Clinical trial NCT04456517
Conditions: Crohn's Disease Inflammatory Bowel Disease
Keywords: Diarrhea
Sponsor: Vanderbilt University Medical Center
Start date: 2022-10-18; Completion date: 2024-04-11
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Crohn's disease is an inflammatory disorder that can affect any part of the gastrointestinal (GI) tract. Some patients still experience persistent diarrhea or other symptoms such as abdominal pain even when their Crohn's disease is in remission. Diarrhea and/or abdominal pain that is not responsive to standard therapies can significantly affect a patient's quality of life and ability to work. The purpose of this study is to test the safety and effectiveness of the drug ranolazine in reducing Crohn's disease-associated diarrhea and other symptoms. Ranolazine is approved by the US Food \& Drug Administration (FDA) for chronic angina (a heart condition). This study is investigating if ranolazine could be used in the setting of Crohn's disease.

Detailed description:

Arms: arm 1: \- Participants first receive a Ranolazine 500 mg tablet twice daily for 12 weeks, they then receive a Placebo tablet (matching Ranolazine 500 mg tablets) twice daily for 12 weeks. This treatment will be given to participants with either active CD or patients with CD that is in remission but who experience continued symptoms arm 2: \- Participants first receive a Placebo tablet (matching Ranolazine 500 mg tablets) twice daily for 12 weeks, they then receive a Ranolazine 500mg tablet twice daily for 12 weeks. This treatment will be given to participants with either active CD or patients with CD that is in remission but who experience continued symptoms
Interventions: intervention 1: Ranolazine intervention 2: Placebo
Intervention descriptions: intervention 1: 500 mg tablet intervention 2: Ranolazine-matched placebo tablet

Protocol documents:
Prot_SAP_001.pdf: 
Reduce Crohn's-Associated Diarrhea With Sodium Channel Therapy 
NCT04456517 
09/01/2022 
 
 


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A randomized, double blind, placebo-controlled, crossover study of ranolazine for the 
treatment of Crohn’s Disease-associated diarrhea 
 
Protocol Version: 9 
 
Principal Investigator Signature:  
 
 
 
Date: 2022.09.01 
 
 
 
Dawn Beaulieu, MD 
Associate Professor of Medicine 
Division of Gastroenterology, Hepatology and Nutrition 
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 


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Contents 
1 
PROTOCOL SYNOPSIS ..................................................................................................... 6 
2 
SCHEMA ............................................................................................................................ 8 
3 
BACKGROUND and RATIONALE ...................................................................................... 8 
3.1 
Crohn’s Disease .......................................................................................................... 8 
3.2 
PheWAS in Drug Repurposing and Discovery ............................................................. 9 
3.3 
Sodium Channels and Gastrointestinal Function .......................................................... 9 
3.4 
Investigational Agent – Ranolazine .............................................................................10 
3.5 
Rationale for Study Design .........................................................................................10 
4 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................12 
5 
PARTICIPANT SELECTION ..............................................................................................13 
5.1 
Recruitment and Screening .........................................................................................13 
5.2 
Inclusion Criteria .........................................................................................................14 
5.3 
Exclusion Criteria ........................................................................................................14 
6 
TABLE OF EVENTS ..........................................................................................................16 
7 
PROCEDURES..................................................................................................................17 
7.1 
Overview .....................................................................................................................17 
7.2 
Randomization Procedures .........................................................................................17 
7.3 
Agent Administration and Duration of Treatment .........................................................17 
7.4 
Safety Assessments ...................................................................................................18 
7.4.1 
Urine Sample Collection ......................................................................................18 
7.5 
Efficacy Assessments .................................................................................................18 
7.5.1 
Crohn’s Disease Activity Index (CDAI) .................................................................18 
7.5.2 
Electronic data collection .....................................................................................18 
7.5.3 
Short Inflammatory Bowel Disease Questionnaire (SIBDQ) .................................19 
7.5.4 
Patient Health Questionnaire (PHQ-8) .................................................................19 
7.5.5 
Harvey Bradshaw Index (HBI) ..............................................................................19 
8 
DESCRIPTION OF STUDY TREATMENT .........................................................................19 
8.1 
Description of Study Drug ...........................................................................................19 
8.2 
Study Drug Accountability and Disposal ......................................................................19 
8.3 
Study Drug Compliance ..............................................................................................20 
9 
CONCOMITANT MEDICATIONS AND PROCEDURES ....................................................20 
9.1 
Permitted Concomitant Medications and Procedures ..................................................20 
9.2 
Prohibited Concomitant Medications and Procedures .................................................20 
10 
STATISTICAL CONSIDERATIONS ................................................................................20 


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10.1 Overview .....................................................................................................................20 
10.2 Study Population Definitions .......................................................................................20 
10.3 Statistical Methods ......................................................................................................21 
11 
ADVERSE EVENTS .......................................................................................................22 
11.1 Definitions ...................................................................................................................22 
11.1.1 
Adverse Event .....................................................................................................22 
11.1.2 
Serious Adverse Event ........................................................................................22 
11.1.3 
Adverse Drug Reaction ........................................................................................24 
11.1.4 
Unexpected Adverse Drug Reaction ....................................................................24 
11.2 Monitoring, Recording, and Reporting of Adverse Events ...........................................24 
11.3 Pregnancy ..................................................................................................................25 
12 
DISCONTINUATIONS ....................................................................................................25 
12.1 Criteria for Removal from Study ..................................................................................25 
12.2 Discontinuation of Treatment ......................................................................................25 
12.3 Replacement of Patients Who Discontinue Early ........................................................26 
12.4 Withdrawal from Study ................................................................................................26 
13 
REGULATORY CONSIDERATIONS ..............................................................................26 
13.1 Investigational New Drug (IND) ...................................................................................27 
13.2 Good Clinical Practice .................................................................................................28 
13.3 Privacy/Confidentiality .................................................................................................28 
13.4 Protocol Review and Amendments .............................................................................28 
13.5 Compliance with Trial Registration and Results Posting Requirements .......................28 
14 
DATA AND SAFETY MONITORING ..............................................................................28 
14.1 Overall Framework ......................................................................................................28 
14.2 Data Management and Reporting ...............................................................................29 
14.3 Source Verification ......................................................................................................29 
14.4 Meetings .....................................................................................................................30 
14.5 Frequency of Monitoring .............................................................................................30 
14.6 Individual or Group Responsible for Monitoring ...........................................................30 
14.7 Process for AE, UP and SAE Reporting ......................................................................30 
15 
REFERENCES ...............................................................................................................31 
16 
APPENDIX A: MRAV EMAIL ..........................................................................................35 
17 
APPENDIX B: PROVIDER SPONSORED EMAIL ..........................................................36 
18 
APPENDIX C: PRE-SCREENING SURVEY ...................................................................37 
19 
APPENDIX D: RECRUITMENT FLYER..........................................................................39 


