Conditions: Idiopathic Gastroparesis
Keywords: Gastroparesis Idiopathic Olanzapine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
Gastroparesis is a disorder characterized by impaired gastric emptying in the absence of obstruction in the proximal GI tract. It is a common condition affecting up to 5 million persons in the United States alone. Despite this, metoclopramide is currently the only FDA approved medication for the treatment of gastroparesis. However, the evidence supporting metoclopramide in gastroparesis is fairly weak and was recently issued a black box warning because of potential irreversible side effects. There is clearly an urgent need for newer therapeutic options with better efficacy and tolerability. Olanzapine is a second generation anti-psychotic that is currently FDA approved for the treatment of schizophrenia and bipolar disorder. Because of actions at several receptors throughout the body, including dopamine and serotonin receptors, Olanzapine may provide anti-nausea and pro-motility effects in the stomach. Long-term use of olanzapine may also increase plasma levels of ghrelin. Ghrelin is a hormone produced by the gut that stimulates appetite and has also been shown to have beneficial effects on gastroparesis. The investigators hypothesize that olanzapine will be effective and safe in controlling symptoms as well as stimulate appetite and weight gain in gastroparesis. The investigators also hypothesize that olanzapine will stimulate gastric motility. Finally, the investigators hypothesize that olanzapine will modulate the secretion of ghrelin in gastroparesis. This pilot study may provide further information on the efficacy and safety of olanzapine in gastroparesis which could be utilized in a larger randomized, prospective study in the future.

Detailed description:

Arms:
arm 1: An open-label pilot study of 20 consecutive subjects ages 18 - 70 with documented delayed gastric emptying within the past 2 years and history of nausea, vomiting, bloating, anorexia, early satiation, post-prandial fullness, and weight loss for at least 6 months without structural or organic cause will be enrolled.

Interventions: intervention 1: Olanzapine
Intervention descriptions: intervention 1: Subjects will initially start on olanzapine 2.5 mg per mouth daily. Subjects will return on days 7 and 14 to determine response to medication and medication dose can be increased to 5 mg and 10 mg, respectively, based on incomplete symptom response (mean change GCSI-DD \< 0.5). The total dose of olanzapine will not exceed 10 mg daily during this study and subjects will continue on treatment for a total of 8 weeks.

Protocol document:
Prot_SAP_000.pdf: 
A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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1 
Title 
A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and 
Gastric Motility in Gastroparesis   
Principal Investigator: 
Allen Lee, MD 
Clinical Lecturer 
University of Michigan 
 
Funding Mechanism: (e.g., grant or cooperative agreement #) 
American College of Gastroenterology 
 
Institution(s):  University of Michigan 
 
Other Identifying Numbers: (e.g., Institution-assigned number, HUM 
HUM104229 
 
Protocol Amendments: 
(Any modifications to the protocol should be annotated on the coversheet or in an 
appendix.  The annotation should note the exact words that are changed, the location in 
the protocol the date the modification was approved, and the date it became effective.) 
 
Draft or Version Number: 2.0 
Day Month Year: 29 August 2016 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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 TABLE OF CONTENTS 
Page 
Title Page…………………………………………………………………………………………1 
Table of Contents ............................................................................................................ 2 
Signature Page ............................................................................................................... 3 
List of Abbreviations ........................................................................................................ 4 
1 
Background/Scientific Rationale .............................................................................. 5 
2 
Objectives ............................................................................................................... 6 
3 
Expected Risks/Benefits.......................................................................................... 7 
4 
Eligibility ................................................................................................................ 10 
5 
Subject Enrollment ................................................................................................ 12 
6 
Study Design and Procedures ............................................................................... 12 
7 
Data Collection and Management Procedures ...................................................... 16 
8 
Data Analysis ........................................................................................................ 17 
9 
Quality Control and Quality Assurance.................................................................. 18 
10 
Statistical Considerations ...................................................................................... 18 
11 
Regulatory Requirements ...................................................................................... 19 
11.1 
Informed Consent ....................................................................................... 19 
11.2 
Subject Confidentiality ................................................................................ 19 
11.3 
Unanticipated Problems ............................................................................. 20 
12 
References ............................................................................................................ 22 
Appendices .......................................................................................................................  
 
 
 
 
 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations. 
Site Investigator:* 
 
Signed: 
 
Date: 
 
 
Allen Lee 
 MD 
 
 
 
* The protocol should be signed by the clinical site investigator who is responsible for 
the day to day study implementation at his/her specific clinical site.


