Clinical trial NCT02389998
Conditions: Functional Abdominal Pain Functional Dyspepsia Irritable Bowel Syndrome Functional Gastrointestinal Disorders
Keywords: Functional Pain Abdominal Pain Irritable Bowel Syndrome IBS Functional Dyspepsia FGID Functional Gastrointestinal Disorders
Sponsor: Boston Children's Hospital
Start date: 2014-07-01; Completion date: 2019-07-01
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is aimed at investigating the efficacy of placebo for symptom relief in children with abdominal pain related functional gastrointestinal disorders.

Detailed description:
The purpose of this research study is to see if prescribing an open label placebo to children with functional gastrointestinal disorders will help improve symptoms and their overall quality of life. Open label means you/your child are aware you are taking liquid placebo drops and not an active medication. Symptoms associated with functional gastrointestinal disorders (FGIDs) of children and adolescents are commonly encountered symptoms in general pediatrics and pediatric gastroenterology. The FGIDs the investigators are studying include functional abdominal pain, irritable bowel syndrome, and functional dyspepsia. The liquid placebo drops contain no active medication.

Recent research studies have shown improvement in gastrointestinal symptoms after taking liquid placebo drops in both children and adults with FGIDs. A randomized research study for a medication used to treat children with FGIDs showed a very significant placebo effect, meaning patients receiving placebo also experienced improvement in their symptoms. Randomized refers to the fact that subjects were randomly selected to receive either the study medication or placebo. A recent adult study gave adult patients a placebo and told them it was a placebo, and these adults also had significant symptom improvement. The goal of this study is to further explore using open label (or non-deceptive) placebo use to treat children with FGIDs.

Arms: arm 1: Arm 1: Subjects take 1/4 teaspoon placebo suspension 2 times a day (morning and night), and a third dose if necessary for a period of three weeks. Subjects will also have access to hyoscyamine as a rescue medication. arm 2: Arm 2: Subjects receive no treatment but have access to hyoscyamine as a rescue medication.
Interventions: intervention 1: Placebo Suspension intervention 2: Hyoscyamine
Intervention descriptions: intervention 1: The study is divided into three phases: 1 one-week baseline assessment followed by 2 three-week study phases (phase A and phase B). Phase A will require subjects to take 1/4 teaspoon placebo suspension 2 times a day (morning and night), and a third dose if necessary. In phase B subjects will not take the placebo. After 3 weeks in initial phase (either Phase A or B), subjects will switch to the alternate phase and continue the study for another 3 weeks. Hyoscyamine is available as a rescue medication during Phase A and Phase B. Half of the subjects will be randomized to begin with Phase A and half will be randomized to begin with Phase B. intervention 2: While not an intervention of interest to our study, patients will have hyoscyamine available as a rescue medication throughout the study. This can be taken on a PRN basis for breakthrough pain a maximum of 4x daily.

Protocol documents:
Prot_SAP_000.pdf: 
 
 1 
 
 
 
Date of last revision: 5/20/2021 
Title of Study: Open label placebo for children with functional abdominal pain and irritable 
bowel syndrome: A randomized crossover trial 
 
NCT: NCT02389998. 
 
Principle Investigator: Samuel Nurko, MD, MPH – Children’s Hospital Boston 
Other Institutions: Nationwide Children’s Hospital, Columbus, OH, and Children’s Mercy 
Kansas City, MO. 
 
A. Specific Aims and Objectives 
This study is aimed at investigating the efficacy of open label placebo for symptom relief in 
children with abdominal pain related functional gastrointestinal disorders. 
B. Background and Significance 
Some of the most commonly used drugs for the treatment of FGIDs have potential severe 
adverse effects including cardiac, psychiatric, urinary and gastroenterological problems. 
Moreover, studies have shown an increase in suicidal ideation in adolescents using some of the 
most commonly prescribed drugs for the treatment of FAP.1,2 As a result the FDA has mandated 
discussing the possible increased risk of suicide among this group of patients. Parents often 
refuse treatment due to the potential life threatening risks.  


