Conditions: Encopresis Autism Spectrum Disorder
Keywords: Constipation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 117
Healthy volunteers: no

Brief summary:
This study is comparing a multidisciplinary intervention for encopresis (MIE), consisting of both medical and behavioral components to treatment as usual control (TAU). Participants are first screened by a pediatric gastroenterologist and assessed and treated for any constipation or other potential medical complications. Following this, caregivers collect data on bowel movements and continence during a home baseline lasting no less than 14 days and no more than 21 days. Participants randomly assigned to treatment as usual or the treatment group, and begin attending daily appointments in clinic for 2 weeks. At appointments, the behavior team implements structured sits on the toilet to promote independent bowel movements (BMs). If an independent BM does not occur, the study team will administer a suppository to promote rapid release of the bowels and prompt the child to remain on the toilet following administration. In doing so, continent bowel movements are predictably evoked while the child is on the toilet, allowing for reinforcement with praise and preferred toys/activities. Eventually, suppositories are gradually decreased until the child is having BMs independently. Caregivers are trained to continue implementing the intervention following the clinic-based portion.

The purpose of the current study is to evaluate MIE using a large randomized clinical trial (RCT), addressing the Department of Defense Autism Research Program, Area of Interest of Therapies to Alleviate Conditions Co-Occurring with autism spectrum disorder (ASD). The researchers will recruit 112 children diagnosed with ASD, randomizing them to two weeks of MIE, or treatment as usual (TAU) consisting of behavioral consultation and medical intervention. This study will evaluate MIE compared to TAU and determine the optimal treatment length.

Detailed description:
Toilet training one's child is a nearly universal challenge for parents, but is a particularly distressing ordeal for parents of individuals with autism spectrum disorder (ASD). Whereas typically developing children generally stop having daytime toileting accidents (i.e., they achieve continence) by 2-4 years of age, most individuals with ASD are either delayed in their acquisition of toileting skills, or never achieve continence. Furthermore, toileting concerns are a significant contributor to the increased stress experienced by caregivers of those with ASD. Besides dramatically increasing their burden of care, not being fully toilet trained negatively impacts the individual with ASD's hygiene, self-confidence, physical comfort, and independence while also causing social stigma. Incontinence can also have serious collateral consequences, such as limiting exposure to important life experiences. Furthermore, without effective treatment these problems generally persist into adulthood.

One reason why strictly behavioral treatments of encopresis have shown only limited success may be due to the fact that it often has a medical etiology. Encopresis is when underwear are soiled by stool in children over the age of toilet training and long-standing constipation is the cause of encopresis in the majority of children who exhibit it. Children with ASD are more likely to have constipation than typically developing children. Constipation causes encopresis by creating a cycle of withholding bowel movements (withholding is the voluntary contraction of the external sphincter to avoid a bowel movement): constipation causes painful bowel movements, which triggers further withholding behavior, exacerbating constipation. Over time the colon adapts by dilating, which leads to larger fecal masses in the rectum. Thus, the passage of larger and harder (i.e., painful) stools further increases an individual's withholding behavior. Over time, the rectum and colon become so dilated that the individual loses sensation. With no urge to defecate, an individual is even more likely to have stool accumulate in the rectum and is also unable to control bowel movements. Looser stool may leak around hard stool leading to an unintended leakage and sometimes large evacuation of stool occurs without the individual realizing it.

Although purely medical approaches can successfully treat constipation in individuals with ASD, they have not shown long term success with encopresis. That is, medical approaches can treat a single episode of constipation, but without acquiring toileting skills, the individual is likely to become constipated again, repeating the cycle. Conversely, purely behavioral strategies have not been shown to be effective at treating encopresis in individuals with ASD, even when they are not experiencing constipation. One reason for this lack of success may have to do with the fact that it is often difficult to predict the timing of a bowel movement so that caregivers can ensure the individual is sitting on the toilet when one takes place and then reinforce continence. Thus, a multidisciplinary approach incorporating both medical and behavioral approaches is necessary in the treatment of encopresis in individuals with ASD.

This is an 8-week, randomized clinical trial of 112 children, ages 5 to 12 years, 11 months with ASD and encopresis. Participants will be randomized to receive either two weeks of MIE or one week of TAU. The study initially had a third study arm of one week of MIE treatment, which was discontinued in October of 2019.

Arms:
arm 1: Participants in this arm will receive the Multidisciplinary Intervention for Encopresis (MIE) for two weeks. MIE consists of daily clinic appointments, each of which lasts until a continent bowel movement occurs or 3 hours elapse. These participants will discontinue the use of medication previously prescribed for the treatment of constipation, other than the suppositories used in the MIE treatment. During MIE, medical professionals resolve any constipation and oversee a regimen of over the counter medications that increase the predictability of a bowel movement. arm 2: Participants randomized to the Treatment as Usual (TAU) group will continue to receive outpatient medical treatment of encopresis according to best practice guidelines by the pediatric gastroenterologist. Additionally, participants in the TAU group will receive a 2-hour long individual appointment with a doctoral level clinician with extensive experience in behavioral treatments for encopresis. arm 3: Participants in this arm will receive the Multidisciplinary Intervention for Encopresis (MIE) for one week. This study arm was discontinued in October 2019.

Interventions: intervention 1: MIE Treatment intervention 2: Glycerin Suppository intervention 3: Treatment as Usual (TAU)
Intervention descriptions: intervention 1: Appointments consist of a series of sitting routines (i.e., "sits"). Each sit consists of 10 min on the toilet, followed by 1 min of standing, then repeating the 10 min on the toilet 1 min off, for up to 32 cumulative minutes of sitting. The first sit occurs prior to the administration of any medication providing an opportunity for an independent continent bowel movement. intervention 2: If no continent bowel movement occurs with the first sit, trained staff administer a dose of a liquid glycerin suppository, immediately followed by another sit to ensure any resulting bowel movement is continent. Glycerin suppositories are replaced by bisacodyl if 2 days pass without a continent bowel movement using the liquid glycerin suppository. Behavioral intervention consists of potent positive reinforcers when a continent bowel movement occurs. As independent continent bowel movements begin to occur, the need for the medical regimen diminishes, and is gradually faded out entirely. intervention 3: Participants randomized to the Treatment as Usual (TAU) group will continue to receive outpatient medical treatment of encopresis according to best practice guidelines by the pediatric gastroenterologist. In addition, participants in the TAU group will receive a 2-hour individual appointment in clinic with a doctoral level clinician with extensive experience in behavioral treatments for encopresis. During the appointment, the clinician will review strategies to increase continence by providing parent education on the following topics: how to collect and evaluate data on their child's bowel movements, how to establish and use a sit schedule, identifying behaviors that are precursors to bowel movements and how to use them to increase the probability of a bowel movement being continent, consequences for incontinence, and reinforcement for continence.

Protocol document:
Prot_SAP_001.pdf: 
Version 4.3, 8/24/2021 
 
Page 1 of 34 
 
A Multidisciplinary Approach to the Treatment of Encopresis in Children with Autism 
Spectrum Disorders 
 
Department of Defense Study 
 
PI: Nathan Call, Ph.D. 
Assistant Professor of Pediatrics - Division of Autism and Related Disorders 
 
Marcus Autism Center 
 
NCT Number: NCT03197922 
 
Protocol Version 4.3 
Protocol date: August 24, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.3, 8/24/2021 
 
Page 2 of 34 
 
History of Protocol Changes 
 
Version 4.3 08/24/2021 
• Added REDCap as a data collection tool for collecting consent signature and 
parent measures. 
Version 4.2 06/15/2020 
• Added in the ADI-R and CARS-2 assessments as additional ASD diagnostic tools 
• Added in the option to do the medical assessment through telehealth, 
specifically zoom 
Version 4.1 03/18/2020 
• Added language to include that TAU and MIE appointments can be through 
Telehealth 
• Corrected total enrollment number to 138 instead of 112 because 112 did not 
include the participants that were previously enrolled into the MIE 1 week 
group 
Version 4.0 10/15/2019 
• Removed MIE 1 week group 
• Corrected visit window and continence language 
 
Version 3.9 05/30/2019 
• Corrected title of protocol 
• Changed IRB notification of “would” to “may” for cases of problem behavior. 
• Removed language about participants being enrolled in IRB #53959. 
• Included information on holds/restraining for participants engaging in problem 
behavior 
 
Version 3.8 01/24/2019 
• We changed the definition of “urine continent” under our inclusion criteria.  It 
will now be “Over half of the voids are continent when the child is with the 
parent and when the child is on a typical toileting routine. 
• We removed number 6 under inclusion criteria because in our last amendment 
we said subject would no longer be enrolled in our IRB# 53959 
• We removed the section on the top of page 22 that says, “Also, subjects will be 
enrolled in IRB 53959 (MAC), which permits and facilitates the collection of their 
data. If the subject does not agree to be in IRB 53959, they will be excluded”  
• Version 3.7 06/18/2018 
• Medical screening can be conducted by a nurse practitioner with consultation 
from a pediatric gastroenterologist 
• Subjects will no longer be enrolled in our IRB #53959 
 
Version 3.6 


Version 4.3, 8/24/2021 
 
Page 3 of 34 
 
• In Recruitment section, revised protocol to state that we will now be using the 
Oral Consent and HIPAA Authorization Script and Information Sheet for Research 
Study Screening instead of the Screening Protocol – IRB# 00057294 
 
Version 3.5, drafted 01/08/2018 
• Randomization to group assignment will now take place after Characterization 
and Medical Screening are completed (after all eligibility criteria have been met) 
• Visit windows for Week 4 (midpoint), Week 8 (endpoint), and Week 28 (follow-
up) will be counted from Baseline Visit (the day baseline measures are collected) 
• Added concomitant medication log to table of measures, baseline, midpoint,   
endpoint and follow up 
• In the Screening Process section, edited protocol to state that we will now be 
using the Oral Consent and HIPAA Authorization Script and Information Sheet 
For Research Study Screening instead of the Screening Protocol – IRB #00057294 
 