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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LIST OF ABBREVIATIONS  
GI, Gastrointestinal 
TD, Tardive dyskinesia 
BMI, Body mass index 
5-HT, 5-hydroxytryptamine 
GCSI-DD, Gastroparesis cardinal symptom index-daily diary 
VAS, Visual analog scale 
BSFS, Bristol stool form scale 
Hgb A1c, Hemoglobin A1c 
TSH, Thyroid stimulating hormone 
WMC, Wireless motility capsule 
EPS, Extrapyramidal side-effects  
CMP, Comprehensive metabolic panel 
EKG, Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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1 
BACKGROUND/SCIENTIFIC RATIONALE 
Gastroparesis is a disorder characterized by impaired gastric emptying in the absence of 
obstruction of the proximal gastrointestinal (GI) tract.  Symptoms typically include postprandial 
fullness, nausea, vomiting, bloating, and pain. In severe cases, anorexia and weight loss may 
be present.  It is estimated to affect up to 5 million persons in the US with an age-adjusted 
prevalence of 37.8 per 100,000 persons [1].  The most common identifiable etiology is diabetes 
mellitus in 30% but 36% are classified as idiopathic [2].  Gastroparesis is a chronic disabling 
condition that is associated with a significantly worse outcome compared to age and sex 
matched controls [3].   
 
Currently, the only FDA approved medication for treatment of gastroparesis is metoclopramide.  
Recently, metoclopramide was issued a black box warning by the FDA because of the risk of 
adverse events, especially tardive dyskinesia, a potentially irreversible neurologic condition 
characterized by uncontrollable facial, oral, and lingual movements.  National guidelines 
suggest the risk of developing tardive dyskinea is 1-15% [4, 5].  Although the actual risk of TD 
may be much lower, the evidence supporting the use of metoclopramide in gastroparesis is 
fairly weak, it may not alleviate symptoms of anorexia and weight loss, and development of 
other agents with better efficacy and less adverse effects is needed [6].   
 
Macrolide antibiotics have also been used in the treatment of gastroparesis.  They act on motilin 
receptors to cause pro-motility effects but have no central effects on nausea, hunger, and 
appetite stimulation [7, 8].  In addition, tachyphylaxis may limit long-term use. 
 
Olanzapine is a second generation anti-psychotic that is FDA approved for the treatment of 
schizophrenia and bipolar disorder.  Second generation anti-psychotics typically have fewer 
extrapyramidal side effects (e.g. akathisia, dystonia, parkinsonian symptoms) as well as tardive 
dyskinesia compared to older anti-psychotics [9, 10].  However, they do carry potential for 
serious metabolic risk, specifically weight gain, hypertension, hyperlipidemia, and ultimately 
development of diabetes mellitus.  Olanzapine has been associated with one of the highest risks 
of weight gain among atypical anti-psychotics [11, 12].  It is unclear if this is related to other 
actions or if it is related to attenuation of the disease process.  Patients with schizophrenia may 
have a predisposition towards obesity with a prevalence of up to twice the general population 
[13].  Genetic predisposition, higher prevalence of smoking, and neuroendocrine changes 
associated with psychosis have all been postulated as possible contributing factors to increased 
obesity in schizophrenia and bipolar disorder [14-18]. 
 
Olanzapine may also have other therapeutic effects outside of controlling psychosis.  Phase I 
and II studies have shown olanzapine significantly relieves nausea and emesis in a palliative 
care setting [19-21].  It was found to be safe in both trials and helped stimulate appetite and 
augment weight gain.   There is also evidence that olanzapine may be beneficial in the 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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treatment of eating disorders.  Several double blind, placebo-controlled trials have shown 
benefit of olanzapine in terms of attaining goal BMI and improving psychological measures [22-
24].  Furthermore, the medication was well tolerated in this population without development of 
adverse metabolic events [22, 23, 25].   
 
Olanzapine has actions at multiple receptors throughout the body, which may make it a unique 
drug for the treatment of gastroparesis.  These include antagonism of dopamine, serotonin, 
alpha1 adrenergic, muscarinic, and histamine receptors [26, 27].  Many of these receptors, 
especially D2 and 5HT3, are involved in the signaling of nausea and emesis [28].  As a result, 
olanzapine may have anti-nausea properties that could be utilized in gastroparesis.  Antagonism 
of D2 receptors may also provide motor effects in the stomach, as this is one of the main 
mechanisms of action for metoclopramide [29-31]. 
 
Furthermore, olanzapine may also have effects on gut neurohumoral signaling that are 
important in regulation of appetite and weight.  Long-term use of olanzapine between 26 and 52 
weeks has been shown to increase plasma levels of ghrelin in mouse models as well as 
humans on long-term treatment for schizophrenia [32-34].  However, short-term use between 2 
to 9 weeks may actually decrease levels of ghrelin [35-37].  Ghrelin is a hormone that is 
produced by the gut, stimulates appetite, and has been shown to improve symptoms as well as 
promote gut motility in gastroparesis [38-40].  Previous data have shown that olanzapine may 
affect only ghrelin levels whereas other gut hormones, e.g. peptide YY, pancreatic polypeptide, 
leptin and GLP-1 were not affected [34, 37].  Because of this data as well as limited resources, 
only ghrelin is going to be evaluated during this study. 
 