 
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A recent adult study has shown that non deceptive placebo use is beneficial in the treatment of 
IBS.3 In this study, patients who were made aware that they would receive placebo had greater 
improvement of symptoms than those in the control group. This study opens the door to the 
possible use of non-deceptive placebo for the treatment of FGIDs in other populations including 
children. The use of placebo could potentially reduce health risks, decrease costs and increase 
parental acceptance. There have been no studies investigating the possible acceptance and 
efficacy of using non deceptive placebos for the treatment of FGIDs in children. 
There are several hurdles to conducting non deceptive placebo studies including ethical issues. 
Although adult studies have used non-treatment as control to assess the efficacy of non-
deceptive placebo, not treating children who are suffering of pain is not ethically acceptable. A 
possible mean of overcoming these ethical issues it to use placebo as an addition to conventional 
treatment. This design would allow assessing the superiority of the addition of placebo to the 
conventional treatment and still provide standard treatment for the child’s symptoms. Standard 
of care of FAP includes use of as needed anticholinergic drugs at times of pain episodes. We 
propose a preliminary study aimed at investigating parental acceptance to the use of non-
deceptive placebo and the possible additional effect of non-deceptive placebo to conventional 
therapy in children with FAP.  
C. Preliminary Studies 
A meta analysis has shown that 40% of adult patients with IBS improve with the exclusive use of 
placebo.4 Studies on children with FGIDs have confirmed these findings by showing a consistent 
high placebo effect in randomized trials.5,6The largest randomized clinical trial investigating the 


 
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efficacy of the use of drugs to treat children with FAP (functional abdominal pain) has shown 
that placebo was as effective as the study drug in the treatment of these conditions.6 
A recent adult study has shown that non deceptive placebo use is beneficial in the treatment of 
IBS. 3  In this study, patients who were made aware that they would receive placebo had 
greater improvement of symptoms than those in the control group. This study opens the door 
to the possible use of non-deceptive placebo for the treatment of FGIDs in other populations 
including children. The use of placebo could potentially reduce health risks, decrease costs and 
increase parental acceptance. There have been no studies investigating the possible acceptance 
and efficacy of using non deceptive placebos for the treatment of FGIDs in children. 
D. Design and Methods 
a. Study Design and Timeline 
This is a prospective multicenter crossover study of the efficacy of administering placebo 
without deception.Eligible patients will complete a 1 week of observation prior to 
randomization to one of two arms: a) Group 1:  Control period (CP) for 3 weeks, followed by 
open placebo (OP) for 3 weeks and b) Group 2 : OP for 3 weeks, followed by a CP of 3 weeks, 
Our aim is to recruit at least 30 subjects in total across all sites (see below). Enrollment at 
Children’s Hospital Boston will occur on Fegan 5, where Dr. Nurko and his colleagues see 
patients regularly. Prior to enrollment the physician will brief potential subjects on what a 
placebo is and how it works. The placebo will be described as an inert or inactive liquid, without 
any medication in it (see below). Additionally, subjects will be told that ‘‘liquid placebo has 
been shown in rigorous clinical testing to lead to improvement of pain symptoms possibly by an 
effect on the interaction between the body and the mind.’’ Following a description of placebos 


 
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and the study process, patients who give informed consent and fulfill the inclusion and 
exclusion criteria will be randomized into two phases: A 1.5 ml of  placebo suspension twice 
daily, and a third dose if the pain has not resolved or B) no placebo. In both phases, subjects will 
be prescribed a rescue medication. The rescue medication prescribed will be hyoscyamine (an 
anticholinergic), which subjects may use to control pain on an as needed basis in both phases. 
Hyoscyamine is considered a standard of care medication for the treatment of functional 
gastrointestinal disorders. 
Standard of Care - While there are no guidelines for the treatment of Functional Abdominal Pain, 
physicians most commonly prescribe an anticholinergic as the first line in treatment. For that 
reason, hyoscyamine, will be used as the rescue medication for subjects in this study. Subjects 
enrolled in this study will have a clinical indication to be prescribed hyoscyamine, per their 
primary gastroenterologist.  
Specific methods 
Patients will complete 1 week of observation and will then return to clinic. Eligible patients will 
then be randomized to one of two arms: a) Group 1:  Control period (CP) for 3 weeks, followed 
by open label placebo (OLP) for 3 weeks and b) Group 2 : OP for 3 weeks, followed by a CP of 3 
weeks There will be no washout period between both treatments phases as there should be no 
carryover effect of an inactive compound.  
 