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20 
APPENDIX E: STUDY WEBSITE LANDING PAGE ........................................................40 
21 
APPENDIX F: INSTRUCTIONS FOR BLOOD PRESSURE MONITOR ..........................41 
22 
APPENDIX G: CROHN’S DISEASE ACTIVITY INDEX ..................................................43 
23 
APPENDIX H: MyCap QUESTIONNAIRE ......................................................................44 
24 
APPENDIX I: SHORT INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE ............46 
25 
APPENDIX J: PATIENT HEATLH QUESTIONNAIRE-8 .................................................47 
26 
APPENDIX K: HARVEY BRADSHAW INDEX ................................................................48 
 
 
 
 


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1 
PROTOCOL SYNOPSIS 
Sponsor 
Vanderbilt University Medical Center 
Protocol Title 
A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Phase of 
Development 
Phase 2 Pilot 
Study drug 
and 
Mechanism 
Ranolazine, sodium channel inhibitor 
Treatment 
Schedule 
Dose/Route 
Ranolazine and placebo will be dispensed as 500 mg oral tablets. The full 
dose is 500 mg twice per day for a total of 12 weeks.  
Objectives 
Primary: Demonstrate the efficacy of ranolazine compared to placebo in 
reducing CD-associated diarrhea  
 
Secondary: Demonstrate the efficacy of ranolazine compared to placebo in 
improving quality of life 
 
Exploratory: Explore the longitudinal effects of ranolazine on loose stool 
frequency 
 
Safety: Demonstrate the safety and tolerability of ranolazine when given in 
combination with other standard CD treatments 
Endpoints 
Primary endpoint: Mean change in daily number of loose stools  
Secondary endpoints: Mean change in CDAI score; Mean change in SIBDQ 
score; Mean change in PHQ-8 score; Mean change in HBI score.  
Exploratory endpoints: Time to 50% reduction in daily number of loose 
stools. 
Safety endpoints: Rate of treatment emergent adverse effects. 
Trial Design 
This will be a single-site, placebo-controlled, randomized, crossover study 
to evaluate the efficacy, safety, and tolerability of ranolazine for the 
treatment of Crohn’s Disease-associated diarrhea.  
Number of 
Patients 
20 (10 in remission and 10 with active inflammation) 
Duration of 
Therapy 
12 weeks ranolazine and 12 weeks placebo 
Duration of 
Follow-up 
12 weeks 
Patient 
Selection 
The study will include subgroup analyses in two distinct patient groups:  
Arm 1) Crohn’s Disease in remission, defined as endoscopic or 
radiographic findings consistent with controlled Crohn’s in the past 2 years 
BUT still experiencing symptoms (e.g., diarrhea, abdominal pain) 


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Arm 2) Active Crohn’s Disease, defined as endoscopic or radiographic 
findings consistent with active Crohn’s in the past 2 years AND have been 
on a stable dose of standard medication for at least one month prior to 
enrollment.  
Inclusion Criteria: 
1. Meet diagnostic criteria for Crohn’s Disease with active diarrhea 
2. Have greater than three loose stools per day 
 
Exclusion Criteria: 
1. Male and female subjects <18 years of age 
2. Significant change in medication including prednisone, 
antidepressant medications, or stimulants within the last 4 weeks 
a.  Allowances include: Rectal hydrocortisone, rectal 
mesalamine, addition of prednisone (up to 20mg) for flares, 
etc.  
3. Regular (daily) use of opioids or other drugs of abuse including 
heavy alcohol or marijuana use 
4. Severe psychiatric disease including schizophrenia, psychosis, 
suicidal depression 
5. Previous use of ranolazine within 2 months prior to enrollment 
6. Prior use of ranolazine which was discontinued for safety or 
tolerability  
7. Metabolic derangement defined as liver function tests >3x upper 
limit of normal or severe renal disease defined as calculated 
creatinine clearance <30 mL/min 
8. Have liver cirrhosis 
9. Concurrent use of strong CYP3A inhibitors or inducers: 
ketoconazole, itraconazole, nefazodone, nelfinavir, ritonavir, 
indinavir, and saquinavir, rifampin, rifapentine, phenobarbital, 
phenytoin, clarithromycin, St Johns Wart, digoxin 
10. A family history of (or congenital) long QT syndrome or known 
acquired QT interval prolongation 
11. Inability or refusal to give informed consent for any reason including 
a diagnosis of dementia or cognitive impairment 
12. Patients who are pregnant or breastfeeding 
13. Patients who are enrolled in other investigational drug studies or 
who have taken investigational drugs within 30 days before 
enrollment 
14. Other factors which in the opinion of the investigator could 
potentially impact the study outcomes (e.g., underlying disease, 
medications, history) or prevent the participant from completing the 
protocol (poor compliance or unpredictable schedule) 