There are few options currently that are efficacious and safe for the treatment of gastroparesis 
and development of other therapeutic options is needed.  Furthermore, in patients with severe 
gastroparesis causing anorexia and weight loss, polypharmacy is often needed to stimulate 
appetite and alleviate symptoms.  Olanzapine may possess unique properties, which makes it a 
potentially attractive therapeutic option for gastroparesis.  We hypothesize that olanzapine will 
be effective and safe in controlling symptoms as well as stimulate appetite in gastroparesis.  We 
also hypothesize that olanzapine will promote gastric motility.  Finally, we hypothesize that 
olanzapine will stimulate the secretion of ghrelin, thereby aiding in the treatment of 
gastroparesis.  This pilot study may provide further insight into the efficacy and safety of 
olanzapine in gastroparesis, which could be utilized in a larger randomized, placebo-controlled 
prospective study in the future. 
2 
OBJECTIVES 
Aim 1:  Investigate the efficacy and safety of olanzapine in the treatment of non-
diabetic gastroparesis. 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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We will utilize the gastroparesis cardinal symptom index daily diary (GCSI-DD) and an 
appetite visual analog scale (VAS) to compare severity of symptoms before and after 
treatment with olanzapine.  Subjects will undergo regular testing of blood glucose, 
insulin, hemoglobin (Hgb) A1c, body mass index (BMI), liver enzymes, thyroid 
stimulating hormone (TSH), and prolactin levels during the study as well as after 
treatment completion to determine the safety of the medication.  All adverse events will 
be compiled to investigate the tolerability of the medication. 
 
Aim 2:  Determine whether olanzapine has prokinetic effects on gastric emptying 
in gastroparesis. 
We aim to test gastric motility, including gastric emptying and antroduodenal contractility 
parameters, by wireless motility capsule (WMC) before and at the completion of the 
study to determine if olanzapine has any pro-motility effects in gastroparesis.  
 
Aim 3:  Examine the effects of olanzapine on neurohumoral regulation of eating 
and appetite. 
We seek to determine whether olanzapine promotes secretion of ghrelin in 
gastroparesis.   
3 
EXPECTED RISKS/BENEFITS 
The data accumulated in this study will advance our understanding of the 
pathophysiology of gastroparesis, and may provide important information on whether 
olanzapine is helpful in the treatment of idiopathic gastroparesis.   
There are potential direct benefits for all gastroparesis subjects in this study.  On study 
entry, physiologic tests of gut function and motility will be performed that may provide 
new insight into causes of symptoms in patients with IBS.  In addition, all subjects will 
be seen by the PI and/or study team frequently during the study.  Adverse events, vital 
signs, and laboratory parameters will be assessed to monitor overall safety and 
tolerability of the medication.  Survey information will also be obtained using validated 
questionnaires including GCSI-DD, appetite VAS, and BSFS.  The GCSI-DD is a 
validated questionnaire composed of twelve questions that takes approximately 10 
minutes to complete.  The appetite VAS is a single item questionnaire that tracks 
changes in appetite over time.  This will take approximately 1 minute to complete.  The 
BSFS is a questionnaire that allows researchers and subjects track changes in bowel 
form and frequency.  This will take approximately 1 minute to complete.  This frequent 
and comprehensive assessment provided as part of participating in this study may allow 
for closer monitoring of disease course. 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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There are potential risks for subjects, including:  
1.  Olanzapine Risks: 
Weight gain: Weight gain is a known risk when patients with schizophrenia or other 
psychiatric illnesses are taking olanzapine.  This may also predispose the patient to 
develop underlying obesity, hyperlipidemia, diabetes mellitus, and coronary artery 
disease.  However, this may be a risk inherent to this specific population and may not 
be applicable to the general population.  Human studies in patients with anorexia 
nervosa and other eating disorders have shown the safety and tolerability of olanzapine.  
We will exclude anyone with a history of diabetes mellitus or hyperglycemia.  We will 
also monitor the subjects closely during the study period and anyone who exhibits 
hyperglycemia (fasting glucose > 150 mg/dl or non-fasting glucose > 180 mg/dl), and/or 
rapid weight gain (> or = 5 kgs/week) will be taken off the study drug.  Subjects will 
continue to be monitored for 14 days after completion of the study drug.  
Orthostatic hypotension: Subjects who are taking concomitant anti-hypertensive 
medications will be warned about the risk of potentiating orthostatic hypotension with 
olanzapine.  They will be asked to exercise caution especially when changing positions 
suddenly.  
Hyperglycemia:  Subjects will be given a handout at the start of the trial discussing 
potential symptoms of hyperglycemia, including excessive thirst, frequent urination, 
blurry vision, and fatigue.  Subjects will be asked to notify the study coordinator 
immediately if they have any of these symptoms. 
Somnolence: Subjects will be asked to take the olanzapine at bedtime to minimize the 
effects. 
Constipation: Subjects will be instructed on potential effects of olanzapine on bowel 
habits and may take laxatives to help with constipation.   
 