Visit 1: First encounter (Day 0/Week 1): Prior to the first encounter, the medical record of children 
seen in clinic will be reviewed to assess study eligibility. Eligible patients may also be sent a 
recruitment letter. The first encounter will occur in gastroenterology clinic.  


 
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1- A member of the research team will approach subjects in one of the gastroenterology 
clinics to introduce the study and to obtain consent.  
a. Families do not have to decide on the day approached if they would like to 
participate in the study. They can take the consent home and consider their 
participation at their leisure. They will be informed, however, that if they decide 
to participate in the study after the fact, that they will not be able to start the 
hyoscyamine until the completion of the 7-day baseline phase.  
2- Daily diary sheets will be provided for the baseline week 1. . This diary will be used to 
gather baseline data (1st week of study)  
3- The daily diary will include the visual analogue scale, and the  Word-Graphic Rating Scale, 
which will help children to rate the severity of their abdominal pain. The subject  will be 
instructed to rate the abdominal pain on a rating scale every day at bedtime.  
 
Visit 2: Second Encounter (start of week 2) 
1- Subject will be randomized into one of the 2 arms of the study  
2- If randomized to Phase A, a three week supply of hyoscyamine  and placebo will be 
provided to the family 
3- If randomized to Phase B, only a three week supply of hyoscyamine will be provided.  
4-  Subjects will be asked a standardized set of questions regarding diagnosis, history and 
characteristics of pain.  
5- Subjects will complete the Pediatric Quality of Life Questionnaire.  


 
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6- Subjects will be given a three week daily diary to complete which will be two pages each 
day inquiring about symptoms and the Diary will also be used by subjects to indicate 
whether hyoscyamine was used that day. 
7- Collection of saliva for COMT testing 
 
Visit 3: Third encounter (start of week 5): Will occur in gastroenterology clinic.  
1- Family returns completed diary forms from 1 week of baseline and 3 weeks of study (the 
3 weeks will either be for Phase A or Phase B).  
2- Clinical evaluation.  
3- Subjects will complete the Pediatric Quality of Life Questionnaire.  
4- Physician addresses any study concerns and questions. 
5- Patients will then be crossovered to the opposite treatment, either placebo with rescue 
medication, or rescue medication alone 
 
Visit 4: Fourth  encounter (End of week 7): Will occur in gastroenterology clinic.  
1- Family returns completed diary forms for alternate phase of study and unused medication 
and placebo.  
2- Clinical evaluation.  
3- Subjects will complete the Pediatric Quality of Life Questionnaire  
4- Family and subject are thanked for participating in the study. 
 


 
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At the conclusion of the study at visit 4 we will schedule four follow up appointments at 3-week, 
3 months, 6 months, and 12 months after the completion of the study to follow up clinically with 
the patient.  
If the patient has demonstrated significant improvement during the placebo treatment phase of 
the study, at the 3-week follow up appointment after completing the study,  the family will be 
given the option to restart the open label placebo for a maintenance period of 6 months. Patients 
who elect to take part in the additional 6 month maintenance phase will be seen back in the 
gastroenterology clinic after 1 month, 2 months, 4 months, and 6 months to assess progress 
during this extended open label treatment phase. This 6-month open label placebo extension is 
entirely optional and will be offered primarily at the request of the patient and/or family in an 
effort to offer an effective therapy with limited potential for side effects. 
All subjects will have the option to discontinue their participation in this study at any point. 
Should a subject begin in the placebo arm, see significant benefits from the study and as a result 
choose not to cross-over to the non-placebo arm, they will have the option to do so. If they do 
choose to do so, they will be provided with the placebo  from the study. Our recruitment goal 
was adjusted to account for subject attrition. 
b. Patient Selection and Inclusion/Exclusion Criteria 
 
The informed consent process will occur in the gastroenterology clinic during the patient’s 
scheduled doctor visit. Prior to each clinic, a member of the research team will review the 
schedule of patients and review the medical chart for each patient to screen for eligible subjects. 
Those children with a diagnosis of FAP or IBS will be considered for this study. Potential subjects 


 
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will be approached in the exam room following the physician’s visit. A member of the research 
team will approach subjects to introduce the study and to obtain consent. The study will be 
introduced as an open label trial of placebo and the potential risks and benefits of placebo will 
be outlined. The families recruited will be given adequate time to read the form and ask questions 
prior to obtaining a signature. If the family consents to entry into the study, written consent will 
be obtained from the parent/guardian of every subject and written assent will be obtained for 
all subjects between the ages of 8 and 18. A copy of the signed consent form will be given to the 
signers. The subject's parent(s) or guardian(s) may request that the subject be removed from the 
study at any time. In addition, the investigator may withdraw a subject from the study if he/she 
determines that it is in the subject's best interests. Medical care will not be altered whether or 
not consent is obtained. 
 
