Clinical trial NCT02435069
Conditions: Fecal Incontinence Neurogenic Bowel
Keywords: cecostomy appendicostomy
Sponsor: Nemours Children's Clinic
Start date: 2016-02-09; Completion date: 2018-03-30
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
There is a surgical procedure to help children with intractable fecal incontinence gain continence for stool through construction of a tube that connects the abdominal wall to the colon near or through the appendix. This tube allows easy administration of enema solution into the first part of the colon. Putting enema solution through that tube into the colon is called an antegrade continence enema (ACE) and has been shown to work well in helping some but not all children prevent stool accidents. The purpose of this study is to compare a large volume ACE flush using a salt water solution called normal saline with a small volume ACE flush using liquid glycerin. The aims of this study are to: 1) find the most effective dose and flush frequency of each solution needed to prevent stool accidents; 2) compare which solution given at the best dose has the least side effects and 3) to determine if administration of either of the ACE flushing solutions causes electrolyte abnormalities or affects colon health.

Detailed description:
Fecal incontinence past the time of toilet training is devastating to affected children. Antegrade continence enema (ACE) therapy administered through a catheterizable stoma surgically placed in the cecum has helped children with intractable fecal incontinence attain continence for stool. There are a number of retrospective studies demonstrating the variable effectiveness rates of ACE therapy. This variability may be due to what is used to flush. There are no prospective trials evaluating the effectiveness of different flushing regimens. The catheterizable stoma used for the antegrade administration of enema solution is frequently made by bringing the appendix out through the abdominal wall or by placing a skin-level device (button) in to the cecum. ACE therapy administration through the appendix or into the cecum has the potential to cause colonic dysfunction. The effects of ACE administration on colonic mucosal health has not been investigated. This pilot study will compare a high volume normal saline (NS) flush and a low volume United States Pharmacopeia (USP) glycerin flush. The primary aims of the study are to compare which solution, given at an optimal dose and frequency, is associated with fewer side effects, while promoting the higher degree of fecal continence, and to determine if antegrade enema solution administration through an appendicostomy/cecostomy causes electrolyte abnormalities or affects gut health.

Arms: arm 1: Baseline data including frequency and severity of fecal soiling and frequency and severity of abdominal pain were collected for a minimum of 2 weeks prior to surgical construction of the ACE stoma. Baseline stool calprotectin and serum electrolytes were collected in the baseline phase prior to initiation of the preoperative bowel prep. Pre-operative data served as the control. arm 2: Initial flush used NS or USP Glycerin randomized to treatment sequence. The starting volume and administration frequency for NS was 10mL/kg and glycerin 20 mL administered every other day. The NS dose was titrated in 10 mL increments to achieve continence so as not to exceed 500 mL daily for a child under five years of age and 1000 mL daily for a child over 5 years of age. USP Glycerin was titrated in 5 mL increments so as not to exceed 50 mL daily. For side effects greater than Wong Bailey Faces Pain Rating Scale (WBFPRS) level 4, NS was decreased by 2.5 mL/kg to the lowest dose of 5 mL/kg daily. USP Glycerin was decreased in 5 mL increments to the lowest dose of 5 mL daily. If the maximum dose did not result in continence, if the dose necessary to minimize side effects resulted in fecal soiling, or if there were side effects greater than WBFPRS level 4 at the lowest dose of administration, the child was be trialed on the alternate therapy and then dropped from the study. arm 3: To prevent statistical bias from subject loss due to treatment failure, each child was randomized to a second treatment sequence once they achieved continence on optimal dosing with minimal side effects.This arm evaluated the long term effectiveness of NS and glycerin at optimal dose and administration frequency for 4 weeks and served as comparison between flush solutions. The study concluded with the child being placed back on 2 weeks of the initial flush in the randomized sequence.