Olanzapine appears to be well tolerated in placebo-controlled trials.  The only adverse 
events occurring more frequently with olanzapine compared with placebo were 
somnolence, constipation, and weight gain.  However, other adverse events have been 
reported in the literature and will be listed below. 
Extrapyramidal side-effects: Animal models as well as human studies have shown low 
potential for olanzapine to cause extrapyramidal side-effects (EPS), such as 
parkinsonism, akathisia, and dystonia.  Subjects will be monitored during the study 
period for development of EPS. 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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Thyroid dysfunction: There is a small risk for causing thyroid dysfunction.  Thyroid levels 
will be checked as part of the screening period and patients with underlying dysfunction 
will be excluded from the study.  If thyroid dysfunction occurs during the study, they will 
have the option of withdrawing from the study. 
Hyperprolactinemia: Olanzapine produces minimal effects on prolactin levels in patients 
with schizophrenia.  This will also be monitored prior to starting the study drug and 
subjects with abnormal levels of prolactin will be excluded.  Patients who exhibit signs 
and symptoms of hyperprolactinemia during the study period will be given the option of 
withdrawing from the study. 
Seizures: Lowering of the seizure threshold has been seen in subjects taking 
olanzapine.  This may be a dose-dependent response and certain factors including 
younger age, female sex, and concomitant SSRI use causes higher serum levels of 
olanzapine.  We intend to use a small dose of olanzapine and will exclude subjects with 
a history of seizure disorder. 
LFT abnormalities: Olanzapine can occasionally cause elevations in levels of hepatic 
transaminases.  However, the elevations appear to be transient and no evidence of 
hepatotoxicity has been reported.   
Hematologic abnormalities: There are no reports of agranulocytosis with olanzapine, 
even in those who previously had experienced olanzapine-induced dyscrasias. 
2. Wireless Motility Capsule Risks: 
WMC may become stuck in the intestines and rarely requires surgery to relieve an 
obstruction.  There is also a small possibility that WMC may interfere with a pacemaker 
or defibrillator. 
3. Blood Draw Risks  
Risks of blood draw include pain, bruising, irritation, or redness at the site where the 
blood will be drawn.  An infection at the site of the blood draw is possible. Subjects 
could become faint. 
4. Childbearing Risks 
The study drug may cause harm to an unborn child or nursing infant, and for this 
reason, no subject may be breast-feeding, pregnant, or plan to become pregnant. 
5.  Electrocardiogram (EKG) Risks 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
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An electrocardiogram (EKG) involves placing electrodes on the chest wall.  There may 
be some soreness in removing the electrodes and patients may develop a rash where 
the electrodes are attached.   
6.  Risks to Privacy 
There is a potential risk to the subject’s privacy.  While every effort will be made to 
maintain privacy, it is possible that others may learn about information acquired from the 
medical records.  Such a breach might lead to problems with getting insurance or a job. 
7. General risks 
This is an interventional study.  Subjects' condition may worsen or improve while 
undergoing intervention with olanzapine.  Participation in this study will not prevent 
normal clinical care of gastroparesis or its consequences.  In addition, some prescribed 
medications may need to be stopped temporarily during the study.  Subjects will also be 
asked to hold any medications that may potential influence GI motility or appetite within 
one week prior to starting and for the duration of the study, including prokinetic drugs, 
macrolide antibiotics (erythromycin), opioid pain medications, GLP-1 mimetics.  If 
subjects are taking any of these medications, their symptoms may return or worsen 
when they are stopped.  However, the stopping of medications is temporary and is not 
felt to cause any undue hardship.  Finally, there is a risk that some of the questions in 
the surveys may produce emotional distress.  If the subject desires, he/she can be 
referred to a mental health specialist within the UMHS or another provider outside the 
UMHS system. 
4 
ELIGIBILITY CRITERIA 
Inclusion Criteria: 
 Male or female between 18 and 80 years of age, inclusive. 
 Has gastroparesis at screening (gastric half-time of emptying > upper limit of 
normal as determined by wireless motility capsule) 
 Must have a > or = 6 month history of relevant symptoms of gastroparesis, (e.g., 
chronic post-prandial fullness, early satiety, postprandial nausea), patients will 
have a mean of the daily scores over a minimum of 7 days indicating > or = mild 
(2) assessed using the GCSI-DD during the screening period prior to 
randomization. 
 A female subject is eligible to participate if she is of non-childbearing potential or 
child-bearing potential and agrees to use one of the approved contraception 
methods.  Female patients must agree to use contraception for at least 5 days 
following the last dose of study medication. 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
Date: 09-29-2016 
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 Male subject must agree to use of contraception.  Contraception must be 
followed from the time of the first dose of study medication through at least 5 
days after the last dose of study medication. 
 BMI ≥ 18 and < 30 kg/m2 (inclusive). 
 Subjects on anti-hypertensive medications may be allowed to participate but 
should exercise caution given risk of orthostatic hypotension 
 Subject has never had a gastrectomy, nor major gastric surgical procedure or 
any evidence of bowel obstruction or strictures within the previous 12 months 
 Dosage of any concomitant medications has been stable for at least 3 weeks. 
 Estimated (or measured) glomerular filtration rate ≥ 30 mL/min. 
 QTcB or QTcF < 450 msec or QTc < 480 msec in patients with Bundle Branch 
Block based on single or average QTc value of triplicate values obtained over a 
brief recording period. 
 Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. 
 AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN; normal 
CBC, TSH, and prolactin levels. 
 