In addition to approaching potential subjects in the gastroenterology clinic, patients may also be 
recruited through an informational flyer or online posting. Both briefly outline the purpose of the 
study and provide contact information for the study team. 
Inclusion criteria:  
1. Age 8 to 18 years.  
2. Diagnosis of functional abdominal pain, or irritable bowel syndrome made by a 
pediatric gastroenterologist according to Rome III Criteria.  
3. Mean daily intensity of pain of 25 mm in the week prior to the initiation of the study, 
based on the Word-Graphic Rating Scale score.  


 
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4. Children will not be excluded if they are adhering to any specific diet. Children will 
be asked to report any specific established diet prior to the study or dietary 
modifications that could have been made during the course of the study. 
5. Normal laboratory tests including complete blood count, erythrocyte sedimentation 
rate, albumin, serum amylase, lipase, liver enzymes, urine analysis, stool examination 
for occult blood and ova and parasites one month prior the initiation of the study. 
Urinary culture will be obtained if the symptoms or urinalysis suggest the possibility 
of a urinary infection.  
6. Normal lactose breath test or history of lack of resolution of symptoms on a lactose-
free diet (2 weeks).  
7. Patients receiving psychological treatment, hypnosis, biofeedback or guided imagery 
will not be excluded of the study if those were started at least one month prior to 
the initiation of the study and are not planned to be discontinued during the length 
of the trial. Patients will need to be prescribed hyoscyamine (clinically indicated) to 
be considered for this study, as the placebo will be in addition to their prescribed 
medication. 
 
Exclusion criteria:  
1. Inclusion criteria not met.  
2. Evidence of organic gastrointestinal disease, hepatic disorders, urinary or cardiac 
disease.  
3. Children below the 5th percentile for weight or height.  


 
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4. Hemoccult positive stools.  
5. Patients with diagnosis of Inflammatory Bowel Disease, hyperthyroidism, CHF, 
cardiac arrhythmias, prostatic hypertrophy, autonomic neuropathy, biliary tract 
disease, children with spastic paralysis or chronic lung disease (we will consult a 
pulmonologist concerning the inclusion of children with chronic lung disease).  
6. Patients who are taking any of the following drugs: AbobotulinumtoxinA, 
Acetylcholinesterase Inhibitors (Central), Cannabinoids, OnabotulinumtoxinA, 
Potassium Chloride, Pramlintide, RimabotulinumtoxinB, Secretin. Patients receiving 
antidepressant or anticholinergic drugs will be excluded from the study. PPIs will be 
allowed as long as the patient had been on a stable dose for at least 12 weeks. 
7. Patients planning to change their diet during the time of the study will be excluded. 
Children will be asked to report any specific established diet prior to the study or 
dietary modifications that could have been made during the course of the study. 
8. Patients planning to start psychological treatment, hypnosis, biofeedback, or guided 
imagery during the course of the study or have started any of these within the 
month prior to consent. 
9. The participant  is pregnant or is planning to become pregnant throughout the 
course of the research study 
 
c. Description of Study Treatments or Exposures/Predictors 


 
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Description of Placebo: The Placebo will be in liquid form. It will be a Humco Brand simple syrup. 
Patients will take 1.5 ml  of the Placebo in the morning and 1.5 ml at night using a plastic 3 ml 
syringe. The placebo will be stored and dispensed by the Children’s Hospital Boston Pharmacy, 
Description of Rescue Medication: Hyoscyamine will serve as the rescue medication for this 
study. Hyoscyamine works by decreasing the motion of the stomach and intestines and the 
secretion of stomach fluids, including acid. Subjects will be provided with a prescription for 
Hyoscyamine pills to use on an as needed basis. Families will be responsible for the cost of this 
medication. Children ages 8 through 21 may not exceed 4 pills per day.  
 