Version 3.4, drafted 11/27/2017 
• Added caregiver log of frequency of child’s continent and incontinent bowel 
movements to the time period between the phone screen and characterization 
appointment 
• Added the Mullen Scales of Early Learning (MSEL) as a possible characterization 
measure 
• Added research coordinators to the list of personnel who will administer 
characterization measures  
• Renamed screening as Characterization and Medical Evaluation to differentiate it 
from Phone Screen. 
• Stipulated that the Characterization and Medical Evaluation can take place 
across 1 or 2 days. 
• Corrected an error in the dosing of the suppository. 
• Increased the visit windows for the Endpoint and Follow up 
• Added Midpoint to the schedule of measures 
• Added statement that the BPI will be reviewed by a doctoral level member of the 
study team at Characterization to determine participants do not meet exclusion 
criterion for interfering problem behavior. 
• Clarified that the sequence of characterization and medical screening can vary 
• Clarified that the TAU appointment can last up to 2 hours, but does not have to 
last exactly 2 hours 
• Added a section describing the informed consent process 
• Added the Verbal Consent form to the Screening process 
 
 
Version 3.3, drafted 09/25/2017 
• Updated the definition of continence 
 


Version 4.3, 8/24/2021 
 
Page 4 of 34 
 
Version 3.2, drafted 09/20/2017 
• Added caregiver log of frequency of child’s continent and incontinent bowel 
movements to the time period between the phone screen and characterization 
appointment 
• Added the Mullen Scales of Early Learning (MSEL) as a possible characterization 
measure 
• Added research coordinators to the list of personnel who will administer 
characterization measures  
• Updated specific aims  
• Added Analytic plan 
• Updated reporting method of AE’s and SAE’s 
• Added dosing table (Table 3.0) 
 
Version 3.1, drafted 09/19/2017 
• Clarified that the visit to the gastroenterologist will be uploaded to the medical 
record 
• Visit windows for Week 8 and Week 28 will be counted from the start of 
treatment and not from Baseline. This is because the Baseline window ranges 
from 2-3 weeks before treatment starts 
• Modified Week 8 visit window to be 6 weeks +/- 3 days from the start of 
treatment and Week 28 visit window to be 26 weeks +/- 5 days from the start of 
treatment  
• Treatment (either MIE or TAU) must occur 12-21 days after Baseline. During this 
time families must collect 7 days of home toileting data (data sheets will be 
provided to families). These 7 days do not need to be consecutive.  
• Added description of Case Panel reviews when exceptions to Inclusion/Exclusion 
criteria occur 
• Changed CGSQ to CGSQ-Short Form (CGSQ-SF) 
• Added CGSQ-SF to Week 8 
 
Version 3.0, drafted 07/06/2017 
• Added Aberrant Behavior Checklist 
• Added King’s Stool Chart 
• Updated Inclusion/Exclusion criteria to clarify that all medical conditions will be 
reviewed by study team to determine eligibility  
• Updated Inclusion/Exclusion criteria to add that we will only enroll subjects with 
one or fewer episodes of incontinent urination each day 
• Added recruitment projection table 
 
 
Version 2.0, drafted 05/02/2017 
• Added description of intervention methods 
• Added schedule of measures 


Version 4.3, 8/24/2021 
 
Page 5 of 34 
 
• Added description of Adverse Event review and Data Safety Monitoring Plan 
• Added visit windows for all assessment visits 
• Described the minimum number of MIE appointments required for both 1- and 
2-week MIE treatment groups 
• Described the different amount of study medication subjects in the MIE 
treatment groups will be sent home with and how this determination is made 
 
Version 1.0, drafted 03/28/2017 
Original protocol submission 
Background & Significance 
 
Toilet training one's child is a nearly universal challenge for parents, but is a 
particularly distressing ordeal for parents of individuals with autism spectrum disorder 
(ASD). Whereas typically developing children generally stop having daytime toileting 
accidents (i.e., they achieve continence) by 2-4 years of age (Blum, Taubman, & Meneth, 
2003; Butler, 1997; Heron, Joinson, Croudace, & von Gontard, 2008; Schum et al., 2005), 
most individuals with ASD are either delayed in their acquisition of toileting skills, or 
never achieve continence. Furthermore, toileting concerns are a significant contributor 
to the increased stress experienced by caregivers of those with ASD (Macias, Roberts, 
Saylor, & Fussell, 2006). Besides dramatically increasing their burden of care, not being 
fully toilet trained negatively impacts the individual with ASD's hygiene, self-confidence, 
physical comfort, and independence while also causing social stigma (Cicero & Pfadt, 
2002; Sells-Love, Rinaldi, & McLaughlin, 2002). Incontinence can also have serious 
collateral consequences, such as limiting exposure to important life experiences. 
Furthermore, without effective treatment these problems generally persist into 
adulthood (Benninga, Voskuijl, & Taminiau, 2004). 
 
Only a small number of studies report successful treatment of encopresis in 
individuals with ASD. In an example of one of the few such studies, Smith (1996) 
describes successful treatment of encopresis in 5 teenage boys. Treatment included 
frequent checks for incontinent bowel movements, with reinforcement for staying 
clean. Participants were also encouraged to sit on the toilet for at least 10 min following 
meals, in the hope that a continent bowel movement would occur that could be 
positively reinforced. Although this and a few other studies report successful treatment 
of encopresis, they have all been case studies with a small number of participants (Lyon, 
1984; Scott, 1977), with the results for the five participants by Smith representing one of 
the largest samples to date. These existing studies have also employed weak 
experimental designs (Lancioni & Markus, 1999). Most also fail to provide information 
about important participant characteristics such as cognitive and receptive language 
skills (Cicero & Pfadt, 2002; Post & Kirkpatrick, 2004). Many also fail to provide basic 
details about training procedures and outcome measures, or included participants with 
and without disabilities (Lancioni, O’Reilly, & Basili, 2001). Perhaps most limiting, the 
majority of published examples of the successful treatment of encopresis have required 


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implementation over long periods. For example, the average duration of treatment in 
the study by Smith was 98 weeks. The combined effect of these limitations is that 
encopresis generally remains untreated in most individuals with ASD. 
 
One reason why strictly behavioral treatments of encopresis have shown only 
limited success may be due to the fact that it often has a medical etiology. That is, long-
standing constipation is the cause of encopresis in the majority of children who exhibit it 
(Chase, Homsy, Siggaard, Sit, & Bower, 2004; Mason, Tobias, Lutkenhoff, Stoops, & 
Ferguson, 2004; Koivusalo, Pakarinsen, & Rintala, 2006). Children with ASD are 3.8 times 
more likely to have constipation than typically developing children (McElhanon, 
McCracken, Karpen, & Sharp, in press). Constipation causes encopresis by creating a 
cycle of withholding bowel movements: constipation causes painful bowel movements, 
which triggers further withholding behavior (Fishman, Rappaport, Cousineau, & Nurko, 
2002), exacerbating constipation. Withholding is the voluntary contraction of the 
external sphincter to avoid a bowel movement. Subsequently, the colon accommodates 
the fecal mass and the urge to defecate is delayed. The postponed bowel movement 
allows more water to be absorbed from the colon and creates a harder stool. Over time 
the colon adapts by dilating, which leads to larger fecal masses in the rectum. Thus, the 
passage of larger and harder (i.e., painful) stools further increases an individual's 
withholding behavior. Of note, 63% of children with encopresis have a history of painful 
defecation beginning before 36 months of age (Lewis & Rudolph, 1997). Over time, the 
rectum and colon become so dilated that the individual loses sensation. With no urge to 
defecate, an individual is even more likely to have stool accumulate in the rectum and is 
also unable to control bowel movements. Looser stool may leak around hard stool 
leading to an unintended leakage and sometimes large evacuation of stool occurs 
without the individual realizing it. 
 
Although purely medical approaches can successfully treat constipation in 
individuals with ASD, they have not shown long term success with encopresis. That is, 
medical approaches can treat a single episode of constipation, but without acquiring 
toileting skills, the individual is likely to become constipated again, repeating the cycle 
(29). Conversely, purely behavioral strategies have not been shown to be effective at 
treating encopresis in individuals with ASD, even when they are not experiencing 
constipation (see above). One reason for this lack of success may have to do with the 
fact that it is often difficult to predict the timing of a bowel movement so that caregivers 
can ensure the individual is sitting on the toilet when one takes place and then reinforce 
continence.  
 
Thus, it is clear that a multidisciplinary approach incorporating both medical and 
behavioral approaches is necessary in the treatment of encopresis in individuals with 
ASD. Medical approaches can resolve episodes of constipation prior to treatment and 
provide a regimen that increases the predictability of a bowel movement, allowing 
clinicians to prompt the individual to sit on the toilet beforehand. Once a continent 
bowel movement occurs it is then amenable to behavioral strategies such as positive 


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reinforcement. A few promising interventions to date have attempted such a combined 
behavioral/medical approach. For example, Piazza, Fisher, Chinn, and Bowman (1991) 
reported successful treatment of encopresis in two participants using hourly trips to the 
toilet, positive reinforcement, and laxatives. Despite promising results, such studies are 
few in number and include only a few participants each. Furthermore, no studies to date 
have incorporated good experimental control. That is, the multiple behavioral and 
medical procedures were introduced and/or removed in a non-systematic fashion, 
making it impossible to determine which elements contributed to the results. 
 
In response to the absence of an effective treatment for encopresis in this 
population, our clinical team developed a novel Multidisciplinary Intervention for 
Encopresis (MIE) in children with ASD.  Within MIE, medical professionals resolve any 
constipation and oversee a regimen of over the counter medications that increase the 
predictability of a bowel movement.  Our medical regimen differs from those employed 
in previous studies. Prior studies have used laxatives, enemas, or a combination of 
these. However, suppositories are more appropriate for this purpose because bowel 
movements generally occur shortly after they are administered. The medication 
regimen employed in this study includes the use of a glycerin suppository. These work 
by attracting water into the rectum and gently promoting a bowel movement (Fleet 
Company Incorporated). If a glycerin suppository is insufficient to elicit a bowel 
movement alone, then a bisacodyl suppository is administered, which directly 
stimulates sensory nerves, amplifies peristaltic contractions, and moves feces out within 
15 minutes to an hour (Physicians’ Desk Reference Network, LLC). When a continent 
bowel movement occurs, potent positive reinforcers that have been identified 
previously are administered. Previous research on treating encopresis and enuresis has 
suggested that such reinforcement is often sufficient to increase the child's motivation 
to have continent bowel movements. As independent continent bowel movements 
begin to occur, the need for the medical regimen diminishes, and is gradually faded out 
entirely. The goal of MIE is to establish sufficient continence during clinic-based 
treatment that the intervention can be turned over to caregivers following training and 
further increase independent continence.  Significantly, treatment in the clinical setting 
lasts for no more than 10 days, with many patients achieving initial continence in as 
little as 5 days.  
 