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Study 
Assessments 
1. Daily number of loose stools 
2. Crohn’s Disease Activity Index (CDAI) 
3. Short Inflammatory Bowel Disease Questionnaire (SBDQ) 
4. Harvey Bradshaw Index (HBI) 
5. Patient Health Questionnaire (PHQ-8) 
 
2 
SCHEMA 
 
Figure 1. Clinical trial schematic 
 
3 
BACKGROUND AND RATIONALE 
 
3.1 
Crohn’s Disease 
Crohn’s Disease (CD) is an idiopathic inflammatory disorder of unknown etiology with genetic, 
immunologic, and environmental influences. CD can affect any part of the gastrointestinal (GI) 
tract affecting some areas of the GI tract and leaving others untouched. The pathology of CD is 
characterized by transmural infiltration of lymphocytes and macrophages, granulomas, fissuring 
ulceration, and submucosal fibrosis. The transmural inflammatory process of CD predisposes 
patients to the formation of fistulas and it has been estimated that approximately 35% of patients 
will have at least 1 fistula during the course of their disease.1 CD patients experience a lifelong 
cycle of a relapsing-and-remitting disease course requiring frequent corticosteroids, and/or 
escalation in immunosuppressive treatment; approximately half of patients will require surgery 


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within 10 years of diagnosis.2 Even patients who achieve remission can experience persistent, 
refractory diarrhea or other symptoms such as abdominal pain, significantly affecting their quality 
of life and ability to work. Over 780,000 Americans are affected by CD and the worldwide 
incidence has been steadily increasing.3,4  
The current standard of care for patients with CD is individualized and based on disease location, 
disease severity, disease-associated complications, and future disease prognosis. Therapeutic 
approaches are a sequential continuum to treat “acute disease” or “induce clinical remission,” and 
then to “maintain response/remission,” the overall treatment goal being to control inflammation 
and symptoms arising from active inflammation. Medical therapy used to treat CD includes the 
categories of 5-aminosalicylates (5-ASA), antibiotics, corticosteroids, immunomodulators, and 
biologics (the anti-TNF agents infliximab, adalimumab, certolizumab pegol; agents targeting 
leukocyte trafficking, including vedolizumab, natalizumab; and the anti-p40 (anti-IL-12/23) 
antibody, ustekinumab). Diarrhea and/or abdominal pain that is not responsive to standard 
therapies may be treated with lomotil or other opioids which have significant side effects and risk. 
Despite significant medical advancements in the treatment of CD, there remains a considerable 
unmet medical need for safe, effective, oral treatments for CD. 
 
3.2 
PheWAS in Drug Repurposing and Discovery 
PheWAS is a method that explores the association between single nucleotide polymorphisms 
(SNPs) and diseases across the human phenome. This approach has been used to identify 
phenotypes associated with SNPs in various genes, including those producing proteins selectively 
targeted by FDA approved drugs. PheWAS leverages Vanderbilt’s informatics and data mining 
expertise combined with robust de-identified health records with associated genomic data in 
BioVU (>250,000 human DNA samples as of May 2019). A PheWAS was performed in a disease-
agnostic cohort of 28,000 BioVU patients in order to identify potential novel genotype-phenotype 
associations related to the SNPs in SCN5A. The effect of carrying at least one minor allele in this 
SNP on the presence of having various medical diagnoses (phenotypes) as defined by PheWAS 
codes derived from ICD-9 billing codes in the electronic health record (EHR) has been evaluated. 
Using this precision drug repurposing method that leverages natural human genetic variation as 
a proxy for – and method of more accurately predicting – the physiologic effects of therapies in 
humans,5 ranolazine was identified as a possible new therapy for CD. A variant (P2006A) in the 
SCN5A gene, which encodes the sodium channel protein type 5 subunit alpha (Nav1.5), 
significantly increases persistent sodium currents, functioning as a natural gain of function variant 
or ‘agonist.’ Sodium channels play a major role in signaling the start of each heartbeat, 
coordinating the contractions of the heart chambers, and maintaining a normal heart rhythm.6 A 
phenome-wide association study (PheWAS) uncovered a significant association between the 
P2006A variant and increased risk for heart palpitations (OR=4.2, P=0.0006), which is expected 
given ranolazine’s known effects. Using this association as an ‘anchor’ in the dataset, phenotypes 
with a risk-causing OR >1 are possible new indications for ranolazine, which is a Nav1.5 
antagonist. PheWAS data show a potential new indication for CD (OR=4.9, P=0.005). 
 
3.3 
Sodium Channels and Gastrointestinal Function 
Human gastrointestinal Nav1.5 is structurally homologous to its cardiac equivalent and bears 
strong electrophysiological, mechanosensitive, and pharmacological similarities.7 Ranolazine 


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blocks both peak amplitude and mechanosensitivity of Na(+) current in human colon smooth 
muscle cells (SMCs) and decreases contractility of human colon muscle strips. Some have 
concluded that this provides a likely mechanistic explanation for ranolazine-induced constipation 
observed in some angina patients.8 Patients with SCN5A channelopathies and known cardiac 
arrhythmias also have an increased prevalence of functional GI disease.7  
 
3.4 
Investigational Agent – Ranolazine 
Ranolazine, sold under the trade name Ranexa® by Gilead Sciences, received FDA approval in 
2006 for chronic angina. Ranolazine is currently under investigation for several other CVD- and 
diabetes-related indications.9 The lower end of the FDA-approved dose for chronic angina, 500 
mg twice daily, will be used in this trial (1000 mg twice daily is also FDA approved for chronic 
angina). Ranolazine will be dispensed as 500 mg oral tablets, purchased and encapsulated by 
IDS, who will also compound matching placebo. When used properly and not concurrently with 
contraindicated drugs outlined in the exclusion criteria, ranolazine has been shown to be safe and 
well-tolerated. Ranolazine’s safety profile has been established by extensive clinical experience. 
The most common side effects include dizziness, nausea, constipation, and headache; less than 
2% of patients experience these side effects.10,11 
 