 Using 4 pills is much lower than the highest recommended dose. In children <12 the maximum 
recommended dose is 0.75 mg, and in those > 12 years it is 1.5 mg The dose we are 
recommending here is 0.6 mg. Even if the patients take more it is unlikely they will overdose. 
Patients will be instructed not to take more than the recommended number of pills. If there is a 
nocebo effect, or more pain, they will be instructed to contact the investigative team.  This 
medication has anticholinergic properties so the families will be instructed on those side effects. 
The first point of contact if there is increasing pain will be the research team. Patients/families 
will be instructed to go to the ED if the investigator thinks there are anticholinergic side effects, 
or judges that the pain merits consultation to rule out surgical problems. This has been added to 
the Risk section of the protocol. 
 
Catecholamines play a key role in cognitive7, behavioral8, sensory9, endocrine10 and 
autonomic nervous system regulation11.  Thus functional polymorphisms in catechol-O-


 
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methyltransferase (COMT), an enzyme that metabolizes catecholamines may be associated 
with a variety of clinical conditions. The most extensively studied COMT single nucleotide 
polymorphism (SNP), rs4680 or val158met, is a G to A transition that encodes a valine (val) to 
methionine (met) substitution at amino acid 158 in the membrane form of the enzyme and 
amino acid 108 in the secreted form12. The G or val variant is 3-4 times more enzymatically 
active than the A or met variant13. The differences in enzymatic activity are inversely correlated 
to endogenous levels of dopamine14 and other COMT substrates including epinephrine, 
norepinephrine and catechol estrogens15,16, both at rest and with stress induced by exercise17 
or cardiac surgery18. In turn, variation in the levels of these signaling molecules have been 
related to functional pain syndromes9, as well as in irritable bowel syndrome in adults19. 
Based on a study conducted in adults with IBS19, in which IBS patients homozygous for 
the COMT val158met methionine allele (met/met) were the most responsive to placebo 
treatment, we hypothesize that the COMT functional val158met polymorphism will be a 
predictor of placebo effects.  
Specific aspects of the encounters: 
Design of a script and validation of the script to introduce the placebo phase 
A defined script to approach each family/individual was designed. Different scripts were 
designed specifically for each group and  visit type including enrollment,  randomization to 
either group and crossover. The script for the placebo group included the following concepts: 
a) the placebo effect is very powerful in randomized clinical trials; 
 b) although we have much more to learn about how it works, we do know that it takes 
advantage of the mind-body connection;  


 
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c) one reason for its effect may be that the body automatically responds to taking the 
placebo suspension and activates responses that help reduce pain and swelling;  
d) the placebo jump-starts this beneficial response;  
e) another good thing about a placebo is that you do not need to believe in it for it to 
work – a positive attitude helps, but is not necessary;  
f) however, for the placebo to work, it is important that you to take the suspension on a 
regular basis, and finally  
g) the great thing about placebos is that there are no side effects. 
 
 
The script were practiced to be sure they were delivered in the same way to all individuals, and 
given the multicenter nature of the trial a video was created and distributed to the centers. One 
of the members of the BCH team then witnessed and validated to scripts at the other sites to 
ensure uniformity.   
 
 
d. Definition of Primary and Secondary Outcomes/Endpoints 
Primary Outcome Measures:  
 
Primary outcome 
The primary outcome that will be used will the mean daily pain (0-100 VAS scale).   It will be 
assessed at the end of the 3-week and 6-week treatment periods (at the end of each treatment 
arm prior to switching to the next arm of treatment) (see statistical section below)  


 
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Secondary outcomes 
 The study will assess two global outcome measures of patient's symptomatic response: 
satisfactory relief of symptoms and overall improvement. Both patient reported outcome (PROs) 
measures have been widely studied 20 and used in adult and pediatric studies including a large 
randomized clinical trial conducted by our research group on a similar group of patients.6 
Landmark studies leading to the approval of medications for IBS have used adequate or 
satisfactory relief of symptoms and overall improvement as outcome measures.21,22 Following 
the design of most high quality clinical trials in IBS both global assessment questions will be 
analyzed as binary outcomes.23 Both binary improvement endpoints have shown excellent 
construct validity and were not impacted by baseline severity in adult studies  24,25 , and have 
demonstrated adequate psychometric properties in pediatric studies conducted by our group.26  
Clinical global improvement will be assessed by obtaining symptomatic improvement  using the 
following questions: 
1- Satisfactory relief:  “Overall how do you feel your problem is?” Patients will select an 
answer from a list of 3 possible answers (better, same, or worse).  In order to establish a 
binary assessment of outcome patients answering: “better” will be compared to “worse” 
and “same” 
2- Satisfaction with treatment: “How did the medication relieve your pain?” Patients will 
select an answer from a list of 5 possible answers (excellent, good, fair, poor, or failed).  