It is important to note that although the use of rectal suppositories may seem 
invasive, a majority of the patients receiving MIE to date have been receiving regular 
administration of suppositories or more invasive procedures (i.e., enemas) prior to 
starting MIE to manage constipation.  Furthermore, long term use of these medical 
procedures is likely to be required without an effective treatment.  For example, we 
treated one young man who required regular sedation (i.e., approximately every 3 
weeks) in order to receive an enema because he almost never had a bowel movement 
and became combative when his caregivers or gastroenterologist attempted to remove 
impacted stool using an enema.  This cycle of highly invasive procedures had become so 
chronic that his doctor was considering inserting a stoma and attached colostomy bag.  


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Instead, this patient successfully completed MIE and is now consistently independent in 
his continence.  Thus, for patients in need of MIE, like this young man, the use of 
suppositories is either not new and/or is less intrusive than the alternatives.  Finally, 
caregivers of participants in a pilot study of MIE did not appear to be concerned about 
the use of suppositories, as on average they rated MIE as 6.9 out of a possible 7 on 
program acceptability. 
 
Further strengthening our project is the fact that our interdisciplinary research group 
has implemented this treatment protocol clinically with good success.  To date, we have 
conducted MIE in the Toileting Services Program of the Marcus Autism Center with 34 
patients (31 males, 3 females), ranging in age from 3 to 14 years (M = 8.37 years).  To 
date we have been able to collect follow-up data on maintenance of continence for 15 
of these patients approximately 4 months after discharge.  Using the definition of 
continence appearing in the literature of fewer than 3 bowel movement accidents per 
week (Blum et al., 2004), 93% of patients who had completed MIE maintained 
continence at follow-up.  Furthermore, for 67% of these patients’ caregivers reported 
that their child had no bowel movement accidents following discharge from MIE.  
 
 
Specific Aims 
Primary Aims  
 
1) Evaluate the efficacy of a two-week, multidisciplinary intervention for encopresis 
(MIE-2) in children with ASD compared to controls receiving Treatment as Usual (TAU). 
We predict, based on parent report, that a significantly greater proportion of subjects in 
the MIE-2 group will achieve continence at endpoint (Week 8) than children in TAU.  
 
2) Evaluate whether the MIE-2 group will have a significantly higher proportion of 
children rated Much Improved or Very Much Improved on the Improvement item of the 
Clinical Global Impression than children in TAU as rated by an Independent Evaluator 
blind to treatment assignment at Week 8.  
 
3) Evaluate whether parents of children in MIE-2 will report greater reduction from 
baseline in parental stress and strain than parents of children in TAU at endpoint (Week 
8) as measured on the Parenting Stress Index and the Caregiver Strain Questionnaire.  
 
 
Procedures 
This is a 28-week, randomized clinical trial of 138 (updated from 150) children, ages 5 to 
12 years, 11 months with ASD and encopresis. Subjects will be randomized in a 1:1 ratio 
to receive either two weeks of MIE or one week of Treatment as Usual (TAU). See Figure 
1 for an outline of study procedures described below.  


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As shown in the Figure, Week 8 is an important nodal point in the study.  At Week 8, 
participants will be classified as having achieved continence or not. This classification at 
Week 8 is the primary outcome for the study. 
 
 
Figure 1 
Screening: Prior to enrollment all potential participants will be evaluated for study 
eligibility through an initial phone screen. At the beginning of this screening, we will 
provide the family with a short study synopsis. We will then complete the Oral Consent 
and HIPAA Authorization Script and Information Sheet for Research Study Screening. 
This is a verbal consent form that gives us permission to collect and store protected 
health information over the phone. This form will be read to the families to ensure they 
understand the information we are collecting and their rights as a research subject.    
This screening will consist of gathering information on the participants’ age, parent 
reported diagnosis, and problem behavior.  Participants will be excluded if their 
caregiver does not report that the child meets the age or diagnostic criteria.  If the 
caregiver indicates that the child engages in problem behavior, additional information 


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will be gathered to determine if problem behavior is likely to interfere with the 
treatment protocol.  If problem behavior is deemed likely to interfere they will be 
excluded from participation.  Caregivers will also be asked to keep a log of the frequency 
of their child’s continent and incontinent bowel movements from the day of the phone 
screen until the characterization appointment to further confirm study eligibility. 
 
Characterization, the Medical Assessment, and collection of Baseline Measures will 
take place across either 1 or 2 days, depending on participant and clinician availability, 
as well as the ability of the participant to tolerate lengthy assessments.  Although the 
medical screening may precede characterization if scheduling requires, characterization 
will take place first whenever possible because participants are thought to be more 
likely to meet diagnostic exclusionary criteria than medical exclusionary criteria. 
 
Consenting: A member of the research team will obtain informed consent from the 
caregiver(s) of each participant prior to completing any study procedures. We will not 
obtain assent from participants because it is anticipated that most will not possess the 
cognitive capacity to give assent and because refusal to comply with toileting routines is 
the condition that is being targeted for intervention. At this meeting caregivers will be 
asked to keep concomitant medications stable and to notify us if this is not the case 
during the study. Caregivers of participants will be provided a handout that addresses 
frequently asked questions about the use of suppositories. 
 
Characterization: Once a participant has completed the phone screening a research 
coordinator will schedule an appointment for characterization.  This appointment will 
include completion of the Autism Diagnostic Observation Schedule (ADOS), Autism 
Diagnostic Interview – Revised (ADI-R), and/or Childhood Autism Rating Scale – Second 
Edition (CARS-2), Vineland Adaptive Behavior Scales-3, Child Symptom Inventory, 
Demographics (i.e., Global Unique Identifier [GUID], The Behavior Problem Inventory 
(BPI) and either The Differential Ability Scales (DAS-II) or The Mullen Scales of Early 
Learning (MSEL) (depending on participant age; See Table 1 – Schedule of Measures). 
Characterization measures will be administered by doctoral level psychologists, post-
doctoral fellows working under the supervision of a licensed psychologist, or research 
coordinators. A doctoral level member of the study team will review the BPI to 
determine whether participants meet the exclusionary criterion based on the presence 
of problem behavior that is likely to interfere with treatment.  
 
 
Medical Assessment: Following the characterization appointment, all participants 
with a confirmed ASD diagnosis will undergo Medical Screening by a licensed and board-
certified pediatric gastroenterologist or a nurse practitioner (NP) working in 
consultation with a board-certified pediatric gastroenterologist, to ensure that the 
participant meets medical inclusion criteria and to provide medical clearance for use of 
glycerin suppositories and bisacodyl suppositories. In addition, during this appointment 
participants will be evaluated to determine constipation status and begin treatment for 


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constipation per established guidelines (Furata et al., 2012), if necessary.  During the 
medical screening, the physician and/or NP will confirm that the participant is eligible 
(i.e. does not meet medical exclusions as above). Participants randomized to the 
Treatment as Usual Group (TAU) and who are also constipated will continue to receive 
treatment for constipation throughout the clinical trial and follow-up.  Participants 
randomly assigned to the MIE treatment group will also be evaluated for constipation 
and receive medical treatment during baseline.  The medical assessment will take place 
either in the building at Marcus or via telehealth, specifically zoom. 
 
Group Assignment: Participants will be randomly assigned to one of the two groups 
after they have it has been verified that they meet all of the eligibility criteria.  
Randomization to 2-week MIE or TAU will be according to a 1:1 ratio using permuted 
blocks stratification on constipation status.  The permuted blocks will be constructed 
and managed by the unblinded statistician.  She will receive an email form from the 
coordinator indicating that the participant meets all inclusion criteria and does not meet 
any exclusion criteria and the participant’s constipation status (constipated/not 
constipated).  This statistician will assign the subject to 2-week MIE or TAU according to 
the permuted block.  We define constipated using the modified Rome III criteria 
appearing above.  All other participants will be considered not constipated. Caregivers 
of participants randomly assigned to the MIE condition (i.e., 2 week) will be provided a 
handout that addresses frequently asked questions about the use of suppositories.   
In the event a participant is unable to attend MIE or TAU visit(s) in the clinic after 
being enrolled into their assigned group, the clinician and therapists have the option to 
administer the intervention or TAU consultation via telehealth with the participant (e.g., 
WebEx, Zoom).  In order to utilize telehealth, a scenario must arise that prevents the 
participant from being able to complete the MIE treatment or TAU consultation in the 
clinic.  If such a scenario arises, on a case-by-case basis, then the therapist and clinician 
may administer via telehealth, but should return to the clinic as soon as possible to 
continue.  Additionally, there will be one extra day added to the MIE 2-week treatment 
totaling 11 days instead of 10.  The extra day is added to the beginning of treatment so 
the clinician can first explain the intervention they will be doing with the caregiver. 
 
Baseline Phase (Weeks 1-2): All participants’ caregivers, regardless of group 
assignment will implement any medical recommendations for constipation throughout a 
Baseline Phase.  In addition, all caregivers will collect data on their child’s bowel 
movements during Baseline.  It is anticipated that this phase will last for 14 days, but 
due to scheduling issues it may last for 12 to 21 days. Data collection will include 
frequency of continent and incontinent bowel movements and whether any medication 
(i.e., a suppository) was used prior to the bowel movement on data sheets provided by 
the research team.  Caregivers will be asked to enter data from the datasheets 
electronically directly into our project database via a unique and secure login provided 
during the characterization visit.  Caregivers who do not enter data for a given day will 
receive a reminder email the next day.  A research coordinator will also call caregivers 
who are missing data on a weekly basis to see if they entered it on the datasheet but did 


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not enter it electronically.  In cases in which the family does not have access to the 
internet, the data will be collected over the phone.  Caregivers will be asked to bring the 
data sheets to their first visit in the clinic.  
 
Baseline Visit: Baseline data will be collected on the first day of MIE or TAU, before the 
appointment occurs. A member of the research team will meet with caregivers to 
complete the remaining baseline measures.  The following measures will be completed: 
Parent Target Problem (PTP), Parenting Stress Index-Short Form (PSI-SF), Aberrant 
Behavior Checklist (ABC) Clinician Global Impression-Severity (CGI-S), Caregiver Strain 
Questionnaire-Short Form (CGSQ-SF), Adverse Event, Safety Review, Concomitant 
Medication Log . 
 
