowel evacuation will be monitored throughout the study visit as described in Table 1. Subjects will be asked to arrive at the Spinal Cord Research Center at the JJP VAMC (Room 7A-13) on the day of their scheduled study visits. Subjects will remain in this position until a bowel movement occurs, or for the next 90 minutes of the study. Subjects will be monitored for a minimum of 90 minutes post drug, and until they reach ± 10% of their baseline heart rate (continuous 3 lead ECG) and airway caliber as measured by IOS.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10468
      • James J. Peters VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Incomplete or complete SCI,
• Tetraplegia or paraplegia,
• Excess time for bowel evacuation (> 60 minutes per bowel training session)

Exclusion Criteria:

• Previous adverse reaction or hypersensitivity to electrical stimulation,
• Known sensitivity to neostigmine or glycopyrrolate,
• Do not require additional bowel care or have "normal bowel function",
• Blockage Bowel or Bladder,
• Myocardial infarction in the past 6 months,
• Blood pressure of 160/100mmHg or higher with or without being on 3 or more different classes of anti-hypertensive medications
• Organ damage (heart & kidney damage) and/or transient ischemic attack (TIA)- cerebrovascular accident (CVA) as a result of hypertension
• Known past history of coronary artery disease or bradyarrythmia,
• Active respiratory disease,
• Known history of asthma during lifetime or recent (within 3 months) respiratory infections.
• Adrenal insufficiency,
• Pregnancy or potential for pregnancy,
• Lactating/nursing females,
• Slow heart rate (<45 bpm)
• Use of any antibiotic in the past 7 days,
• Use of medications known to affect the respiratory system,
• Use of medications known to alter airway caliber,
• Concurrent participation in other clinical trials (within 30 days).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bowel Evacuation Study with NEO and GLY; The study design will consist of a screening visit to determine each individual's response to a previously established IV dose of NEO and GLY, followed by a dose titration study (two visits) of iontophoresed NEO and GLY. Study visits will be separated by no less than 2 days and no more than 14 days.	Drug: Neostigmine and Glycopyrrolate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biological Responses to Study Drugs (quantified by the presence and strength of biological responses (changes in bowel sounds, heart rate and airway resistance and bowel movement occurrence)	We aim to determine the efficacy of transcutaneous (TC) neostigmine (NEO) with glycopyrrolate (GLY) delivered via iontophoresis in promoting bowel movement in persons with chronic SCI. This will be quantified by the presence and strength of biological responses (changes in bowel sounds, heart rate and airway resistance and bowel movement occurrence).	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of Study Medication (quantified through monitoring of side effects during study visits and through patient self report as measured by the Treatment Satisfaction Questionnaire)	We aim to determine the safety and tolerability of TC NEO and GLY in persons with SCI when used to promote bowel movement. This will be quantified through monitoring of side effects during study visits and through patient self report as measured by the Treatment Satisfaction Questionnaire.	6 Months

Collaborators and Investigators

• Sponsor: James J. Peters Veterans Affairs Medical Center
• Investigators: Principal Investigator: Mark A Korsten, MD, James J. Peters VA Medical Center

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: February 19, 2015
• First Submitted That Met QC Criteria: February 24, 2015
• First Posted (Estimate): February 25, 2015

Study Record Updates

• Last Update Posted (Actual): March 7, 2017
• Last Update Submitted That Met QC Criteria: March 6, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Spinal Cord Injury; Neurogenic Bowel; Bowel Evacuation; Gut Motility
• Additional Relevant MeSH Terms: Digestive System Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Trauma, Nervous System; Spinal Cord Diseases; Spinal Cord Injuries; Neurogenic Bowel; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Adjuvants, Anesthesia; Cholinesterase Inhibitors; Parasympathomimetics; Glycopyrrolate; Neostigmine
• Other Study ID Numbers: KOR-13-02