3.5 
Rationale for Study Design 
Ranolazine may improve Crohn’s Disease symptoms by acting on one of more interrelated 
pathways (see Figure 2):   
Ranolazine may reduce inflammation: Transmural inflammation of the gastrointestinal tract is 
considered a hallmark of CD and is implicated in endothelial dysfunction and gut dysmotility, both 
described below. Given the ability of inflammation to induce channelopathies in the GI smooth 
muscle, some have proposed that clinical symptoms of gut disorders such as inflammatory bowel 
syndrome may be regulated at the level of the ion channel.12 Clinical and experimental data also 
suggest that changes in sodium channels may play a role in inflammatory pain and therefore, 
sodium channel blockers like ranolazine may have some therapeutic potential.13 There is some 
evidence suggesting that ranolazine may have an effect on inflammatory biomarkers.14,15 Specific 
examples of anti-inflammatory effects observed with use of ranolazine include: attenuation of pro-
inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) in a rat model of congestive heart failure;16 
significant decrease in the pro-inflammatory cytokines IL-1β and TNFα, and a significant increase 
in anti-inflammatory PPAR-ɣ expression in cultured rat astrocytes;15,17 and stimulation of 
myogenesis and with concurrent reduction in measures of a pro-oxidant inflammation/oxidative 
condition in murine myoblastic cells.18 Further, among individuals with stable coronary artery 
disease treated with ranolazine, investigators observed anti-inflammatory effects including 
reduced C reactive protein and asymmetric dimethylarginine.14 More broadly, sodium channel 
blockade itself has been shown to have effects concordant with decreased inflammation, with 
phenytoin reducing by approximately 50% the release of several pro-inflammatory cytokines (IL-


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1α, IL-1β, TNF-α) in lipopolysaccharide-stimulated microglia, with smaller but similar decreases 
observed with another sodium channel inhibitor, TTX.19 
Ranolazine may reduce endothelial dysfunction: Endothelial dysfunction occurs when there is 
impairment in homeostatic functions of endothelium, ranging from control of vascular tone and 
leukocyte trafficking to surveillance of platelet adhesion and thrombus formation.20 A growing 
body of evidence suggests the involvement of intestinal microvascular endothelial cells, a non-
immune cell lineage, in the pathway to the development and maintenance of IBD. Changes in 
endothelial structure and function, mediated by a complex network of chemokines, cytokines and 
inflammatory growth factors, are a distinctive feature of active disease and their magnitude is 
related to disease severity.20,21 In addition, it has been shown that human intestinal microvessels 
taken from chronically inflamed IBD mucosal tracts exhibit endothelial dysfunction with significant 
impairment 
of 
endothelium-dependent 
vasodilation.20,22 Endothelial dysfunction has 
been evaluated in IBD patients using brachial 
artery flow-mediated vasodilatation (FMD), a 
well-established 
measure 
of 
endothelial 
function; significantly lower FMD in IBD patients 
compared to controls has been found, 
suggesting endothelial dysfunction as one 
etiological factor of IBD.20,23 A strong and 
independent association between endothelial 
dysfunction 
and 
the 
risk 
for 
future 
cardiovascular disease (CVD) has been 
established in the literature;20,24 IBD is also a 
risk factor for CVD, suggesting endothelial 
dysfunction is a shared mechanism in both IBD 
and CVD.25 A crossover study of coronary 
artery disease patients found that ranolazine 
improved 
endothelial-dependent 
vasodilatation, 
a 
marker 
of 
endothelial 
dysfunction.14 Given this evidence, ranolazine 
may improve endothelial function in CD 
patients, which could lead to reduction of CD 
symptoms.     
Ranolazine may restore normal, coordinated gut motility: Gastrointestinal motility results from 
coordinated interaction of multiple cooperating mechanisms and is modulated by the enteric 
nervous system. Both interstitial cells of Cajal (ICC) and intestinal smooth muscle cells (SMCs) 
serve a fundamental role in normal gastrointestinal motility and express the sodium channel alpha 
subunit NaV1.5, which is targeted by ranolazine. ICC are ubiquitously present in the human 
gastrointestinal tract and generate pacemaker activity through slow electrical waves. They are 
electrically coupled to SMCs via gap junctions ensuring coordinated GI motility.26 GI dysmotility is 
a feature of CD and is interrelated with the other features of the disease. For example, multiple 
studies have shown inflammatory effects to be correlated with reduced intestinal motility; studies 
using MR enterography have found a significant difference in terminal ileum motility in patients 
with small bowel CD compared with healthy subjects,27 and when comparing inflamed and non-
inflamed small bowel segments of CD patients.28 Hypermotility and gastrointestinal lesions also 
 
Figure 2. Interrelated pathways contributing to
Crohn’s Disease symptoms that may be affected
by ranolazine. 


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have a close relationship. The collective results of several rat studies indicate that intestinal 
hypermotility with its high-amplitude contractions likely disrupts the mucus layer of the intestines, 
interrupting the host defense barrier, exposing the luminal contents to the epithelium and allowing 
bacterial invasion of the mucosa, which then triggers an inflammatory response.29–38 Instances of 
severe gastrointestinal dysmotility have been reported in CD patients without clinically active 
disease (no active inflammation or mechanical obstruction) as well.39 Given this evidence, 
ranolazine may reset and maintain the calibration and synchronicity of the gut’s motility 
mechanism, resulting in a reduction of Crohn’s-associated diarrhea or other symptoms that impact 
quality of life.  
 