Treatment (Weeks 3-4): Participants randomized to the TAU group will continue to 
receive outpatient medical treatment of encopresis according to best practice guidelines 
by the pediatric gastroenterologist.  In addition, participants in the TAU group will 
receive an individual appointment lasting up to 2-hours in clinic or via telehealth with a 
doctoral level clinician with extensive experience in behavioral treatments for 
encopresis.  This outpatient appointment will include didactic presentation of a 
PowerPoint presentation and consultation regarding treatment of encopresis.  During 
the appointment, the clinician will review strategies to increase continence.  Specifically, 
the clinician will provide parent education on the following topics: how to collect and 
evaluate data on their child’s bowel movements, how to establish and use a sit 
schedule, identifying behaviors that are precursors to bowel movements and how to use 
them to increase the probability of a bowel movement being continent, consequences 
for incontinence, and reinforcement for continence.  These recommendations will be 
individualized based upon data collected during baseline.  In addition, participants in the 
TAU group will continue to implement any medical treatment for constipation as 
prescribed.  
 
Following the baseline phase, participants randomly assigned to the MIE group (i.e. 
2 weeks) will begin treatment in the form of daily clinic visits or via telehealth (≤3 
hrs./appointment) for 2 weeks (5 days/week).  In addition, these participants will 
discontinue the use of medication prescribed for the treatment of constipation, other 
than the suppositories used in the MIE treatment.  [RATIONALE: it is expected that 
participants will have daily bowel movements during the 2 weeks of MIE, and laxatives 
or other medicines may interfere with participants’ ability to recognize and act upon the 
need to have a bowel movement (i.e., “pushing”)].  During treatment all participants 
receiving MIE will be monitored for constipation and the pediatric gastroenterologist 
will be contacted to determine if additional medications are needed if more than three 
days pass without a bowel movement.  At the conclusion of the clinic-based phase of 
treatment caregivers will be trained to implement MIE with ≥90% fidelity to the 
protocol, and told to continue to use the procedures upon discharge.   
 
Assessments during the randomized trial Assessment of therapeutic response and 


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adverse events will be conducted at Midpoint (Week 4) and Endpoint (Week 8).  
Outcome measures, including the Parent-nominated Target Problem (PTP), will be 
conducted by separate independent evaluators (IE) each of whom are blind to 
treatment assignment. Additional measures collected at the Endpoint visit include the 
Parent Target Problem, Parent Stress Index, Caregiver Strain Questionnaire, and 
Treatment Acceptability Rating Form- Revised, Aberrant Behavior Checklist, Clinician 
Global Impression-Improvement, Clinician Global Impression-Severity, Concomitant 
Medication Log, Safety Review, and Adverse Events(see Table 1). 
 
Follow-up (Weeks 26-28): At Week 17 caregivers will be reminded that we will 
evaluate their child’s progress during Weeks 27 and 28.  Data collection during this 
follow-up period replicates the procedures during baseline and treatment (caregiver 
recording of continent/incontinent bowel movements, the use of medication, and self-
initiation).  In addition, all measures collected at the endpoint visit in the randomized 
trial will be repeated at the conclusion of Follow-up (Week 28), including the Parent 
Target Problem, Parent Stress Index, Caregiver Strain Questionnaire, and Treatment 
Acceptability Rating Form- Revised, Aberrant Behavior Checklist, Clinician Global 
Impression-Improvement, Clinician Global Impression-Severity, Concomitant Medication 
Log, Safety Review, and Adverse Events.  
 
Schedule of Measures 
 
Table 1.0 – Schedule of Measures 
 
Characterization & 
Medical 
Assessment 
Baseline 
Measures 
Treatment 
(MIE) 
Week 4 
(Midpoint) 
Week 8 
(Endpoint) 
Week 28 
(Follow Up) 
Staff 
Time 
(m) 
ABC 
 
X 
 
X 
X 
X 
IE 
15 
ADOS, ADI, and/or 
CARS-2 
X 
 
 
 
 
 
CAC 
60 
BPI 
X 
 
 
 
 
 
RC 
15 
CGI-I 
 
 
 
X 
X 
X 
IE 
5 
CGI-S 
 
X 
 
X 
X 
X 
IE 
5 
CGSQ-SF 
 
X 
 
 
X 
X 
CG 
7 
Constipation Status 
X 
 
 
 
 
 
GI 
30 
MPHR 
X 
 
 
 
 
 
RC 
10 
CSI 
X 
 
 
 
 
 
RC 
15 
DAS or Mullen 
X 
 
 
 
 
 
CAC 
45 
Demographics 
X 
 
 
 
 
 
CG 
10 
PSI 
 
X 
 
 
X 
X 
CG 
5 
PTP 
 
X 
 
X 
X 
X 
IE 
20 
TARF-R 
 
 
 
 
X 
X 
IE 
15 
Concomitant 
Medication Log 
 
X 
 
X 
X 
X 
IE 
10 
Adverse Event 
 
X 
 
X 
X 
X 
IE 
5 
Safety Review 
 
X 
 
X 
X 
X 
IE 
10 
Vineland (Survey) 
X 
 
 
 
 
 
RC 
30 
Therapist Measures 
 
 
 
 
 
 
 
 
Continence 
 
 
Daily 
X 
 
 
TH 
- 


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during 
MIE 
Independence 
 
 
Daily 
during 
MIE 
X 
 
 
TH 
- 
 
Table 2.0 - Caregiver Home Data Collection Schedule 
Study Phase 
Baseline 
Treatment 
No Contact 
Follow Up 
Study Phase duration 2-3 Weeks 
8 Weeks 
18 Weeks 
2 Weeks 
Measures 
 
 
 
 
Continence 
Daily 
Daily 
- 
Daily 
Independence 
Daily 
Daily 
- 
Daily 
King’s Stool Chart 
Daily 
Daily 
- 
Daily 
 
Reminder Calls: During the 18 Week Home Implementation Phase, the study team will 
make monthly, scripted phone calls to participants. These phone calls will serve to 
remind the parents to continue to implement the intervention procedures they were 
taught and to confirm that they have an adequate supply of study medication. These 
calls will be scripted and parents will not be given any additional insight or clinical 
guidance. If necessary, parents will be reminded that they are participating in a research 
study and that the goal is to determine the intervention’s effectiveness up to their Week 
28 Follow Up visit. Parents will also be reminded that they will receive clinical guidance 
after completion of their Week 28 visit. However, the study team may intervene 
clinically and terminate study participation if they feel the child is in need of immediate 
emergency medical treatment.  
 
Visit Windows 
 
The visit window between Characterization/Medical Assessment and Baseline/MIE 
Treatment or the TAU consultation visits is 12 – 21 days. MIE Treatment or the TAU 
consultation visit must occur after the Week 2 Baseline.  During this time, parents must 
collect a minimum of 7 days of toileting home data. These days do not need be 
consecutive.  
 
The Week 4 Midpoint visit will occur 7-21 days after the Week 2 Baseline Visit (2 weeks 
+/- 7 days). The Week 8 Endpoint visit will occur 35-49 days after the Week 2 Baseline 
Visit  (6 weeks +/- 7 days).Week 28 Follow Up will occur 175-189 days after the Week 2  
Baseline Visit (26 weeks +/- 7 days).  
 
Study Measures 
 
Characterization Measures:  
 
Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000) The ADOS is an 


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investigator-based procedure that places the child in naturalistic social situations 
demanding specific social and communication reactions. The ADOS provides a sample of 
the child’s behavior in a naturalistic setting. Behaviors are coded in the areas of social 
communication, social relatedness, play and imagination, and repetitive behaviors. The 
ADOS contributes to the DSM 5 diagnosis of ASD.  
Autism Diagnostic Interview-Revised (ADI-R) (Rutter, LeCouteur, & Lord, 2003). The ADI-
R is a structured interview that is used to diagnose autism. The interview can be 
administered to a caregiver and is composed of 93 items. The instrument includes the 
three functional domains related to ASD: Language and Communication, Reciprocal 
Social Interactions, and Restricted, Repetitive, and Stereotyped Behaviors and Interests. 
 
Childhood Autism Rating Scale-Second Edition (CARS-2) :The CARS-2 (Schopler, Van 
Bourgondien, Wellman, & Love (2010) is rating scale used to identify children with 
autism and distinguishing them from those with other developmental disorders. It 
includes 15 items that are rated by direct behavioral observation and has been 
empirically validated. 
 
Differential Abilities Scale-Second Edition (DAS-II):  The DAS-II is a standardized test that 
measures an individual’s General Conceptual Ability (GCA) and yields a standard score 
(M=100, SD=15).  It consists of several subtests measuring Verbal Ability, Nonverbal 
Reasoning Ability, and Spatial Ability and can be administered to children between the 
ages of 2 years, 6 months and 17 years, 11 months.  The results of this test are used to 
identify a child’s cognitive strengths and weaknesses across a wide range of domains 
that are relevant to development and learning.  This assessment takes between 30-50 
minutes to complete.    
 
The Mullen Scales of Early Learning assess cognitive and motor ability.  Five scales – 
Gross Motor, Visual Reception, Fine Motor, Expressive Language, and Receptive 
Language – are used for targeting strengths and weaknesses in children.   Included in 
the questionnaire are three different forms depending on the age of the participant; a 
15 minutes test for 1-year old participants, 25-35 minutes for 3-year old participants, 
and 40-60 minutes for 5-year old participants. 
 
Participants who are older than 5 (the ceiling of the Mullen) but with an apparent 
cognitive level below the floor of the DAS will receive a Mullen. 
 
Child Symptom Inventory (CSI; Gadow et al., 2002): The CSI is a 132-item, DSM 5 based 
checklist that asks parents to rate the severity of symptoms on a four-point scale 
ranging from 0 (never) to 3 (very often).  Scores of 2 or higher are usually regarded as a 
positive symptom. The CSI will assist with the identification of DSM 5 diagnoses other 
than ASD.  
 
Vineland Adaptive Behavior Scales (VABS-III Survey Interview Form Sparrow, Balla, 
Cicchetti, 1984): This instrument measures adaptive behavior and yields a standard 


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score in four domains— Communication, Daily Living, Social, and Motor, as well as an 
Adaptive Behavior Composite.  Adaptive functioning is a core component of an ASD 
diagnosis and includes toileting skills. 
 