Interventions: intervention 1: Dose Response - NS and USP Glycerin - First Intervention intervention 2: Effectiveness - NS and USP Glycerin - Second Intervention
Intervention descriptions: intervention 1: This trial used a repeated measures, single subjects alternating treatments A-B-C-B'-C'-B1' withdrawal design in which all subjects were tested under all conditions and each subject acted as his or her own control. The subjects were randomly assigned to either normal saline or USP glycerin to control for order effects. Baseline data A served as the control and was obtained pre-operatively. The B-C arm evaluated dose-response relationship and was used to identify the minimum dosing volume and frequency of ACE administration of NS and USP Glycerin necessary to promote fecal continence. When the optimal dose as identified, the child continued on that dose for 2 weeks to insure treatment stability and effectiveness. intervention 2: To prevent statistical bias from subject loss due to treatment failure, each child was randomized to a second treatment sequence once they have achieved continence with minimal side effects on optimal dosing The second phase B'-C'-B1' of the study compared the two regimens at optimal dose and administration frequency. This phase was used to confirm the effectiveness of NS and USP Glycerin at optimal dosing on continence and assess side effects.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
A Within Subjects Comparison of Two Antegrade Flushing Regimes in Children 
NCT02435069 
08/23/2019 
 


This study was a part of a dissertation presented to the Graduate School of the University of Florida in 
partial fulfillment of the Doctor of Philosophy degree requirements. 
Study design 
This study compared two flushing regimens utilizing a cross-over design embedded in a single subject A-
B-C-Bʹ-Cʹ-B1ʹ design with subjects acting as their own control; thereby ensuring the highest possible 
degree of equivalence across treatment conditions and allowing greater precision and efficiency in 
estimates of treatment effects (Janosky, Leininger, Hoerger & Libkuman, 2009; Piantadosi, 2005; 
Portney & Watkins, 2009). In both methods subjects were randomized to treatment sequence 
decreasing the threat of order effects, increasing group equivalency in the cross-over design, minimizing 
variability in measurement due to subject or period differences, and increasing internal validity (Chow & 
Liu, 2014; Jones & Kenward, 2003). This study was well suited to single-subject repeated measures 
design, because children requiring an ACE procedure constitute a very small population with widely 
variable anatomic and physiologic causative factors making sample homogeneity difficult. The design 
allowed for frequency and volume adjustment of each flushing regimen as needed facilitating dose 
response comparison and aiding in identifying which flushing regimen required the minimal dose and 
administration frequency and had fewer side effects while achieving stool continence (Gast, 2010; 
Janosky et al., 2009; Kazdin, 2011). Subjects were limited to children who were scheduled for a 
cecostomy or appendicostomy ensuring a naïve gut to the effects of a flushing regimen and allowing for 
a true no-treatment baseline. Flush effects were reversible, making this intervention amenable to a 
withdrawal design. Specimen collection occurred after an active wash out period at the completion of 
each flushing regimen facilitating comparison of treatment effects on electrolytes and stool calprotectin, 
negating the possibility of carry-over effects. 
Regulatory Considerations 
The potential risks associated with this study conferred no greater than minimal risk as categorized by 
the National Institutes of Health (National Institutes of Health [NIH], 1998). However, it involved 
vulnerable subjects necessitating full Institutional Review Board (IRB) approval, legal guardian informed 
consent by at least one parent, and child assent for children age 7 and above (Knox & Burkhart, 2007; 
Pieper, 2008). In addition, although normal saline and USP glycerin have been used for over three 
decades in the clinical setting as ACE flushing solutions, administration of either solution through an ACE 
stoma is considered off-label use and therefore the study required FDA approval.  Prior to submission to 
the IRB, the study design was reviewed by the Nemours Children’s Clinic (NCC) Research Committee 
which made suggestions for revision but deferred to the investigator’s Dissertation Committee for 
approval of study design and analysis. The UF IRB deferred to the NCC IRB because the study was to be 
completed at NCC. An IRB authorization agreement was completed, and the contract was signed by all 
parties. The proposal was submitted to the FDA and an IND was obtained.  A Nemours Children’s Clinic 
IRB application was completed. As a part of the NCC IRB application process, submissions for research 
involving investigational drugs and biologics and management of research pharmaceutical products 
were completed and approved. NCC IRB approval was obtained and renewed annually. Legal guardian 
informed consent and child assent for children 7 and above were obtained for each subject prior to the 
start of data collection.  