Exclusion Criteria: 
 Subject has a history of diabetes mellitus, hyperglycemia, hyperlipidemia, 
cardiovascular disease, cerebrovascular disease, seizures, hyperprolactinemia, 
Parkinson’s disease, or dementia. 
 Subject has a history of elevated glucose level (fasting blood glucose level of 
100-126 mg/dl and/or non-fasting glucose level of 140-200 mg/dl) 
 Subject has history of underlying schizophrenia, bipolar disorder, suicidal 
ideation/attempt, or has used olanzapine in the past. 
 Subjects with a pacemaker and/or defibrillator  
 Subject has acute severe gastroenteritis 
 Subject has a gastric pacemaker 
 Previous gastric surgeries 
 Subject is on chronic enteral (e.g., feeding tube) or parenteral feeding 
 Subject has pronounced dehydration 
 Subject has evidence of severe cardiovascular autonomic neuropathy (e.g. 
history of recurrent syncope in the last 6 months) 
 Subject has a history of eating disorders (anorexia nervosa, binge eating, 
bulimia) 
 Use of medications potentially influencing upper gastrointestinal motility or 
appetite within one week of the study (e.g., prokinetic drugs, macrolide antibiotics 
(erythromycin), GLP-1 mimetics) 
 Regular opiate use 
 Subjects who are taking drugs that potentially interact with olanzapine including 
diazepam, lorazepam, alcohol, carbamazepine, fluvoxamine, olanzapine and 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
Protocol # HUM104229 
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fluoxetine in combination, CNS acting drugs, levodopa and dopamine agonist, 
and olanzapine when used in combination with lithium or valproate 
 History or presence of clinically significant gastro-intestinal, hepatic or renal 
disease or other condition that would in the opinion of the investigator or medical 
monitor make the subject unsuitable for inclusion in this clinical study. 
 The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
 History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator would make 
the subject unsuitable for inclusion in this clinical study 
 Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within a 56 day time-period. 
 Pregnant females as determined by positive serum or urine hCG test (from the 
first urine of the day) at screening or prior to dosing. 
 Lactating females. 
 Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
 Subject has a history of dysphagia. 
 Subject has had intrapyloric botox injections within the past 6 months. 
5 
SUBJECT ENROLLMENT 
Most patients with gastroparesis are seen in gastroenterology or general medicine 
clinics.  Patients will be recruited from gastroenterology and general medicine clinics at 
Taubman Center and in the satellite clinics within the University of Michigan Health 
System.  Eligible subjects will be contacted and given material explaining the nature of 
the study, including information related to wireless motility testing and introduction to 
olanzapine.  They will be given time to read the materials.  If they choose to participate, 
they will sign the consent document in the presence of the PI and/or Designee.  
Subjects will be enrolled on a first come, first served basis.  This approach will ensure 
that subjects are representative of the population of patients with gastroparesis in 
Southeast Michigan. 
 
Emails to providers in the General Medicine and Gastroenterology clinics in the 
University of Michigan System, public advertisements, and telephone calls will be 
utilized to recruit subjects. 
 
Subjects who do not meet inclusion/exclusion criteria will not be enrolled in the study.  
All data collected from subjects who are screen failures will be saved for data analysis. 
 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
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6 
STUDY DESIGN AND PROCEDURES 
This is a pilot study of 10 consecutive subjects ages 18 – 80 with documented delayed 
gastric emptying within the past 2 years and history of nausea, vomiting, bloating, 
anorexia, early satiation, post-prandial fullness, and weight loss for at least 6 months 
without structural or organic cause will be enrolled.  This will be an open label trial 
without a placebo arm to determine efficacy and safety of the medication in this 
population.  This will be a single center study with subjects being enrolled at the 
University of Michigan.  Dr. Braden Kuo at Massachusetts General Hospital will act as a 
co-I and will assist with data analysis but will not enroll any patients.  Dr. Kuo will 
receive only de-identified information. 
 
The study will consist of a screening/baseline period of up to 30 days, an 8-week 
treatment period, and a 14-day post treatment safety follow-up visit and assessment of 
symptoms.   
 
Screening/Baseline: 
Subjects will participate in a screening/baseline visit within 30 days prior to study 
dosing.  Subjects will be instructed to fast prior to the screening visit at which time they 
will undergo blood sampling for complete blood count (CBC), complete metabolic panel 
(CMP), lipid profile, insulin, Hgb A1c, prolactin, TSH, and urine or blood pregnancy 
screen (if applicable).  A baseline ECG will also be performed.  Ghrelin levels will be 
measured.  Baseline vital signs, height, weight, and BMI will also be calculated.  They 
will also have their gastric emptying assessed by wireless motility capsule (WMC).  To 
be eligible for the study, the subjects’ gastric emptying time, as determined by WMC, 
needs to be greater than 5 hours.  Potential subjects will complete the gastroparesis 
cardinal symptom index daily diary (GCSI-DD) evaluation, appetite visual analog score 
(VAS), and Bristol Stool Form Scale (BSFS) for a minimum of 7 days to determine 
baseline level of symptoms [41].  Questionnaires will be completed in the evening after 
dinner.  Mean total GCSI-DD score must be ≥ 2 in order to qualify for the study.   
 