Medical and Psychiatric History Review: This NDAR caregiver questionnaire covers 
the child’s prenatal, perinatal, and postnatal health problems. This information will be 
used to identify past or current major medical or psychiatric problems that would be 
incompatible with the study. 
  
Behavior Problems Inventory-01 (BPI-01): This caregiver completed inventory of 
problem behavior asks caregivers to indicate the frequency and severity of 52 forms of 
problem behavior most commonly exhibited by individuals with ASD or other 
developmental disorders (Rojahn, Matson, Lott, Esbensen, & Smalls, 2001).  Specific 
problem behaviors are grouped into three categories (self-injury, stereotyped behavior, 
and aggressive/destructive behavior).  For each individual problem behavior, a caregiver 
rates the behavior in terms of frequency from “0 – Never” to “4 – Hourly”, and the 
severity from “1 – Slight” to “3 – Severe”.  We will use this inventory to identify problem 
behavior that may exclude participation because of its likelihood of interfering with MIE. 
 
Globally Unique Identifier (GUID): This form gathers demographic information that is 
used to generate a unique identifier, which allow for the use of de-identified data in the 
rest of the study.  
 
Constipation Status: This will be determined during the medical screening by a 
licensed and board-certified pediatric gastroenterologist or a nurse practitioner in 
consultation with a board-certified pediatric gastroenterologist using the criteria below, 
which are based on the Rome III criteria (Tabbers et al., 2014):  
> 2 of the following must occur for a participant to meet criteria for being constipated 
1. 
≤ 2 defecations per week 
2. 
History of excessive stool retention, including retentive posturing or excessive 
volitional stool retention 
3. 
History of painful or hard bowel movements 
4. 
Presence of a large fecal mass in rectum 
5. 
History of large-diameter stools that may obstruct the toilet 
6. 
History of irritability, decreased appetite, and/or early satiety, which may 
disappear immediately following passage of a large stool 
 
≤ 2 of the above will serve as an indicator that the participant is not constipated 
 
We have made two modifications to the published criteria: First, we have eliminated 
the requirement of a developmental age > 18 months [RATIONALE: this criterion is 
included in the original definition to account for an expectation that the individual has 
already achieved independent bowel continence. However, participants in this study will 
have not yet achieved continence, so developmental age distinction is unnecessary]; 


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Second, we have added the sixth criterion above [RATIONALE: many children with ASD 
will lack the verbal skills to self-report pain or discomfort due to constipation (Criterion 
#3). Thus, the symptoms described in Criterion #6 will serve as replacement indicators 
of constipation for these participants.]  
 
Dependent Measures 
 
Continence: Defined as 60% of days are continent days and no more than 1 day of 
incontinence over a 7 day period or no more than 2 days of incontinence over a 14 day 
period based on parent report.  This definition is stricter than what has appeared 
elsewhere in the literature (e.g., Blum et al., 2004) in that it allows for less frequent 
incontinent bowel movements and also includes a requirement that the participant also 
have continent bowel movements.  The latter requirement is included because children 
with ASD and encopresis are more likely to be constipated, and so a lengthy period 
without a bowel movement alone should not be considered an indicator of treatment 
success.  Caregivers and therapists will collect daily data on each of the participant’s 
bowel movements in terms of: (a) continent vs. incontinent, (b) self-initiation (the 
participant spontaneously using or requesting to use the bathroom), and (c) date and 
time of the bowel movement.   
 
Toileting independence: Caregivers and therapists will record whether medical 
intervention was required to elicit any bowel movements, and if so, which medication 
(e.g., glycerin suppository vs. bisacodyl).  A continent bowel movement without the use 
of any medications will constitute an independent bowel movement, and is an 
important measure of treatment success.  A child will be considered independent in 
toileting if they exhibit continent bowel movements without the use of medication for 
60% of days with no more than 15% incontinent days based on parent report. 
 
Parent target problem (PTP): At baseline, an independent evaluator (IE) will use the 
PTP interview to record the caregivers’ estimate of the frequency of incontinent bowel 
movements and the impact of their child’s encopresis on their family.  From this 
description, the IE (who will be blind to treatment assignment) will generate a brief 
narrative describing the participant’s encopresis and its impact.  The IE will read this 
narrative back to the caregiver and ask him/her to provide corrections and/or add any 
pertinent missing information.  This process will continue until the caregiver reports that 
the narrative is an accurate description.  This narrative and all available information 
collected at baseline (caregiver collected home data, Vineland, etc.) will be used by the 
IE to rate the overall severity using the 7-point, Clinical Global Impression for Severity 
(CGI-S; Aman, Bailey, & Lord, 1985).  At the conclusion of the clinic-based phase of 
treatment (Week 4), and again after follow up (Week 28), the narratives will be 
reviewed with the caregiver, revised by the IE, and integrated with all available 
information to rate the Improvement scale of the Clinical Global Impression (CGI-I; 
Busner & Targum, 2007).  The CGI-I is a 7-point scale with anchors including 1 (Very 
Much Improved), through 4 (No Change), and 7 (Very Much Worse).  By convention, 


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ratings of Much Improved and Very Much Improved define positive response.  We have 
already begun to train the IEs to reliability on the CGI and recording of PTPs.  In addition 
to ratings by the IE in real time, at the end of the trial, a panel of judges, who are blind 
to group assignment, will review the narratives at baseline (Week 2), endpoint (Week 8), 
and follow-up (Week 28).  The change from baseline to each subsequent time point will 
be independently rated by the panel of judges on a 9-point scale (where 5 = no change, 
4 = minimal improvement, 3 = definite improvement, 2 = much improved and 1 = very 
much improved; scores of 6 through 9 follow the same pattern in the worsening 
direction).  Our team has used this approach in prior studies (Arnold et al., 2003; 
McGuire et al., 2014), and have shown that a panel of judges is highly reliable and that 
this method is sensitive to treatment effects.  
 
Parenting Stress Index (PSI; Abidin, 1995): This is a 36-item parent-completed 
questionnaire (short form) for families of children 12 years of age and younger.  It has 
been empirically validated.  The PSI has three scales: Parental Distress, Difficult Child 
Characteristics, and Dysfunctional Parent-Child Interaction.  The 36-item PSI has been 
used in several studies by RUPP Autism Network.  
 
Caregiver Strain Questionnaire – Short Form (CGSQ-SF; Brannan, Heflinger & 
Bickman, 1997): This questionnaire measures the impact of having a child with ASD in 
the family.  The questionnaire includes 7 items that assess three dimensions of caregiver 
strain: objective strain, internalized subjective strain, and externalized subjective strain.  
Each item is rated on a 5-point scale ranging from 1 (not at all a problem) to 5 (very 
much a problem).  
 
Treatment Acceptability Rating Form-Revised (TARF-R; Reimers & Wacker, 1992): The 
TARF-R is a 20 item measure of treatment acceptability that is completed by caregivers 
following completion of either MIE or TAU.  It will be administered at the Midpoint 
(Week 4) and Endpoint (Week 8).  The survey takes approximately 5 minutes to 
complete. 
 
Aberrant Behavior Checklist (ABC): The ABC is a 58-item parent-report measure with 
five subscales: Irritability (includes agitation, aggression and self-injurious behaviors, 15 
items); Social Withdrawal (16 items); Stereotypies (7 items); Hyperactivity (16 items); 
and Inappropriate Speech (4 items), (Aman et al., 1985, Aman et al., 1987). The ABC is 
commonly used in clinical trials in children with ASD (Aman et al., 2009; King et al., 
2009; RUPP Autism Network, 2002 and 2005). The use of the ABC in the current study 
will permit easy comparison of the study sample to subjects in past studies. It will also 
be used as an exploratory outcome measure. 
 
King’s Stool Chart (KSC): The King’s Stool Chart is a visual guide characterization of 
fecal matter into 12 different categories based on consistency, texture and size. It has 
been validated for use in free-living individuals as well as patients with various GI 
issues. 


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Study Drug and Dosing 
The study involves the use of two medications: a Glycerine and Bisacodyl suppository. 
Glycerin suppositories are composed of a hyperosmotic agent consisting of glycerin 
(active ingredient), purified water, sodium hydroxide, and stearic acidand.   Bisacodyl is 
a derivative of triphenylmethane consisting of Bisacodyl (active ingredient), acadia gum, 
ammonium hydroxide, beeswax, carnauba wax, D&C Yellow #10 aluminum lake, D&C 
Red #30 aluminum lake, glycerin, glyceryl monostearate, iron oxide, lactos 
monohydrate, magnesium stearate, methacrylic acid ethyl acrylate copolymer, methyl 
paraben, modified corn starch, polyethylene glycol 6000, polysorbate 80, povidone, 
propyl paraben, shellac, sodium benzoate, sucrose, talc, titanium dioxide, and triethyl 
citrate.  Both these medications are available over the counter. 
 
Medications will be dispensed quarterly by the Children’s Healthcare of Atlanta 
Research Pharmacy and stored on site in a locked cabinet in the nurse’s office at the 
Marcus Autism Center. Both types of suppositories are sealed in plastic (PVC/PE) cavities 
within a cardboard carton in pack quantities of 12. Consistent with manufacturer 
recommendations, the cabinet in which these will be stored will remain dry, below 25°C, 
and away from direct light.  A medication log will be maintained to track each dose 
removed from storage and administered as part of the study.  This log will include the 
following information: date, time, participant, and dose.  See Table 3.0 below. 
 
 
 
A trained therapist will administer the liquid glycerin suppository as recommended by 
the manufacturer via the rectum using the following dosing recommendations: 7.5ml 
(Fleet Adult Liquid suppositories) or 3.5ml4 ml (Fleet PediLax) pediatric size given to 
participants 2-5years old; adult size given to participants ≥ 6yo.  When bisacodyl is used 
the following dosing recommendations will be followed: 5 mg for all participants 
(administered via the rectum).  Depending on when or if the participant has a bowel 
movement (see intervention section) participants may receive between 0-2 
Table 3.0 - Doses of Liquid Glycerin Suppositories by Age and the Single Strength of Bisacodyl   
Drug  
Suppository Dose 
Ranges allowed 
Liquid 
glycerin  suppository  
Children age 2-5 years:  4 
ml/applicator1 
Children 2-5 years: 1 dose per day or as 
directed 
Liquid glycerin 
suppository 
Children age 6-12 
years:  7.5ml/applicator1 
Children ≥6 years: 1 dose per day or as 
directed 
Bisacodyl suppository 
  
5 mg2 
Children 2–10 years: 5 mg/day  
Children >10 years: 5–10 mg/day  
1. Recommended by the manufacturer 
2. Tabbers MM, DiLorenzo C, Berger MY et al. (2014) Evaluation and Treatment of Functional 
Constipation in Children: Evidence-Based Recommendations from ESPGHAN and NASPGHAN. J Pediatric 
Gastroenterology and Nutrition, 58(2): 258-274. 