 
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In order to establish a binary assessment of outcome patients answering: “excellent” and 
“good” will be compared with those answering: “fail”, “poor” and “failed”. 
 
Other secondary outcomes were the use of rescue medication (assessed by pill count) , change 
in disability, anxiety  and quality of life before and after the placebo or the control period. 
 
Evaluation tools and questionnaires 
1- Demographic Information (age, race, gender).  
 
2- QPGS.- Questionnaire on Pediatric Gastrointestinal Symptoms: Rome III version (QPGS-RIII), 
Validated questioannire to establish Rome criteria () 
3- Word-Graphic Rating Scale is a simple, valid, sensitive and developmentally appropriate self-
report test to assess pain intensity in children. It consists of a 10 cm horizontal scale anchored by 
the words “no pain”, “little pain”, “medium pain”, “large pain” and the “worst possible pain” at 
regular intervals from left to right end of the line respectively.  
4- Functional Disability Inventory consists of 15 self-report items assessing the perceived degree of 
physical and psychosocial difficulty in functioning due to the patient’s health status. This 
inventory has high levels of internal consistency, construct validity and high levels of test–retest 
reliability for patients with recurrent abdominal pain. The FDI is sensitive to changes in patient 
status subsequent to medical treatment making it an appropriate instrument for outcome 
measure.  


 
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5- Pediatric quality of life.- Validated age appropriate questionnaire to assess quality of life in 
children 
6- Pediatric Quality of Life GI Questionnaire- the GIPedsQoL is a validated age appropriate 
questionnaire that was used in multiple studies of GI  pain in children {Kovacic, 2017 
#861;Krasaelap, 2020 #1128} 
7- RCADS.- The Revised Child Anxiety and Depression Scale (RCADS) is a 47-item, youth self-report 
questionnaire with subscales including: separation anxiety disorder, social phobia, generalized 
anxiety disorder, panic disorder, obsessive compulsive disorder, and low mood (major depressive 
disorders 
8- CDI. Children's Depression Inventory 2™ (CDI 2) is a brief self-report test that helps assess 
cognitive, affective and behavioral signs of depression in children and adolescents 
9- Children’s Somatization Inventory assesses the extent of children's somatic complaints on the 
previous two weeks. The CSI had good concurrent validity with another self-report measure of 
somatic symptoms and a low but significant correlation with parents' reports of their children's 
somatic symptoms on the parent version of the CSI. A total score is obtained by summing the 
ratings of its 35 questions and can range from 0 to 140.5-  
10- To assess expectations of success the question: “How well do you think the treatment will work 
in a scale 1-10” will be asked at the beginning of each arm of the study 
 
Informational Pamphlet 
 


 
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A 1-page informational pamphlet will be given to subjects and their families. This short pamphlet 
provides additional information about the placebo effect and the ability of placebo treatments 
to provide symptom relief for patients with certain conditions. The aim of this pamphlet it to 
provide subjects and their families with standardized and consistent background information on 
the placebo effect.  
 
 
E. Adverse Event Criteria and Reporting Procedures 
Adverse events will be considered as significant deviations from normal health, especially any 
gastrointestinal symptoms which require hospitalization. If health issues arise in any subjects we 
will refer them to their primary care physician. Treatment will be made available to the subject 
at Children’s Hospital Boston should they choose to see us. Cost of treatment will be the 
responsibility of the patient. The investigator may choose to remove these subjects from the 
study. 
All adverse events will be evaluated and reported on case report forms by Dr. Samuel Nurko on 
a daily basis. He will record  any adverse events , and Children’s Hospital will be the 
coordinating center., The chair of the DSMB will receive the information from all centers on a 
monthly basis, unless serious in which case they will be reviewed by the DSMB within 72 hours. 
All adverse events will be reported to the committee on clinical investigation within 7 days. 
Severe adverse events will be reported within 24 hours. Once a report is issued, responses such 
as suspensions will be quickly verbally communicated to study investigators. 