 


Subjects  
Subject characteristics’ data were collected and included age in years and months, ethnicity, diagnosis, 
description of level of spinal cord lesion or anal-rectal malformation when appropriate, description of 
physical examination of anus, and the reason for undergoing an ACE procedure.  
Setting  
Following parental consent and child assent, baseline data were collected daily for a minimum of 2 
weeks prior to surgery. Baseline data included the frequency of fecal soiling, and the frequency and 
severity of abdominal pain. Baseline blood sample for electrolytes and stool for calprotectin were 
obtained in the preoperative period. The baseline samples were collected prior to initiation of the pre-
operative bowel prep. Postoperatively, the child was randomly assigned to either start the saline or USP 
glycerin flush protocol. A clinician from the surgical division at NCC met with the parent and child in the 
immediate postoperative period for initiation of the first antegrade flush. At that time, the clinician 
reviewed the flush protocol in detail, including materials and procedures. The child received the first 
antegrade infusion during that hospital visit. A home visit was scheduled by the investigator for the 
initial antegrade flush following hospital discharge. Procedural reliability was ascertained by calculating 
procedural fidelity for each procedural variable to assure the intervention was accurately implemented 
in keeping with the methods section of the proposal. Procedural fidelity was ascertained prior to each 
regimen change during the clinic visit scheduled prior to each phase change.   
Measures  
Dependent variables collected at baseline were recorded daily and included the number of episodes of 
fecal soiling per day, the frequency and severity of abdominal pain measured using the Wong-Baker 
Faces Pain Rating Scale (WBFPRS) as the age-appropriate visual analog scale, serum electrolytes, and 
stool for calprotectin. The WBFPRS scale ranges from 0 (very happy without pain) to 10 (the worst pain 
imaginable). The WBFPRS has undergone extensive testing and has well established psychometrics in 
children (Tomlinson, von Baeyer, Stinson, & Sung, 2010; Wong & Baker, 1988). 
Dependent variables collected postoperatively were obtained daily throughout all phases of the dosing 
and maintenance phases and included the number of episodes of fecal soiling per day, frequency and 
severity of abdominal pain and pain associated with antegrade flush administration measured using the 
WBFPRS as the age appropriate visual analog, and the presence of flush associated vagal symptoms. 
Serum electrolytes and stool for were calprotectin collected at the end of each dosing phase. Total flush 
volume was recorded with each flush and measured in mL.  Direct parental observation with event 
recording was used to track and tally soiling episodes defined as non-toilet elimination. Dependent 
variables were measured and recorded by the parent using a data collection sheet specifically designed 
for this study.  The parent was requested to call if the child was having accidents, discomfort greater 
than a 4 on the WBFPRS associated with the antegrade flush, or vagal symptoms. The investigator 
documented any event that could potentially cause a change in level, stability, or trend of the 
dependent variable not related to the intervention (i.e. initiation of antibiotics or an intercurrent illness).   
Materials  
Each child had a low-profile button in place to ease flush administration.  A cabinet was identified in the 
clinic space for storage of the flushing solution with continuous temperature monitoring using a MCC 


USB 501-LCD thermometer. The cabinet was locked with restricted key access. The temperature in the 
storage cabinet was consistently maintained between 15 and 30 degrees Centigrade.  A temperature 
monitoring log was completed daily. No ambient temperature excursions occurred. Flush solution type, 
volume dispensed, lot numbers, and flush solution dispensing time and date were recorded in a 
dispensing log.   