Week 1 – Week 8: 
Subjects will initially start on olanzapine 2.5 mg by mouth daily to be taken at bedtime.  
Subjects will return on days 7 and 14 to determine response to medication.  Medication 
dose can be increased to 5 mg on day 7 and 10 mg on day 14, respectively, based on 
incomplete symptom response, which is defined as a mean change in GCSI-DD score < 
0.5 from baseline.  Height and weight will be measured on Day 7.  The total dose of 
olanzapine will not exceed 10 mg daily during this study.   
 


A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis                              
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14 
Subjects will be monitored for adverse events and undergo blood sampling for glucose, 
insulin, and Hgb A1c on day 14.  Vital signs, height, weight, and BMI will also be 
evaluated.  Subjects will be instructed to bring their study medication with them on day 
14 for assessment of study drug accountability.   
 
Subjects will be contacted by phone at least once within 2 weeks following the day 14 
visit to assess for potential side effects.  Subjects may also come in for an extra/optional 
study visit between the Day 14 and Day 35 visits, if warranted by side effects. 
 
Subjects will return on day 35 to monitor for adverse events, vital signs, height, weight, 
BMI, and glucose check. 
 
During the study, subjects will rate their gastroparesis symptoms on a daily basis by 
completing the GCSI-DD and appetite VAS questionnaires.  Subjects will also record 
daily the number of stools and their consistency [42].  Subjects will be asked to 
complete all diaries after the evening meal.  The subjects will fast prior to returning to 
clinic on the morning of day 56 to undergo assessment of their gastric emptying time by 
WMC and complete an appetite VAS.  Blood sampling for LFTs, glucose, insulin, Hgb 
A1c, and ghrelin levels will be performed.  Vital signs, height, weight, and BMI will also 
be measured.  All remaining study medication will be returned to the clinical unit for final 
drug accountability.  Subjects will continue to rate their gastroparesis symptoms for 14 
days following the end of dosing. 
 
Adverse events, vital signs, and laboratory parameters will be assessed to monitor 
overall safety and tolerability of the medication.  Common potential adverse effects of 
the medication include orthostatic hypotension, weight gain, hyperglycemia, 
hyperlipidemia, increased prolactin level, akathisia, somnolence, and tremor.  Serious 
adverse effects include sudden cardiac death, diabetic coma, venous 
thromboembolism, cerebrovascular disease, seizure, and suicidal intent.  A subject will 
be withdrawn from the study if they experience any serious adverse events or if they 
develop hyperglycemia (fasting glucose level > 150 mg/dl or non-fasting glucose level > 
180 mg/dl), or weight gain (≥ 5 kg/wk).  The FDA definition for serious adverse events 
(SAE) will be used which is defined as an AE resulting in any of the following outcomes: 
Death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect related 
to the adverse event. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 


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require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  The PI will determine whether the SAE is related or possibly related to the 
drug.  The trial will stop if any SAE related to the drug is encountered. 
Subjects will be allowed to use ondansetron, promethazine, and/or prochlorperazine as 
rescue medications during the study.  Laxatives, including Miralax, magnesium, 
Dulcolax, stool softeners, fiber supplements, and/or linaclotide may also be used during 
the study to treat underlying constipation.  Subjects will not be allowed to use any 
prokinetic agents, such as Reglan, domperidone, or macrolide antibiotics (e.g. 
erythromycin) during the study.  Rescue and concomitant medications (prescriptions or 
OTC medications) ongoing at the Screening Visit and/or started from the Screening Visit 
onwards until the last study related activity will be documented in the Prior and 
Concomitant Medication and Rescue medication pages of the Case Report Form 
(CRF).  Subjects will be asked to monitor and record usage and frequency of rescue 
medications and laxatives used during the study. 
 
Post-Treatment Assessment: 
At the conclusion of 56 days of dosing, subjects will return for a follow-up visit 14 days 
(+ 2 days) after the last dose of study medication.  All subjects will have blood sampling 
for CBC, CMP, lipid profile, TSH, prolactin, insulin, Hgb A1c, and ghrelin.  Height, 
weight, and BMI will be calculated.  One final appetite VAS will be completed.  The 
duration of each patient’s participation in the study from screening to follow-up visit will 
be approximately 14 weeks.   
 
Subjects are free to discontinue participation in the study at any point.  If a subject 
decides to prematurely discontinue from the study, they will be contacted within two 
weeks for safety follow-up visit(s).  Reasons for withdrawal will be documented by the 
PI.  If the reason for removal of a subject from the study is an AE, the principal specific 
event will be recorded on the CRF.  The subject will be followed until the AE is resolved. 
 