4 
STUDY OBJECTIVES AND ENDPOINTS 
 
The safety, tolerability, and efficacy of ranolazine given in combination with standard CD 
treatments will be assessed as outlined in the endpoints below.  
Primary endpoint:  
• 
Mean change in daily number of loose stools  
Secondary endpoints:  
• 
Mean change in CDAI score 
• 
Mean change in SIBDQ score 
• 
Mean change in PHQ-8 score 
• 
Mean change in HBI score 
Exploratory endpoints:  
• 
Time to 50% reduction in daily number of loose stools  
Safety endpoints:  
• 
Rate of treatment 
emergent adverse 
effects  
The crossover design was 
selected to yield a more 
efficient comparison of a 
treatment that aims to 
alleviate symptoms. Given 
the short, seven-hour half-
life 
of 
ranolazine, 
the 
scientific value of adding 
an extra study visit to account for a 1.5-3 day washout was outweighed by the extra burden placed 
on patients. All patients will be able to continue their standard medication throughout the duration 
of the study.   
 
 
Objective 
Outcome(s) 
Primary 
Demonstrate the efficacy of ranolazine 
compared to placebo in reducing CD-
associated diarrhea and other symptoms 
CDAI, Daily 
# loose 
stools, HBI 
Secondary 
Demonstrate the efficacy of ranolazine 
compared to placebo in improving quality of 
life 
SIBDQ, 
PHQ-8 
Exploratory Explore the longitudinal effects of 
ranolazine on loose stool frequency 
Daily # loose 
stools 
Safety 
Demonstrate the safety and tolerability of 
ranolazine when given in combination with 
other standard CD treatments 
Adverse 
events 
Table 1. Clinical trial objectives 


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5 
PARTICIPANT SELECTION 
 
5.1 
Recruitment and Screening 
The primary recruitment strategy is to recruit all 20 patients directly from the ~5000 patients 
currently seen at the Vanderbilt IBD Center. Throughout the enrollment period, a dedicated clinical 
research coordinator will review EHRs of patients who have upcoming routine clinic visits to 
identify those who meet eligibility criteria. These patients will be flagged for recruitment and be 
presented the study during a routine visit. Patients who express interest will then meet with the 
clinical research coordinator immediately after their routine visit to receive more information about 
the study and for further screening, which entails an in-depth review of current medications and 
comorbidities. Those who meet eligibility criteria will have the opportunity to consent and enroll in 
the study. Enrolled participants will complete clinical assessments, provide urine for pregnancy 
testing (limited to women of childbearing potential), and be randomized to their treatment 
sequence. Their next study visit will be scheduled, and they will be sent home with study 
medication.  
Other recruitment methods may include: 
MyResearchAtVanderbilt (MRAV) was a participant repository recruitment tool available to 
Vanderbilt researchers that reached over 18,000 My Health at Vanderbilt users that previously 
confirmed they would like to be contacted directly for research. This repository provided 
investigators a forum for advertising to volunteers for a specific study. Email notifications are 
limited to IRB approved language, describe study specifics and provide contact information 
(Appendix A). To utilize this initiative, investigators complete a MRAV Access Request that is 
reviewed to ensure the recruitment tool and requested number of contacts are appropriate. 
In our prior study (IRB #191478), the above resource was leveraged to identify patients with 
Crohn’s disease.  A patient survey was sent to 342 patients who met the definition of Crohn’s 
disease according to a validated Crohn’s phenotype algorithm based on a combination of ICD 
billing codes and medications in their medical record.  A total of 69 patients responded to the 
survey, and 64 of those patients agreed to be contacted for a future study.  We have medical 
record numbers for those respondents.  The study coordinator will pre-screen these patients via 
review of their medical records to determine if any meet the study criteria.  Individuals who are 
eligible for the study will be contacted via phone for further screening. 
Provider Sponsored Emails from the Principal Investigator may be used to recruit additional 
VUMC patients (Appendix B). Emails will be sent to VUMC patients not in MRAV, identified using 
Vanderbilt’s Research Derivative (a database of clinical and related data derived from the Medical 
Center’s clinical systems and restructured for research40), who have 2 or more Crohn’s Disease 
diagnostic codes, and an e-mail address within their EHR though the Data Coordinating Core 
(DCC). 
Both the MRAV/MHAV email and the provider sponsored email will include links to a REDCap 
screening survey (Appendix C).  
Flyers will also be used as an additional recruitment tool.  They will be placed in clinic locations 
around Tennessee including but not limited to Davidson and Williamson counties (Appendix D). 


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Public-Facing Study Website landing page is another recruitment tool that will be used. It provides 
an overview of the study and contact information for the study coordinator, and it will be available 
at: https://drugrepurposing.org/react/. This landing page (Appendix E) will be on the Vanderbilt 
Institute for Clinical and Translational Research (VICTR) drug repurposing website 
(https://drugrepurposing.org) and maintained by Meghan Vance, Associate Program Manager, 
and Jessica Abner, Project Manager. The purpose of this website is to provide visitors with an 
overview of the clinical trial, with the overall goal of raising awareness about the study. 
 