High Volume Flush  
Each child had a low-profile button in place to ease flush administration.  The normal saline was infused 
using a 1,000 mL enteral feeding bag with drip chamber and roller clamp hung from an IV pole or a hook 
on the bathroom wall located 5 feet above the toilet seat. Enteral feeding bag tubing and the low- 
profile device access tubing was primed with the high-volume flush prior to connecting the access tubing 
to the low-profile device and initiating the flush infusion. Step by step procedural directions were 
reviewed verbally with the parents and were reinforced through the provision of written instructions 
located in a parent notebook. The written procedure served as a check-off list to document procedural 
integrity which was checked during the initial home visit and each clinic visit scheduled with every 
change in flush solution and change in phase.  
Low Volume Flush  
 Each child had a low-profile button in place to ease flush administration.  For the low volume flush, 
room temperature USP glycerin was mixed with room temperature normal saline in a calibrated six- 
ounce plastic container with a screw top and subsequently poured into a 60 mL catheter-tipped syringe 
attached to the low-profile device access tubing. The tubing was primed and connected to the low -
profile device. The syringe containing flush solution was held at the child’s shoulder level while the flush 
solution infused. Following flush completion, the tubing and bag or syringe were washed in warm soapy 
water, thoroughly rinsed, and allowed to air dry. Step by step written procedural directions were 
included in a parent notebook and served both as procedural reinforcement and as a check-off list to 
document procedural integrity which was checked during the initial home visit and with each 
subsequent scheduled clinic visit completed with every change in flush solution and every change in 
phase.   
Procedures  
Randomization to one of the two treatment sequences occurred in the immediate postoperative period 
using restricted random assignment to force equal sample size and was accomplished using the SAS 
random number generator. 
High Volume Regimen   
The high-volume regimen consisted of normal saline flush at a starting dose of 10mL/kg infused every 
other day and adjusted by flush volume and frequency of administration until stability of target 
outcomes was achieved.  Notification of any fecal soiling resulted in an additional 5 mL/kg volume 
adjustment with a subsequent increase in administration frequency, if needed, so as not to exceed a 
maximum dose of 500 mL administered daily for a child under five years of age and 1000 mL 
administered daily for a child over 5 years of age. If the child could not achieve continence on the 
maximum dose and had not been trialed on the alternate therapy, they were trialed on USP glycerin but 
did not proceed to the maintenance phase of the study.  If the child experienced side effects greater 


than 4 on the WBFPRS at the starting saline dose, flush volume was incrementally decreased as needed 
by 2.5 mL/kg to the lowest dose of 5 mL/kg. The goal of the dosing phase was to identify the lowest 
effective dose and flushing frequency that resulted in continence with minimal side effects. If the dose 
required to minimize side effects resulted in fecal soiling or the child had side effects greater than 4 on 
the WBFPRS at the lowest flush dose, and had not been trialed on the alternate therapy, they were 
trialed on USP glycerin but did not proceed to the maintenance phase of the study.   
Low Volume Regimen  
The low volume regimen consisted of USP glycerin diluted in normal saline instilled through the low- 
profile device starting on a dose of 20 mL of USP glycerin mixed in >20 mL of saline and adjusted by flush 
volume and frequency of administration until stability of target outcomes was achieved.  The saline 
served as a diluent and was mixed at a sufficient dose to allow easy infusion of the solution through the 
ACE access tubing. Notification of any fecal soiling resulted in the addition of 5 to10 mL with subsequent 
increase in frequency of administration, if needed, so as not to exceed 50 mL of USP glycerin 
administered daily. If the child could not achieve continence on the maximum dose and had not been 
trialed on the alternate therapy, they were trialed on high volume normal saline but did not proceed to 
the maintenance phase of the study.  If the child experienced side effects greater than 4 on the WBFPRS 
at the starting USP glycerin dose, flush volume was incrementally decreased as needed by 5 mL 
increments to the lowest dose of 5 mL. The goal of the dosing phase was to identify the lowest effective 
dose and flushing frequency that resulted in continence with minimal side effects. If the dose required 
to minimize side effects resulted in fecal soiling or the child had side effects greater than 4 on the 
WBFPRS at the lowest flush dose, and had not been trialed on the alternate therapy, they were trialed 
on normal saline but did not proceed to the maintenance phase of the study.   