Gastric Motility: 
Gastric motility will be tested by using the WMC wireless capsule system (The SmartPill 
Corporation, Buffalo, NY).  This offers a potentially more complete examination into 
possible etiologies for gastroparesis including delayed gastric emptying as well as 
gastric and small bowel contractility abnormalities.  We will follow the protocol for 
measuring gastric emptying by wireless motility capsule as described previously in the 
literature [43]. Gastric emptying time (GET) is defined as the duration of time from 
capsule ingestion to entry of the capsule into the duodenum.  Subjects will swallow the 
WMC capsule with 50 ml of water followed by ingestion of a standardized meal 
comprising of a nutrient bar, which has a total caloric value of 255 kcal (72% 


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carbohydrate, 24% protein, 2% fat, and 2% fiber) [44].  Because of the low risk of 
capsule retention especially once the capsule enters the colon, plain abdominal 
radiograph (KUB) will be performed only if there is no documentation of the capsule 
passing the ileocecal valve and the patient has symptoms of capsule retention.  
Pressure data recorded by the WMC capsule will be analyzed for 1 hour before and 
after the WMC empties the stomach (GET).  The analyzed parameters are: number of 
contractions (Ct), and motility index defined as: MI = Ln (sum of pressure amplitudes * 
number of contractions +1) [45]. 
 
Stopping Criteria: 
The purpose of this study is to ensure that severe complications to olanzapine in 
gastroparesis are rare and to see whether olanzapine might improve symptoms in 
gastroparesis.  We will treat ten patients with gastroparesis.  The trial will stop if any 
SAE related to the drug is encountered. 
 
Study Timeline: 
 
Visit 1 (Day -30)
Eligibility
Baseline symptom 
questionnaires
Labs including CBC, 
CMP, insulin, lipid 
profile, Hgb A1c, 
prolactin, TSH, ghrelin
Wireless Motility 
Testing
Visit 2 (Day 0)
Subjects start on 
olanzapine 2.5 mg daily
Visit 3 (Day 7)
Medication efficacy and 
tolerability assessed
Olanzapine dose may be 
increased to 5 mg daily 
Visit 4 (Day 14)
Medication efficacy and 
tolerability assessed
Study drug 
accountability
Labs for glucose, insulin, 
and HgbA1c
Olanzapine dose may be 
increase to 5 or 10 mg 
daily


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Figure 1 Gastroparesis Subject Timeline 
7 
Data Collection and Management Procedures 
Data Handling and Entry:  All data including questionnaire results and physiologic 
testing will be recorded and reviewed by the study team.  Data will then be entered into 
an electronic case report form (eCRF) that complies with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11).  All passwords will be strictly confidential to protect 
subject’s protected health information (PHI).  Only the Primary Investigator (PI) and 
Study Coordinator will have access to the data and subject identifiers.  Only the PI and 
Study Coordinator will be allowed to enter data onto the password-protected web-based 
server. 
Computer Systems:  Data entry will be entered into REDCAP which is validated and 
conforms to regulatory requirements.  Only the Primary Investigator (PI) and Study 
Coordinator will have access to the data and subject identifiers.  Only the PI and Study 
Coordinator will be allowed to enter data onto the password-protected web-based 
server. 
Data Validation:  Validation checks will be programmed within the eCRF system as 
well as supplemental validation performed by review of the downloaded data, will be 
applied to the data in order to ensure accurate, consistent, and reliable data. 
Direct Access to Source Data:  A developed review procedures that complies with 
Good Clinical Practice (GCP) guidelines. 
Visit 5 (Day 35)
•Medication efficacy and 
tolerability assessed
•Glucose check
Visit 6 (Day 56)
•Medication efficacy and 
tolerability
•Labs including LFTs, glucose, 
insulin, Hgb A1c, and ghrelin
•Wireless Motility Testing 
performed
Visit 7 (Day 70)
Safety check
Labs including CBC, CMP, 
TSH, prolactin, insulin, 
lipid profile, Hgb A1c, 
and ghrelin


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Source Document/Case Report Form Completion:  Source documents and the 
eCRFs will be completed for each study patient.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the patient’s 
source document/eCRF.  The source document/eCRF should indicate the patient’s 
participation in the study and should document the dates and details of the study 
procedures, AEs, and patient status. 
Record Retention:  The Investigator will maintain all study records according to 
applicable regulatory requirement(s). 
8 
DATA ANALYSIS 
Procedure for Accounting for Missing, Unused, and Spurious Data:  The primary 
outcome measure in our study is whether olanzapine is efficacious and safe for the 
treatment of idiopathic gastroparesis.  We will use multiple imputation with 10 imputed 
datasets to replace missing values on outcome and predictor variables [46].  If 10 
imputed datasets are not sufficient to ensure stability of estimates, we will use 20 
imputed datasets.  This allows for maximal use of available data while maximizing 
statistical power.   
9 
QUALITY CONTROL AND QUALITY ASSURANCE 
The PI and Study Coordinator will be responsible for Quality Control and Quality 
Assurance and will be performed in accordance with Standard Operating Procedures at 
the University of Michigan. 
10 
STATISTICAL CONSIDERATIONS 
Changes in measures from baseline will first be examined using descriptive statistics 
and graphical analysis.  Significance of changes by the post treatment assessment will 
be determined using paired t tests or Wilcoxon rank sum tests, depending on the 
normality of the measures.  Hierarchical regression will be used to analyze patterns of 
change across all measurement times, with time as a nested factor within subject.  
Adverse events will be summarized by proportions and 95% confidence intervals. 
 