5.2 
Inclusion Criteria 
The study will include two distinct patient groups:  
Arm 1) Crohn’s Disease in remission, defined as endoscopic or radiographic findings consistent 
with controlled Crohn’s in the past 2 years BUT still experiencing symptoms (e.g., diarrhea, 
abdominal pain) 
Arm 2) Active Crohn’s Disease, defined as endoscopic or radiographic findings consistent with 
active Crohn’s in the past 2 years.  
Inclusion Criteria: 
1. Meet diagnostic criteria for Crohn’s Disease with active diarrhea (≥3 loose stools per day 
on average) 
 
5.3 
Exclusion Criteria 
 
Exclusion Criteria: 
1. Male and female subjects <18 years of age 
2. Significant change in medication including prednisone, antidepressant medications, or 
stimulants within the last 4 weeks 
a.  Allowances include: Rectal hydrocortisone, rectal mesalamine, addition of 
prednisone (up to 20mg) for flares, etc.  
3. Regular (daily) use of opioids or other drugs of abuse including heavy alcohol or marijuana 
use 
4. Severe psychiatric disease including schizophrenia, psychosis, suicidal depression 
5. Previous use of ranolazine within 2 months prior to enrollment 
6. Prior use of ranolazine which was discontinued for safety or tolerability  
7. Metabolic derangement defined as liver function tests >3x upper limit of normal or severe 
renal disease defined as calculated creatinine clearance <30 mL/min 
8. Have liver cirrhosis 
9. Concurrent use of strong CYP3A inhibitors or inducers: ketoconazole, itraconazole, 
nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir, rifampin, rifapentine, 
phenobarbital, phenytoin, clarithromycin, St Johns Wart, digoxin 
10. A family history of (or congenital) long QT syndrome or known acquired QT interval 
prolongation 
11. Inability or refusal to give informed consent for any reason including a diagnosis of 
dementia or cognitive impairment 


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12. Patients who are pregnant or breastfeeding 
13. Patients who are enrolled in other investigational drug studies or who have taken 
investigational drugs within 30 days before enrollment 
14. Other factors which in the opinion of the investigator could potentially impact the study 
outcomes (e.g., underlying disease, medications, history) or prevent the participant from 
completing the protocol (poor compliance or unpredictable schedule) 
 


6 
TABLE OF EVENTS 
 
 
Pre-Enrollment 
Period 1 
Crossover 
Period 2 
 
Day -7-0 
Day 0 
Days 1-83 
Day 84 
Days 85-167 
Day 168 
Procedure/ 
Assessment 
Prescreen 
patients with 
upcoming SOC 
appts 
Visit 1 
Screen, enroll, 
randomize/  
Period 1 baseline 
Daily text 
message and 
paper diary data 
collection 
Visit 2 
Period 1 
endpoint/ 
Period 2 baseline 
Daily text 
message and 
paper diary data 
collection 
Visit 3 
Period 2 
endpoint 
EMR review  
X 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
Medical history 
 
X 
 
X 
 
X 
Physical exam including vital signs 
 
X 
 
X 
 
X 
Concomitant meds 
 
X 
 
X 
 
X 
Urine pregnancy test 
 
X 
 
X 
 
 
Crohn’s Disease Activity Index 
(CDAI) 
 
X 
 
X 
 
X 
Short Inflammatory Bowel Disease 
Questionnaire (SIBDQ) 
 
X 
 
X 
 
X 
Patient Health Questionnaire-8 
(PHQ-8) 
 
X 
 
X 
 
X 
Harvey Bradshaw Index (HBI) 
 
X 
 
X 
 
X 
Randomization 1:1 
 
X 
 
 
 
 
Start study drug 
 
X 
 
X 
 
 
Assess medication compliance 
 
 
 
X 
 
X 
Daily number of loose stools  
 
X 
X 
X 
X 
X 
Adverse event monitoring 
 
X 
X 
X 
X 
X 


7 
PROCEDURES 
 
7.1 
Overview 
Patients will be enrolled in the study for a total of 24 weeks. Patients entering the clinic for a 
routine visit will be recruited, consented, enrolled, and randomized at that same visit. They will 
undergo eligibility screening and be sent home with investigational medication. They will return at 
the end of the first 12-week study drug administration period for a mid-point study visit at which 
they will provide Period 1 endpoint/Period 2 baseline measurements and crossover to the second 
study drug administration period. As during the first administration period, they will return for the 
third and final study visit at the end of the second 12-week study drug administration period (Week 
24/Day 168). Alternatively, patients can decide to participate in the study through virtual visits. 
The same timeline will be followed. Participants will be sent a blood pressure cuff and given 
instructions (Appendix F) to take their own measurements. Between study visits, the study 
coordinator will call or text participants with reminders about study visits and the completion of 
the daily survey. 
 
7.2 
Randomization Procedures 
Participants will be allocated to treatment sequence (ranolazine first/placebo second or vice 
versa) using a block randomization module in REDCap. Equal numbers of participants will 
randomized to the ranolazine-first and placebo-first groups. Participants will also be stratified 
based on remission status so that equal numbers of participants are enrolled in Arms 1 and 2. 
Only the IDS team members and biostatisticians will have access to the randomization module. 
 
7.3 
Agent Administration and Duration of Treatment 
The investigator will instruct all patients to take the study drug exactly as specified in the protocol. 
The study team will assess medication compliance at each study visit. Ranolazine and placebo 
will be dispensed as 500 mg tablets, encapsulated by IDS. The full dose is 500 mg twice per day. 
Patients will be given a sufficient number of capsules to last until the next visit. All patients will 
take ranolazine and placebo, each for 12 weeks. Patients may contact the study team if 
experiencing side effects and receive instructions about how to reduce their dose to 500 mg BID.   
Study drugs should be taken at approximately the same time each day, preferably in the morning 
and evening, and no earlier than 1 hour and no later than 4 hours after the scheduled time. Each 
dose of ranolazine should be taken with a glass of water. Ranolazine may be dosed with or without 
food. Ranolazine capsules should never be chewed, cut, or crushed. The entire contents of the 
ranolazine capsules should be consumed; the dose should not be divided.  
If a dose is missed (i.e., not taken within 4 hours after the scheduled dosing time), the patient 
should resume dosing with the next scheduled dose. Missed or vomited doses will not be made 
up.  
Patients will also be given instructions for self-administration as to the number and strength of the 
capsules to take. Patients will be instructed to bring all unused capsules to each study visit for 
assessment of compliance and medication disposal. 