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Page 20 of 34 
 
suppositories per day.  Participants will never receive two of the bisacodyl suppositories.  
However they may receive two of the liquid glycerin suppositories or one of each in a 
given day. We will ensure that all participants keep concomitant medications stable and 
to notify us if this is not the case during the study. 
 
Part of treatment may involve physical management of participants, such as to address 
problem behavior (e.g., aggression, disruption, self-injury) to ensure the safety of 
participants, caregivers, and the therapist.  Therapists are trained and will implement 
personal protective procedures (e.g., blocking hits, releasing grabs) if the participant is 
aggressive (hurting others) to minimize any harm, prioritizing the safety of the 
participant.  In addition, the below procedures may be used as needed.  
• 
Prompting procedures: to gently guide the participant to sit on the toilet, or to 
prompt him or her to engage in redressing or hygiene tasks. This may involve 
hand-over-hand physical guidance. 
Emergency restraint: If a researcher determines that a participant cannot be kept safe 
by any other means, they will implement an emergency restraint procedure.  This will be 
done only until it is deemed that the participant is safe.  If a caregiver is not there to 
observe the procedure, the caregiver will be notified by the researcher as soon as 
possible that this procedure occurred.  A licensed psychologist is consulted for any 
restraint procedure used. 
 
Home Implementation - After the MIE treatment phase, subjects will be given 
suppositories to utilize at home and a handout that addresses frequently asked 
questions about the use of suppositories. MIE treatment group subjects will leave with 
one of three planned regimens: one Glycerin suppository a day, two Glycerin 
suppositories a day or one Bisacodyl suppository a day. The determination of which 
group subjects are in will be made by the study team based on subject’s response during 
MIE treatment. It is anticipated that most subjects will leave with the plan of one 
Glycerin suppository a day. Subjects in both the one Glycerin or one Biscaodyl 
suppository a day will be given a 30-day supply of study medication upon completing 
the MIE treatment phase (e.g. 30 suppositories). Subjects receiving two Glycerin 
suppositories a day will leave with enough medication to also last 30-days while taking 
two Glycerin suppositories (e.g. 60 suppositories). Note that subjects in the two Glycerin 
suppository group may only need to receive a single suppository if the child begins to 
have bowel movements after administration of one suppository.  
 
Intervention Content 
MIE consists of daily clinic appointments, each of which lasts until a bowel movement 
occurs or 3 hours elapse.  Each appointment consists of a series of scheduled sitting 
routines (i.e., “sits”) that last up to 32 min.  Each sit consists of 10 min on the toilet, 
followed by 1 min of standing, then repeating the 10 min on the toilet 1 min off, for 30 
cumulative minutes of sitting.  The first sit is conducted prior to the administration of 
any medication to provide an opportunity for an independent continent bowel 
movement.  If no continent bowel movement occurs, trained staff administer a dose of 


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Page 21 of 34 
 
a liquid glycerin suppository to elicit a bowel movement, immediately followed by 
another sit to ensure any resulting bowel movement is continent.  Any continent bowel 
movements result in immediate delivery of a potent positive reinforcer, identified 
previously via systematic preference assessments (Deleon et al., 1996).  The 
appointment ends following a continent bowel movement.  If a bowel movement is not 
observed the participant receives a 30 min break, followed by a second dose of the 
glycerin suppository.  The participant is once again guided to complete the sitting 
routine following the second administration, with the same consequences for 
continence.  After the third sit the appointment ends even if a continent bowel 
movement did not occur.  Glycerin suppositories are replaced by bisacodyl if 2 or more 
days pass without a continent bowel movement using the liquid glycerin suppository.  If 
bisacodyl is required it is administered prior to the second sit (i.e., after no bowel 
movement occurs on the opportunity for independent continence) to ensure that the 
medication has sufficient time to work prior to the end of the appointment.  Medication 
fading occurs each time there are two consecutive days with continence by replacing 
bisacodyl with a glycerin suppository (if bisacodyl was necessary), and/or reducing the 
dose of the glycerin suppository by 50% until continent bowel movements occur 
independently during the first sit (i.e., without medication).  Caregivers are trained to 
implement the toileting routine during the final two days of MIE until they demonstrate 
90% fidelity with the protocol.  Upon completion of MIE they are instructed to continue 
to implement the intervention until independent continence is achieved. 
 
Subjects receiving MIE will be expected to receive a minimum number of treatment 
appointments prior to ending the MIE treatment phase. Subjects in the 2-week MIE 
treatment group will be expected to complete 10 MIE appointments within 17 days. This 
will ensure all subjects received an adequate level of treatment intervention prior to 
receiving parental intervention exclusively at home. Subjects who do not meet the 
minimum number of appointments within the time frame will be documented as 
protocol deviations.  
 
Inclusion & Exclusion Criteria 
 
Inclusion Criteria 
1. Males and females > 5 years of age and ≤ 12 years 11 months of age.  
2. DSM-5 diagnosis of Autism Spectrum Disorder as established by clinical assessment, 
corroborated by the Autism Diagnostic Observational Schedule, Autism Diagnostic 
Interview-Revised and/or Childhood Autism Rating Scale-Second Edition. 
3. Fewer than 60% of days are continent days or more than 1 day out of 7 is an 
incontinent day over the previous 7 days (a continent day is defined as a day with at 
least one continent bowel movement. An incontinent day is a day with an incontinent 
bowel movement regardless of whether a continent bowel movement also occurs). 
4. Medication free or on stable medication (no changes in past 6 weeks and no planned 
changes for the next 6 months) [RATIONALE: Inclusion of children on stable medication 


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eliminates a potential confounding variable and enhances the generalizability of study 
findings].  
5. Urine continent – Over half of the voids are continent when the child is with the 
parent and when the child is on a typical toileting routine. 
 
Exclusion Criteria 
1. Presence of a known medical condition in the child (based on medical history or 
physical examination by a gastroenterologist or nurse practitioner working in 
consultation with a gastroenterologist) that would interfere with child’s ability to 
control his/her anus. These include:  
• History of any anal surgery 
• Spinal dysraphism (e.g., spina bifida) 
• Other neurologic disorder affecting anal function 
• Prolonged/recurrent gastrointestinal infectious disease (e.g. Clostridium 
dificile colitis) 
 
In addition, the following may constitute exclusions following evaluation by a 
physician: 
• Inflammatory bowel disease 
• Short gut syndrome 
• Chronic diarrhea 
• History of intestinal/abdominal surgery  
[RATIONALE: inability to control the anus is highly likely to prevent the success of 
any treatment for encopresis. All medical conditions will be reviewed by study team 
to make a final determination of eligibility.] 
2. Presence of a current serious behavioral problem or psychiatric condition that would 
require another treatment (e.g., psychotic disorder, major depression, moderate or 
greater aggression, severe disruptive behavior), based on information collected at 
screening and the Behavior Problems Inventory-01 (BPI-01; as described below). 
[RATIONALE: presence of an untreated serious behavioral problem or psychiatric 
condition would interfere with the child’s ability to participate in the treatment.] 
3. Currently receiving and caregiver refusal to discontinue ongoing behavioral or 
alternative medical intervention for encopresis [RATIONALE: presence of other ongoing 
treatments would confound results of this study.] 
 
 
Exceptions to Inclusion and Exclusion Criteria 
 
These inclusion and exclusion criteria reflect our best estimate for subject selection in 
this clinical trial.  In our past trials in children with ASD, we have encountered a few 
subjects who did not satisfy all selection criteria, but, in the judgment of the research 


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team, appeared appropriate for the study. For example, a healthy child with a 
developmental disability who was not toilet trained could not provide a urine sample.  
Therefore, we could not say with certainty that his urine test was “normal.”  To exclude 
such a child would threaten the application of the study findings to lower functioning 
children.  In the event of a need to consider a potential exception to the 
inclusion/exclusion criteria the case panel (e.g., Drs. Call, McElhanon, Lomas-Mevers, 
Scahill) will review the case and decide whether to enter a child with findings that 
challenge application of entry criteria. In making such decisions, the case panel will 
insure that the exception 1) does not decrease the benefit-risk ratio for the subject in 
question; 2) does not compromise the scientific integrity of the study; and 3) does not 
depart from good clinical practice.  Such exceptions and rationale will be documented 
on a case report form. 
 
Risk of Participation 
Potential risks and discomforts associated with this study include: 
• The primary risk to participation in the study is in the area of participant 
confidentiality.  A number of safeguards will be put in place to protect the 
privacy of participants and confidentiality of data, which are described more fully 
below within “plans for data management and monitoring”. 
• Some participants may experience distress when separating from caregivers 
and/or during study procedures, which include requiring the child to remain 
seated on a toilet for up to 30 minutes at a time and administration of 
suppositories.  
• The medications to be administered are over-the-counter, are dosed as on 
packaging, and used under protocol created by a pediatric gastroenterologist. 
They represent no more risk than listed on Children’s Healthcare of Atlanta 
Lexicomp® formulary:  Glycerin suppository adverse reactions are abdominal 
cramps, rectal irritation, and tenesmus. Bisacodyl adverse reactions listed are 
labeled rare and apply to oral and rectal preparations: abdominal cramps (mild), 
electrolyte disturbance (metabolic acidosis or alkalosis, hypocalcemia), nausea, 
rectal irritation (burning), vertigo, and vomiting. Additional steps to be taken to 
minimize risks of distress to participants include providing them with preferred 
items during separation from caregivers. In addition, if a participant exhibits 
significant distress during study procedures they will be discharged from the 
study.  
 
 
Benefits to Subjects 
       Participants in the proposed study will receive compensation for participation in the 
amount of $10 for each week of data collection, comprising a total of $100. In addition, 
participants may learn to have predicable bowel movements in the toilet.  
 