Sample size was based on variance estimates from prior studies using GCSI-DD and 
the appetite VAS in patients with gastroparesis [41, 47], and was computed using a 2-


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sided type I error rate of 0.05.  Conservatively using the largest variance reported for 
any of the GSCI subscales, and conservatively using a within-subject correlation of 0.6, 
a sample size of 10 patients will provide 88% power to detect a 1-point decrease in 
GCSI-DD, which we judged to be a clinically meaningful change in the subscales and 
total scale.  For a more likely within-subject correlation of 0.8, power would be >99%.  
For the appetite VAS, we judged a 10 mm change to be clinically significant.  Again 
conservatively using the largest of the reported variances, 10 patients will give 80% 
power to detect a 10mm change if the within-subject correlation is 0.6 and 97% power if 
the within-subject correlation is 0.8.  A sample size of 10 subjects will also provide 
sufficient precision in parameter estimates from this study for use in power calculations 
for future studies of olanzapine in patients with gastroparesis. 
11 
REGULATORY REQUIREMENTS 
11.1 Informed Consent 1 
Informed consent will be signed in person by the subject after the protocol is explained 
by either the PI, co-I or study coordinator.  If a subject is a patient of the PI or Co-I, the 
study coordinator will be responsible for obtaining informed consent to avoid potential 
issues of coercion.  Before signing, subjects will be given ample opportunity to ask 
questions about the protocol.  Consent forms will be signed in the Taubman Center or in 
the GI Physiology Laboratory in the Medical Procedures Unit.  Please see Informed 
Consent for full details. 
 
11.2 Subject Confidentiality  
All study team members will make every effort to protect each subject’s confidentiality.  
Participants will have privacy in a closed exam room to be able to provide information to 
the PI and/or study coordinator regarding medical history, current condition, and any 
other relevant information pertaining to the study.  Research records, data, and/or 
specimens will be kept in a locked office and/or locked cabinet with access restricted 
only to study team members.  Study members will also secure electronic data on 
computers by using password protection, installing and regularly updating security 
software, as well as encryption of data.  Only the PI and the Study Coordinator will have 
                                            
 
1 The IRB may waive some or all elements of  informed consent – consult the IRB for consenting 
requirements. 
 


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access to the data and subject identifiers.  Only the PI and the Study Coordinator will be 
allowed to enter data onto the password-protected web-based server. 
  
11.3 Unanticipated Problems2 
All adverse clinical experiences, whether observed by the investigator or reported by the 
subject, must be recorded, with details about the duration and intensity of each episode, 
any actions taken, and the subject’s outcome. The Principal Investigator must evaluate 
each adverse experience for its relationship to the study and for its seriousness. 
 
The Principal Investigator must appraise all abnormal laboratory results for their clinical 
significance. If any abnormal laboratory result is considered clinically significant, the 
Principal Investigator must provide details about the action taken and about the 
subject’s outcome.  The PI and study team will meet on at least a monthly basis to 
assess study recruitment, data integrity and quality, AEs, withdrawals, and compliance 
with the protocol plan.  A DSMB will not be employed as this is a single-center open-
label trial.   
 
All AEs will be assessed by the Investigator(s) and will be recorded in the CRF, 
including the date of onset and resolution, severity, relationship to study medication, 
outcome, and action taken with study medication.  All AEs will be reported to the IRB 
that meet reporting criteria.  Toxicity will be graded according to the Common Toxicity 
Criteria as follows: 
0 = No adverse event or within normal limits 
1 = Mild AE, not requiring treatment 
                                            
 
2 The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to subjects or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-
related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; 
 
related or possibly related to participation in the research (in the guidance document, possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
 
suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. 
 
An incident, experience, or outcome that meets the three criteria above generally will warrant consideration of substantive 
changes in order to protect the safety, welfare, or rights of subjects or others.   


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2 = Moderate AE, resolved with treatment 
3 = Severe AE, resulted in inability to carry on normal activities and required 
professional medical attention 
4 = Life threatening or disabling AE 
5 = Fatal AE 
 
Serious adverse event (SAE) is defined by the FDA as an AE resulting in any of the 
following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Once an AE or SAE is known, research team members at the study site will 
ensure that participants receive appropriate care and all actions taken by the PI and/or 
co-investigator after observing the AE or SAE will be documented. 
 
The Principal Investigator is responsible for complying with local and institutional 
requirements related to the reporting and documenting of SAEs.  These reports must 
include submission of all qualifying SAEs to the Institutional Review Board (IRB) and/or 
Independent Ethics Committee (or others).  Any serious and unexpected AEs will be 
reported to the IRB and the FDA within 7 days of the occurrence or immediately if the 
event is fatal or life threatening.  The guidelines established in the Committees on 
Human Research “Adverse Event and Unanticipated Problems Reporting Policy” will be 
followed.   


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12 
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