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7.4 
Safety Assessments 
 
7.4.1 Urine Sample Collection 
Urine will be collected from female participants of childbearing potential during study visits 1-2 for 
a urine pregnancy test. The study team will provide over the counter pregnancy tests for 
participants who decide to participate in the study remotely. These tests will be shipped to 
potential participants to confirm eligibility. Pregnancy is an exclusion criterion for this study.  
 
7.5 
Efficacy Assessments 
 
7.5.1 Crohn’s 
Disease 
Activity Index (CDAI) 
The CDAI, considered the ‘gold 
standard’ for defining clinical 
endpoints in CD trials, is an 
assessment predominantly used 
in research settings to quantify 
CD symptoms. The CDAI is a 
composite score ranging from 0 
to approximately 600, with higher 
scores indicating greater disease 
activity. The 8 components used 
to assess the CDAI and their 
weighting factors are noted in Table 2.41 Since blood draws will not be performed as part of this 
study, the hematocrit component of the CDAI will not be assessed.  
Clinical remission based on CDAI score is defined as a CDAI score of <150. Clinical response is 
defined as CDAI reduction from baseline of ≥100 points or CDAI score <150. Clinical remission 
based on abdominal pain and stool frequency is defined as an average stool frequency score ≤3 
with a stool frequency no worse than baseline and an average abdominal pain score ≤1.  
 
7.5.2 Electronic data collection 
We will collect data directly from patients using MyCap or, if installation and use of an app is not 
possible, through a paper version. MyCap is a secure mobile application developed by the 
REDCap team at Vanderbilt and integrated into the REDCap database system. Participants install 
the application on their personal device. All interaction with the app is secure and requires the 
user to enter a 6-digit pin. Once a patient has consented, they join a study for data collection by 
scanning a unique QR code. Then, patients receive a notification each day to answer questions 
about their number of loose stools and antidiarrheal medication use. This provides the capacity 
for collecting patient reported outcomes in a secure and robust manner.  If patients are unable to 
use this application or unwilling to install it, they will be provided with a paper version of the 
Clinical or Laboratory Variable 
Weighting  
Number of liquid or soft stools each day for 7 
days 
x 2 
Abdominal pain (graded 0-3 on severity) each 
day for 7 days 
x 5 
General well-being, from 0 (well) to 4 (terrible) 
daily for 7 days  
x 7 
Presence of extraintestinal complications 
x 20 
Taking diphenoxylate/atropine, loperamide, or 
opiates for diarrhea 
x 30 
Presence of an abdominal mass (0 as none, 2 
as questionable, 5 as definite) 
x 10 
Hematocrit of <0.47 in men and <0.42 in 
women 
x 6 
% deviation from standard weight 
x 1 
Table 2. CDAI components and weighting 


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questionnaire.  This minimizes loss to follow up and maximizes the efficiency of the study.  
Research teams have had great success using REDCap-based mobile data collection for multiple 
studies including collection of data about quality of life and exercise after heart 
surgery (NCT03270124), pain reporting in sickle cell disease (NCT03629678), and pain using a 
visual analog scale (VAS) during an interventional drug study (NCT03865940). 
 
7.5.3 Short Inflammatory Bowel Disease Questionnaire (SIBDQ) 
The SIBDQ is a 10-item shortened version of the original 32-item IBDQ. The SIBDQ measures 
quality of life in four domains: bowel symptoms, emotional health, systemic symptoms, and social 
function.42 
 
7.5.4 Patient Health Questionnaire (PHQ-8) 
The PHQ-8 is a 8-item module that screens for the presence and severity of depression and can 
be used to make a depression diagnosis using DSM-IV criteria.43 
 
7.5.5 Harvey Bradshaw Index (HBI) 
The Harvey-Bradshaw index (Harvey-Bradshaw Index - HBI) was conceived in 1980 as a 
simplified version of the CDAI to foster a systematic collection of clinical data related to Crohn's 
disease. The index considers five parameters, exclusively clinical (patient well-being, abdominal 
pain, number of liquid or soft stools, abdominal mass, complications). For each parameter a 
specific score is assigned.44 
   
8 
DESCRIPTION OF STUDY TREATMENT 
 
8.1 
Description of Study Drug 
The study drug, 500 mg extended release generic ranolazine tablets, will be obtained by 
Vanderbilt’s Investigational Drug Service (IDS). IDS will over-encapsulate ranolazine tablets at 
the IDS pharmacy. The tablet will be covered with microcrystalline cellulose in the capsule. The 
matching placebo manufactured for this study will be identical in appearance and will also be 
compounded at IDS. Ranolazine and placebo can be stored at room temperature for up to 6 
months.   
 
8.2 
Study Drug Accountability and Disposal 
Investigational drug should not be used for purposes other than as defined in this protocol.  
The Principal Investigator will provide study drug only to the identified subjects of this study, 
according to the procedures described in this study protocol. All supplies of study drug will be 
accounted for in accordance with Good Clinical Practice. Both the Investigational Drug Service 
and the Principal Investigator will maintain accurate records of the disposition of all investigational 
supplies received during the study. The records should include the amounts and dates that the 
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8.3 
Study Drug Compliance 
It is the Principal Investigator’s responsibility to ensure that subjects are correctly instructed on 
how to take their study drug, and that each subject is fully compliant with his/her assigned dosing 
regimen. The study coordinator will assess medication compliance at each study visit. Subjects 
will be asked to return all unused study drug at the end of the study. The study drug should be 
dispensed by the Principal Investigator, or by a qualified individual under the Principal 
Investigator’s supervision.  
 
At each visit, previously dispensed study drug capsules will be collected by the Principal 
Investigator, or by a qualified individual under the investigator’s supervision, and compliance 
assessed. Subjects exhibiting poor compliance, i.e. 2 or more missed medication days in 1 week, 
as assessed by medication counts at each visit, should be counseled on the importance of good 
compliance to the study dosing regimen. Subjects who are persistently noncompliant (<80% or 
>120%) may be removed from the study.  
 