Setting 
The study will take place at the Marcus Autism Center. Caregivers of children 
meeting inclusion criteria will be invited to give informed consent for inclusion of their 


Version 4.3, 8/24/2021 
 
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Years 
Year 1 
Year 2 
Year 3 
Year 4 
Months 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
19-21 
22-24 
25-27 
28-30 
31-33 
34-36 
37-39 
40-42 
43-45 
46-48 
n per period 
3 
7 
4 
5 
6 
8 
12 
9 
9 
9 
9 
9 
9 
9 
4 
completion 
Cumulative N 
3 
10 
14 
19 
25 
33 
45 
54 
63 
72 
81 
90 
99 
108 
112 
∑ = 112 
child in the study. The experimental sessions will be conducted in private client 
restrooms at the Marcus Autism Center.  
 
Recruitment 
The Marcus Autism Center currently sees approximately 5,000 unique patients 
annually who may be eligible to participate in this study, including a number of families 
who have already requested the opportunity to participate. A clinician will contact 
families (via phone, email, or face to face) currently waiting to receive services for 
encopresis to explain the research opportunity. Then, if parents are still interested in 
participating with their child, they will be asked to provide basic information by 
telephone regarding their child’s difficulties via the Oral Consent and HIPAA 
Authorization Script and Information Sheet For Research Study Screening ) to determine 
if they meet the eligibility criteria for the study. Flyers will also be posted throughout 
Marcus, on the Marcus website, and social media to help with recruitment. 
 
Some participants may have a history of engaging in problem behaviors including, 
but not limited to, aggression, destructive behavior, self-injury, running away, or 
dropping to the floor. All members of the study team who interact with participants are 
trained in the Marcus Crisis Prevention Program, which consists of protective 
procedures in order to safely manage problem behavior. When obtaining informed 
consent for participation in this study, the person obtaining consent will also describe 
the protective procedures and emergency protocols to the family. The consent forms 
giving permission to use those procedures are the same as those used with clinical 
families. Low-intensity problem behavior will be managed within the context of the 
study, but more serious problem behavior will result in the study team discontinuing 
study procedures temporarily in order to safely manage problem behavior and may be 
reported to the IRB.  
 
A total of 150 participants will be enrolled in the study and randomly assigned to one of 
three groups (60 in 2-week MIE, 60 in 1-week MIE, and 30 in TAU group).  Starting year 3 
a total of 112 participants will be enrolled in the study and randomly assigned to one of 
two groups (56 in 2-week MIE and 56 in TAU group).  We will recruit the necessary 
sample over a 4-year period, with 19 participants enrolled in Year 1 to allow for ramp 
up, and 22 in Year 4 to leave sufficient time for participants to complete 3-months of 
caregiver implementation prior to follow-up and for data analysis.  We will recruit 35 
participants in Year 2 and 45 in Year 3.   
 


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Families will be asked to provide basic information by telephone regarding their child’s 
difficulties via the Oral Consent and HIPAA Authorization Script and Information Sheet 
For Research Study Screening to determine if they meet the eligibility criteria for the 
study. 
 
Training 
 
Sessions will be conducted by research personnel at the Marcus Autism Center who 
have significant experience delivering clinical care to children with ASD and/or 
facilitating research participation by children with ASD. Training includes basics of 
behavior analysis, data collection, and protective procedures. Staff members are 
supervised by a doctoral level behavior analyst and licensed psychologist. Following 
treatment, staff members will train caregivers to implement the treatment with at least 
90% fidelity.  
 
Informed consent 
Caregivers of children who meet inclusion criteria of the current study will be verbally 
invited to consent to have their child participate in the study using lay language. If the 
caregiver expresses assent and wishes to learn more about the study, he or she will be 
presented with a typed copy of the consent form, which will be explained to them by 
the study coordinator, principal investigator, or research assistant in greater detail. 
Assent will not be obtained from the children with developmental disabilities included in 
the study. Based on historical data and the population served at the Marcus Autism 
Center, caregiver consent is required in all cases for the individuals with disabilities (i.e., 
these individuals with developmental disabilities do not possess the pre-requisite 
communication skills to give assent). Because children with developmental disabilities 
often lack the capacity to grant assent for participation, the research study cannot be 
carried out without a waiver of child participant assent. Each child’s participation in the 
study involves a minimal risk of harm.  
 
Caregivers will be informed of confidentiality procedures, the rights of children 
participating in the study, plans for data management and monitoring, and also that 
their decision to have their child to participate will not influence the quality of services 
that they will receive at the Marcus Autism Center. Additionally, caregivers will be told 
that they will receive compensation for their participation and that they may withdraw 
any or all responses from the study at any time. Caregivers will review a printed copy of 
the consent form as well as the contact information for the principal investigator and 
the project coordinator.  
 
Withdrawing Participation: Parents are free to withdraw from the study at any time. 
This will be clearly stated during the consent process. Parents who indicate intention to 
withdraw from the study will be offered to confer with the study team to discuss the 
matter.  If the discussion indicates that the child needs another treatment, we will assist 
the family in locating that treatment. Parents who are willing will be invited to return for 


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child assessments. Data from children who drop out of treatment, but return for 
assessments, will be analyzed in the originally randomized group.  
 
Plans to inform participants of new findings 
Because this study is an evaluation of the efficacy of a novel intervention for 
encopresis and to demonstrate the feasibility of the intervention, the caregivers will 
receive periodic updates regarding progress made throughout the study. They will also 
be informed of any new information that the study team may become aware of during 
the study. 
 
Compensation 
Parents will be offered $10 for each week of data collection for a total of $100 
 
Confidentiality 
Participants will be de-identified during the data collection and analysis procedures, 
with each participant randomly assigned a study identification number (DEX ID). Only 
the authorized study personnel will have access to the codes that link identifiers to 
participants. These codes will be stored on a password protected, secured server 
located at the Marcus Autism Center (Marcus Data Exchange or DEX).  
 
Case report forms (CRFs) contain the subject’s DEX ID number – but no identifying 
information. DEX is a secure, password protected data base. The folders containing CRFs 
data will be kept in locked files and access to these files is only granted to members of 
the research team.  
 
Access to study records (case report forms) will be restricted to study staff. To maintain 
the treatment blind, the independent evaluators will keep records in a separate folder 
from the unblinded staff. Others that have access to the record include individuals with 
regulatory responsibility at Emory, Children’s Health Care of Atlanta (CHOA). All clinical 
trials are subject to routine audits by offices at Emory or CHOA.    
 
Data storage  
    The data management system has several features designed to protect confidentiality 
such as “role-based” user privileges. For example, individuals can be allowed 1) “read 
only” access to study data, 2) “read/edit” access, 3) to see only certain case report 
forms, and/or 4) to run reports or export data for analysis. The data system maintains 
an electronic audit trail of all modifications to the data base, including the user who 
made the change, the date and time, and the previous value and new value of the data 
point. 
 
The research coordinator will enter data on the DEX web site. All data are double-
entered (with an automated validation check comparing the two entries for errors). 
Only staff members trained in the DEX system have access to data entry (password 
protected).  The progress of data collection is monitored with web-based electronic data 


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form reports, which will produce a profile of all forms expected and received for each 
study subject.  Missing-forms reports are electronically accessible by the data manager 
and the coordinator.  All studies follow informatics standard operating procedures and 
produce monthly reports on audits conducted to examine study fidelity and data 
quality. These audits are conducted by an assigned data manager from each study. 
Outliers and unusual values will be checked for accuracy. Data questions or problems 
will trigger queries back to the study team to assure that all forms are entered and 
available for analysis. Recurring problems with the data entry system will be resolved via 
discussion between the data manager and coordinator and PI as necessary.  
 
REDCap Utilization: REDCap (Research Electronic Data Capture) is a web-based 
application used to create forms and manage databases in order to support data 
capture and surveys for research studies. Participants will be given the option to sign  
the consent and study measures using the REDCap link to the specific survey(s). Forms 
will be delivered to the participant via an email to the parent with a unique link to 
complete online. Participants will continue to have the option to fill out forms by hand 
(in-person, by phone, mail, email). 
 
Analytic plan  
During the trial, the statistician will monitor missing data and errors, enrollment and 
attrition. When the trial is completed, descriptive statistics will be calculated for 
baseline data across treatment groups. Additional analyses will be undertaken to inspect 
data for errors, inconsistencies, and incomplete information across time points. This will 
include examining the data with simple frequency tables and scatter plots. Data 
anomalies and outliers will be examined and corrected if necessary.  These preliminary 
analyses will include descriptive statistics in each treatment group for all outcome 
variables, plots of longitudinal data over time, and examination of distributions within 
groups at important nodal points (e.g., Baseline, weeks 2, , 4, 8, 28).  All the analyses will 
apply the intent-to-treat principle. For modeling and hypothesis testing, the proposed 
likelihood-based approach regards missing data as missing at random (MAR; i.e, missing 
data are independent of unobserved data). Although there is no proven method for 
verifying the MAR assumption, the likelihood-based solutions are robust to violations of 
ignorable missing data (i.e, situations where the MAR assumption is not met). 
Nevertheless, prior to analyses for efficacy, we will examine the frequency, reasons, 
pattern and time to dropout and missing values across treatment groups. If substantial 
differences in missingness occur across treatment groups that cannot be adequately 
explained by observed variables, secondary sensitivity analyses will be performed. These 
techniques will be considered cautiously in our analyses as they require certain 
assumptions that cannot be evaluated from the data under analysis. Statistical 
significance will be assessed at the 0.05 level unless otherwise noted.  All analyses will 
be conducted using SAS v9.4 for Windows (Cary, NC, USA). 
 
Primary outcome: A Chi-square test will be used to compare the proportion of children 
who achieve continence (60% of days are continent days and no more than 1 


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incontinent day over a 7 day period and no more than 2 incontinent days over a 14 day 
period) based on parent report at Week 8 (endpoint of acute randomized trial). The 
contrast will be MIE-2 vs TAU.   
  
Secondary Outcome #1: A Chi-square test will be used to compare the proportion of 
children who are rated by the Independent Evaluator as Much Improved of Very Much 
Improved on the CGI-I at Week 8. The contrast will be MIE-2 vs TAU.   
 