Optimal Dose Regimen   
Following optimal dose determination, the child was maintained on that volume and administration 
frequency for at least 2 weeks. A clinic visit was scheduled once the above criteria had been met. At that 
visit, the child was flushed at the optimal dose, labs were drawn, a stool sample collected, the procedure 
for the next regimen was reviewed with the parent and child, and procedural fidelity was ascertained.   
Regimen Maintenance Phase  
Following successful completion of the dose-response phase, patients were randomized for a second 
time to either a saline-glycerin-saline or a glycerin-saline-glycerin sequence. The maintenance phase of 
the study began by administering the established effective dose and frequency of administration for the 
first flush in the sequence. The child remained on treatment for 4 weeks. The treatment was withdrawn.  
The child was subsequently placed on the next treatment in the sequence at the pre-established 
effective dose and frequency for 4 weeks. The second flush was then withdrawn and the initial flush in 
the sequence was reintroduced for an additional two weeks. If the child experienced recurrence of fecal 
incontinence or discomfort greater than a 4 on the pain scale, they were dropped from the study. If they 
successfully completed the maintenance phase, the child was placed on the flushing regimen of his/her 
choice at the dose and frequency of administration that maintained continence.   
 


Specimen Collection  
A stool sample for calprotectin was obtained during the baseline phase prior to any pre-operative bowel 
prep and additional stool samples were obtained at the completion of each dosing phase for a total of 3 
samples. Blood samples for electrolytes were drawn preoperatively and postoperatively at the end of 
each dosing phase at the time stool samples were obtained for a total of three samples. Funding was 
secured. Accounts were set up with an outside lab for processing blood samples for electrolyte 
determination and a second outside lab for processing stool samples for calprotectin.  
Statistical Analysis  
This study was a within subjects design with all subjects demonstrating consistent fecal incontinence at 
baseline and sufficient intervention and post-intervention data points to allow for time series analysis. 
Data points were graphed on an equal interval 2:3 ratio ordinate and abscissa scale line graph to prevent 
data distortion during visual analysis.  Dependent measures were graphed on the ordinate scale with 
time-by-day graphed on the abscissa scale. Independent variable effects on target behaviors were 
analyzed using well established single-case methodology (Gast, 2010; Hartmann et al., 1980; Ma, 2006; 
Kazdin, 2011; Portney & Watkins, 2009).  Clinicaltrials.gov is not configured to allow reporting outcomes 
from most methods of within subjects data analysis. Reported data was limited to the results from 
numeric descriptive and inferential analysis that could be adapted to the Clinicaltrials.gov format. 
In addition to single-case analytic methodology, descriptive and inferential analysis was used to 
compare interventional effects and increase the reliability of visual methods analysis.  Both the dosing 
and maintenance phase of the study constituted a 2-treatment crossover design with each child 
receiving both treatments in both interventional phases of the study (Portney & Watkins, 2009).    
Descriptive statistics included mean, median, range and standard deviation. A cross-over design 
compares two treatment sequences; therefore, the groups are independent (Chow & Liu, 2014). Of 
concern, carry over and direct-by-period interaction is a potential confound with cross-over designs, 
which if present, could bias treatment effects (Jones & Kenward, 2003; Senn, 2002; Shuster, 2007).  The 
decision was made to use a two-tailed, two-sample pooled variance t-test to lend precision in the 
presence of carry over effects, and precision and accuracy in the presence of unequal sample size 
(Shuster, 2009).  Significance level was set a priori at 0.05.  Effect size was used to determine the 
magnitude of the treatment difference (Polit, 2010; Rempher & Silkman, 2007).