 
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The DMSB will be responsible for monitoring the data, and will be involved in the interim 
analysis if necessary. We do not anticipate any interim analysis for early discontinuation for 
efficacy due to the small sample size and the descriptive and exploratory nature of the study. 
After half the patients are enrolled, an interim analysis will be performed primarily focused on 
adverse events, data quality and completeness, and study accrual. For the interim analysis, a 
committee will be formed comprised of two physicians and one biostatistician, none of whom 
are involved in the study. The trial may be discontinued at any time at the recommendation of 
the investigator or Data Safety and Monitoring Board (DSBM) based on a significant number of 
severe adverse events of similar nature. 
 
Stopping rules: 
The stopping rules will be the following: a) Worsening of the pain to the point that the 
parent/child think is unbearable 
b) Visit to the ED because of the pain 
c) Admission to the hospital because of the abdominal pain. 
d) Development of vomiting or weight loss 
 
The DMSB may recommend stopping the trial before its planned end for any of the following 
reasons:  
a) Placebo administration to patients suffering from FGIDs worsens the pain experienced  
b) adherence to trial protocol may be below acceptable goals, such that the ability of the trial to 
achieve its goals would be severely compromised or  


 
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c) adverse events may be unacceptably high. 
The investigators from the respective sites have a well-established relationship working 
collaboratively in the area of pediatric gastrointestinal research. If at any point an adverse 
event or new development arise at any of the sites, the principal investigator of that site will 
verbally communicate the findings or data to the corresponding site within 24 hours. Any follow 
up information or recommendations of the IRB will be forwarded as it is received. All data 
communicated between sites will not have identifiers and PHI attached. Subjects will be 
referred to by their assigned study ID number only in all communications. 
In the event of an injury resulting directly from a patient’s participation in this research study, 
medical treatment will be provided if the injury is reported in a timely manner to the Principal 
Investigator, Dr. Samuel Nurko, and the  research team. If any research-related injury occurs, 
you/your child should contact research staff using the phone numbers provided at the end of 
this form to report the incident. Provision of such medical care will not imply any negligence or 
other wrongdoing on the part of Boston Children’s Hospital or any of the physicians or other 
personnel involved in the study (in Boston or a coordinating center). Where applicable, BCH 
reserves the right to seek payment from third-party payers for any medical care or services 
rendered. The Hospital has no program to provide the research participants with any additional 
compensation as a result of any such injuries. 
 
UNFORESEEN INJURIES 
The use of placebo’s in children and adolescents with functional gastrointestinal disorders is not 
well studied and is not an approved treatment. It is possible that there may be some side 


 
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effects or risks with the use of the placebo that are not yet known. Sometimes, during the 
course of a study, we may learn new information about the placebo that might change whether 
or not the participants want to continue in the study. If this happens, the Principal Investigator 
(Dr. Samuel Nurko) will tell the participants about it in a timely manner, and they will be given 
an opportunity to withdraw from the study.  
Additionally, there may be an additional unforeseeable risk to participants who are pregnant or 
become pregnant throughout the course of the study. The use of placebo in pregnant women 
has not been extensively studied and could carry a risk to the embryo or fetus, which is 
currently unforeseeable. If the participant is or becomes pregnant throughout the course of the 
study, they will be requested to inform Research Staff as soon as possible. 
If significant new findings occur during the course of the research that may relate to the 
subject’s 
willingness to participate, such information will be disclosed to them in a timely manner and 
they will be given the opportunity to withdraw at that time and will be reminded it will be with 
no consequences (Just as if they were to withdraw at any other time) 
 
This information is available in the ICF. 
 
