Transdermal Administration of a Prokinetic Agent for Bowel Evacuation in Persons With SCI
Condition: Spinal Cord Injury; Neurogenic Bowel
MeSH terms: Neurogenic Bowel; Spinal Cord Injuries
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

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.
    

Intervention name(s): Neostigmine and Glycopyrrolate
Intervention type(s): Drug
Intervention MeSH terms: Glycopyrrolate; Neostigmine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Spinal Cord Injury; Neurogenic Bowel; Bowel Evacuation; Gut Motility