Secondary Outcome #2: ANCOVA will be used to compare change in parental stress and 
strain from baseline to Week 8 as measured on the Parenting Stress Index and the 
Caregiver Strain Questionnaire.  The contrast will be MIE-2 vs TAU.   
 
Sample Size and Power Calculation for Primary Outcomes. As noted above, we will 
perform one planned pairwise comparison for the primary outcomes at Week 8: MIE-2 
vs TAU. We set our significance level for alpha as 0.05 to control the family-wise Type I 
error rate at the 5% level.  Based on our pilot data, we conservatively estimate the 
following rates of children achieving continence at Week 8: 10% of participants in TAU, 
75% of those in the MIE-2 group and 50% for the MIE-1 group. With a sample size of 54 
in each of the TAU MIE groups, we can detect a 29% difference in response rate on our 
primary categorical measure with 15% dropout rate and type I error rate of 0.05. We 
propose that this will be a valid test of the Two-week medical-behavioral intervention, 
which was, and remains, the primary aim of the study.   
 
Data Security  
    Electronic Protected Health Information (ePHI) is carefully guarded within the 
database. All full and incremental database backups are compressed and encrypted 
before being sent using secure sockets layer (SSL) to a secure, geo-redundant backup 
infrastructure.  All communication with the server for normal usage, maintenance and 
backups is encrypted using SSL. 
 
The DEX database has the following Security features: 
 
Hot Security The server runs a highly secure operating system (FreeBSD), providing 
immediate resistance to many common attacks and exploits. A unique web-server is 
used to reduce system exposure to attacks. The web server is written in a high-level 
language that substantially reduces the effectiveness of most common attacks (such as 
buffer-overflows). All communication between the site server and remote workstations 
(any modern computer capable of running the Firefox web browser) is logged and uses 
SSL encryption. The system fully supports journaling to ensure data integrity, to support 
audit trails, and to simplify disaster recovery. Furthermore, all collected data, as well as 
the journal itself, can be mirrored (in encrypted form) on redundant remote servers. In 
the rare case that the server is compromised, any modification to system resources can 
be undone by simply contacting Prometheus Research, who will restore the system from 
backup. 


Version 4.3, 8/24/2021 
 
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Cold Security RexDB® servers employ twin mirrored and encrypted hard drives to 
prevent data access should the server ever be stolen or compromised. This also virtually 
eliminates downtime should one drive fail. All RexDB® backups are stored on servers 
kept in locked racks in physically secure locations. 
In all studies, the database is maintained within the existing data management system 
providing high degree of security and quality monitoring.  Data are backed up according 
to the following specifications: 
 
Remote Backups Secure, automated backups of all server data are provided using a 
redundant infrastructure of Tarsnap.com and hosted servers.  All data are encrypted 
using asymmetric keys before leaving the site server.  All data are sent securely via an 
OpenVPN and SSH connection to the remote backup server.  The decrypt key is kept on 
neither the site server nor the backup server; instead, it is stored locally on a separate 
server.  
 
Frequency of Backups Nightly system backups are archived for seven days; weekly 
backups are archived for four weeks; monthly backups are archived for as far back as 
space will allow. Incremental (binary) backups of all database changes occur every 15 
minutes; the write-ahead log monitors incremental changes in the interim and increases 
backup frequency under heavy usage. 
 
Data Sharing During the consent process, we will explain to parents that data collected 
in the study is for research purposes and that research records will not be merged with 
medical records. The exception to this is the visit to the gastroenterologist/nurse 
practitioner. This visit is considered standard clinical care and therefore it will be 
uploaded to their medical record.   Further, data collected in the study or the results of 
tests conducted in the study can be obtained by the parent.  
 
Adverse Event Collection and Reporting 
The IE will monitor adverse events – whether related to the study treatment or not. 
Adverse events will be documented according to onset, offset, severity and action taken. 
The Safety Review also enquires about concomitant treatments that will be documented as 
needed. 
 
If questions arise about a subject’s possible deterioration, the situation will be discussed 
at the weekly team meeting. If the team determines that the subject’s symptoms are 
becoming distressing or dangerous, we will hold a clinical conference with the 
participants caregiver and determine the best course for the subject. This may include 
withdrawal from the study in order to institute a treatment plan.  
 
NOTE: In keeping with the intention to treat principle, we will ask parents of subjects 
who withdraw from treatment to return for study assessments and the subject’s data 
will be analyzed with the original randomized group. 


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Safety Review: A safety review for adverse effects and concomitant medications will be 
conducted at baseline and every assessment visit by the IE. To accomplish this 
systematic review, the IE will use the Safety Review Form that has been used in several 
multi-site clinical trials in children with ASD. It contains a general inquiry about the 
child’s health complaints, medical visits and new medications, and several questions 
about daily activities (e.g., sleep, appetite, energy level, and bowel and bladder 
functions) since the last study visit.  
 
New adverse events (whether considered related to the treatment or not) will rated 
mild, moderate or severe. The ratings: mild, moderate or severe are defined as follows:  
mild= present, but no intervention required;  
moderate=present, may be bothersome or may require intervention;  
severe=present, bothersome and requires intervention.  
 
All new adverse events (mild, moderate or severe) will be documented on the adverse 
event log. The status of previously-reported adverse events will be monitored as well. 
The adverse event log requires the independent evaluator to label the AE (a list of 
preferred terms will be provided) and to document the severity, onset, course, 
outcome, and attribution. 
 
Decisions on the appropriate care of the subject will be made by the independent 
evaluator (who will be blind to treatment assignment) and the PI and in collaboration 
with the family’s primary care provider as needed.    
  
The attribution of reported AEs will be classified as follows:  
• Definite: AE is clearly related to the study participation.   
• Probable: AE is likely to be related to the study participation.  
• Possible: AE may be related to the study participation.  
• Unlikely: AE is doubtfully related to the study participation.  
• Unrelated: AE is clearly not related to the study participation.  
 
Serious adverse events: A serious adverse event (SAE) is defined as one that poses a 
threat to the participant’s life or functioning. We note that “severe” is not equivalent to 
“serious.” A severe rash may not be a serious adverse event, whereas a heart attack of 
any severity is likely to be a serious adverse event. An SAE is defined as an event that 
entails one of the following:  
• Death;  
• Threat to the individual’s life;  
• Inpatient hospitalization or prolongation of existing hospitalization;  
• Persistent or significant disability or incapacity;  
• Intentional drug overdose;  
• Any other significant event that jeopardizes the participant.  


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Routine reporting of AEs will be documented on the Adverse Event Log as described 
above.  All AE data will be captured in the electronic database and reviewed by Drs. Call 
and McElhanon every 6 months. AEs occurring at a greater than expected frequency or 
severity will be reviewed with the Steering Committee (Drs. Call, McElhanon, Lomas-
Mevers, Scahill and McCracken). Investigators will provide this information to the Emory 
IRB according to IRB Policy & Procedures. The Steering Committee will decide if 
modifications to the protocol or consent form are required. 
  
Reporting of Serious Adverse Events (SAE). If an adverse event meets the definition of 
an SAE, the PI in consultation with Dr. McElhanon (and Steering Committee if needed) 
will determine whether the SAE is possibly, probably of definitely related to the study 
intervention. The PI will report SAEs to the IRB and the funding agency within 10 days of 
the determination that the event meets one of these criteria: a) serious AND 
unanticipated AND possibly, probably or definitely related events; and b) anticipated 
adverse events occurring with a greater frequency than expected.  
Serious adverse events that do not meet any of these circumstances will be reported 
with IRB re-approvals.  
 
Data Safety and Monitoring Plan 
The study will be conducted in accordance with “good clinical practice” as outlined in 
the International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (Dixon & Hallinan, 1999).  
 
The study team will meet weekly and decisions will be made by consensus. The study 
team will provide oversight and ensure that the study is conducted in accordance with 
the protocol. The coordinator and the statistician have direct access to the PI if data 
quality or data safety issues emerge from reviews conducted by either the coordinator 
or the statistician.  
 
The statistician will serve as an independent monitor of data quality and safety with 
input from study team. The statistician will have direct access to the data base to 
provide an additional check on missing data, attrition, adverse events and treatment 
response. As a single site study in a population that is well known to the clinical research 
team at Marcus, we do not see a need for an external Data and Safety Monitoring 
Board.  The statistician will review the data set every six months. Questions and 
concerns will be brought to the study team and PI. To protect the blind, treatment 
assignment will not be divulged. The discussion with the study team is likely to focus on 
individual cases and overall trends. Given the sample size of 138(updated from 150), we 
have not declared any stopping rules for benefit or futility. In the highly unlikely 
occurrence that adverse events show group differences, the study team will seek advice 
from the Marcus Center Director, Dr. Ami Klin. He is supportive of the study, but not 
directly involved.   
 


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Smith, L.J. (1996). A behavioural approach to the treatment of non-retentive encopresis 
in adults with  learning disabilities, Journal of Intellectual Disability Research, 
40(2), 130-139. 
 
Rutter M, Le CA, Lord C. Autism Diagnostic Interview-Revised (ADI-R). Los Angeles, CA: 
Western Psychological Services; 2003. 
 
Schopler E, Van Bourgondien M, Wellman J, Love S. Childhood Autism Rating Scale, 
Second edition (CARS-2): Manual. Los Angeles: Western Psychological Services; 2010. 
 

ICF_000.pdf: 
Informed Consent Form 
 
Title: A Multidisciplinary Approach to the Treatment of Encopresis in 
Children with Autism Spectrum Disorders 
 
NCT Number: NCT03197922 
 
Date of IRB Approval: April 11, 2022 
 


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/9
9B7CIF5;9MCIHCH5@?K=H<IG56CIHMCIF7CB79FBG
IRB Approved
<=@8 <
<
4/11/7<=@8
7<=@8


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F9GI@HG
IRB00095849
IRB Approved
4/11/2022


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#" '""!!! ""	"
 "
IRB00095849
IRB Approved
4/11/2022


		5A
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MCIFD9FA=GG=CB=:H<9M5F95@@CK98HC8CGC6MH<9@5KGH<5H7CJ9FH<9A
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89G=;B5H98F97CF8G9H=G85H5H<5H=B7@I89GA98=75@
IRB00095849
IRB Approved
4/11/2022


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IRB00095849
IRB Approved
= :
4/11/=B:CF
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IRB00095849
IRB Approved
4/11/2022