F. Data Management Methods 
The diary forms and questionnaires will be identified by a study ID number and not include 
subject names. The Study ID number will be a 3 digit number including one random digit and will 
not in any way be derived from personal patient information. The data will be analyzed as a whole 


 
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by the statistical department at Children’s Hospital Boston; individual survey results will not be 
disclosed. All links to individual subjects will be deleted at the end of data collection. Data will be 
stored on a password-protected database that only the research staff will have access to. The 
data from all institutions will be transferred to Children’s Hospital Boston, and data transfer 
agreements will be in place. 
G. Quality Control Methods 
Possible Risks 
Risks of PLACEBO: 
Some research studies have shown that subjects may have a negative response to the use of 
placebo.30 In studies where subjects are not told whether they will receive medication or a 
placebo some subjects in the placebo group will experience the side effects associated with 
medication given in that particular study. Other studies have shown that subjects who enter a 
study with negative expectations (or a pessimistic attitude) may also have a negative response 
to placebo.31,32  
There is also a potential for the participant and family members to loose trust in the 
participant’s gastroenterologist who is dispensing a placebo to treat their problem. There is 
limited knowledge to date regarding children’s perception of placebos. The participant and 
family members will be reassured that they are being recruited into this study because their 
child’s primary gastroenterologist believes there is a possibility of symptom improvement from 
their child’s participation. 
GENERAL RISKS: 


 
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The participant will receive a prescription for hyoscyamine at the beginning of this trial, but will 
be asked to hold off on taking the medication for the first 7 days (baseline phase). There is a risk 
here that the participant could experience symptoms during this period, and we are asking that 
they, if possible, delay taking the rescue medication until the first phase of the trial begins in 
order to get an accurate baseline measurement. The participant and family will be asked to 
delay hyoscyamine usage, but will not be forced to delay treatment should the symptoms be 
unbearable. 
 
Due to the possibility of a breach of confidentiality personal identifiers (other than date of birth 
and gender) will be removed from all documents before they are placed in the central research 
record to insure confidentiality. Subjects will be assigned an identification number, which will be 
used in place of personal identifiers. The study database will be password protected and all 
information will be handled confidentially. To minimize the risks associated with placebo, 
subjects will be provided with rescue medication to take on an as needed basis. 
This study involves filling out questionnaires on quality of life and pain. It is possible that filling 
out questionnaires may not be comfortable for the patient so they will be informed verbally and 
through the ICF that this is voluntary and it is not absolutely mandatory that they fill out the 
questionnaires. They will just be asked to fill out as many as they feel comfortable with.  
Possible Benefits 
There is the possibility that subjects will feel better and have improved symptoms following 
participation in this study. Subjects may also benefit by participating in this study because the 
results will be used to benefit future patients and their medical treatment. 


 
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H. Data Analysis Plan, Statistical Power and Sample Considerations 
I. Power Analysis  
J. The within-subjects design of the study allowed each participant to serve as his or her 
own control, which tends to increase statistical power. We used G*Power 3 software to 
conduct the power analysis. Using a two-tailed test with alpha set at 5%, we calculated 
that a repeated measures analysis of variance with a sample size of 30 would provide 
99% power to detect large effects (e.g., 2p = .14), and 75% power to detect medium 
effects (e.g., 2p = .06).  
K. Statistical Analysis 
Values will be expressed as mean + SD when normally distributed, or as medians if 
applicable. For the categorical outcomes of interest, either a Fisher’s Exact test of a chi-
square test will be used.  Each of the outcomes will be analyzed separately. Paired tests 
will be used when comparing baseline values to values after the different interventions . 
Statistical significance will be set at p<0.05.  
As an assessment as to the necessary inclusion of potential covariates, the drug therapy 
and the drug + placebo groups will be compared on descriptive variables (e.g., age, etc.).  
If the groups are statistically different on any of these variables, then they will be 
included as covariates in subsequent analyses. 
The order of the two conditions (open label placebo vs. no treatment control) will be 
counterbalanced to minimize order effects methodologically (we also controlled for 
order effects statistically, as detailed below).  The primary outcome measure will mean 
daily pain (0-100 VAS scale). We will compare mean daily pain scores during the 3-week 


 
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open label placebo condition with mean daily pain during the 3-week no treatment 
control condition using a repeated measures analysis of variance. In addition, we will 
control for treatment order and for mean daily pain during the 1-week baseline period 
by including those variables in the model as covariates. The model will also include the 
interaction between order and treatment condition, as well as the interaction between 
baseline pain and treatment condition, thus controlling statistically for these interaction 
effects as well. Effect sizes will be computed using partial eta-squared (2p), which can 
be interpreted as the percent of variance in the dependent variable that can be 
accounted for by the independent variable, after controlling for all other variables in the 
model. By convention, 2p = .01 is considered a small effect, 2p = .06 is considered 
medium and 2p = .14 is considered large 
 
 
 
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