9 
CONCOMITANT MEDICATIONS AND PROCEDURES 
 
9.1 
Permitted Concomitant Medications and Procedures 
Any medication that is considered necessary for the subject’s health and is not expected to 
interfere with the evaluation of or interact with ranolazine may be continued during the study. All 
patients must remain on a stable dose of their standard Crohn’s Disease medications throughout 
the course of the study. Use of antidiarrheals such as loperamide is permitted and will be tracked.  
 
9.2 
Prohibited Concomitant Medications and Procedures 
Prohibited concomitant medications are listed in the exclusion criteria.  
 
10 STATISTICAL CONSIDERATIONS 
 
10.1 Overview 
The hypothesis to be tested in this study is that sodium channel dysfunction may contribute to 
diarrhea among Crohn’s Disease patients, and that inhibition of sodium currents may be 
beneficial. Our overall goal is to conduct an exploratory clinical trial of the sodium channel blocker, 
ranolazine, in a population of Crohn’s Disease patients who are experiencing persistent diarrhea.  
 
10.2 Study Population Definitions 
The following analysis populations will be used in the statistical analysis: 


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• 
Intent-to-treat (ITT): The ITT analysis population will 
consist of all randomized subjects from the screened 
analysis population who receive at least one dose of study 
medication. Outcomes for the subjects in the ITT analysis 
population will be analyzed according to actual treatment 
received during the study drug administration period when 
the outcome measure was collected. The primary 
analysis population for all efficacy endpoints will be the 
ITT analysis population. 
• 
Safety: The safety analysis population is defined as all 
subjects who are randomized and receive at least one 
dose of study medication, analyzed by actual treatment 
received.  
• 
Per-protocol (PP): The PP population will consist of all 
patients in the ITT population who adhere to the protocol. 
This population will be used in sensitivity analyses of the 
primary and key secondary endpoints to evaluate the 
influence of major protocol violators and protocol 
deviators on the primary results.  
10.3 Statistical Methods 
We will test for differences in the average effect of treatment for each proposed outcome using 
separate paired t-tests. For subjects randomized to receive ranolazine first, we will compare the 
response at the end of Period 1 (Visit 2) to the response at the end of Period 2 (Visit 3); for 
subjects randomized to receive placebo first, we will compare Visit 3 to Visit 2. Results will be 
expressed as the mean effect of treatment with corresponding 95% confidence intervals. We will 
use semi-parametric approaches to adjust for multiple comparisons among correlated hypotheses 
and anticipate that randomization and the paired analysis approach will mitigate confounding. 
To utilize the longitudinal data collected at multiple visits and test hypotheses related to the timing 
of treatment effectiveness, we will also generalize the paired t-test to a regression model 
framework. Separate longitudinal regression models will be estimated that include fixed effects of 
time, treatment-group indicator, and the time by treatment indicator interaction. To account for 
correlation arising from taking repeated measurements on the same subject over time, we will 
use either random effects (continuous outcomes) or generalized estimating equations with the 
robust Huber-White sandwich estimator clustering on subject identifier (binary, ordinal, count 
outcomes). For outcomes measured at visits 1-3, time will be modeled as a factor (categorical) 
variables, and for diary data collected daily, we will flexibly model time using regression splines. 
These models will allow us to estimate the changing effect of treatment over time. We will use the 
diary data to evaluate compliance and model changes in the number of stools per day over time. 
While our primary analysis will be intent to treat, we will consider secondary analyses to determine 
if rate of compliance modifies the effect of treatment. For the number of stool per day analysis, a 
Poisson longitudinal regression model will allow us to estimate the quantities described in Figure 
3 including to time to symptom reduction and time to symptom recurrence after treatment 
discontinuation.  
Power and sample size. We plan to enroll 20 total subjects (10 in each arm). Based on potential 
20% dropout rate, we are aiming to have 16 or more completers for this study. We used previously 
 
Figure 3. Potential effect of 
ranolazine 
on 
Crohn’s 
symptoms 


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published42 and preliminary data collected at Vanderbilt to estimate the standard deviation of the 
difference based on the standard deviation of the outcome and intraclass correlation. Accounting 
for multiple comparisons at a significance level of 0.05, we will have 80% power to detect changes 
of 63, 9.4, and 4.1 points for the CDAI, SIBDQ, and PHQ-8 outcomes. Using a rate of 3 loose 
stools per day, we will have 80% power to detect a reduction of 1.05 stools per day, or 7.35 per 
week (primary endpoint).  
 
11 ADVERSE EVENTS 
 
11.1 Definitions 
 
11.1.1 Adverse Event 
An AE is defined as “any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment”. An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
AEs include any of the following: 
• 
Worsening (change in nature, severity or frequency) of conditions present at the onset of 
the trial 
• 
Subject deterioration due to the primary illness 
• 
Intercurrent illnesses 
• 
Drug interactions 
• 
Events related or possibly related to concomitant medications 
• 
Abnormal laboratory values or changes of vital signs, as well as significant shifts from 
baseline within the range of normal, which the Investigator considers to be clinically 
significant 
 
CD relapse and related symptoms will be monitored as study endpoints and thus will not be 
recorded as AEs.  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered the AE rather than the procedure itself.  
Abuse, withdrawal, sensitivity or toxicity to a study drug should be reported as an AE. Overdose, 
accidental or intentional, that are associated with an AE should be reported on the eCRF. Any 
sequela of an accidental or intentional overdose of a study drug should be reported as an SAE 
on the AE eCRF. The overdose resulting from in the SAE should be identified as the cause of the 
event on the SAE Report Form and eCRF but should not be reported as an SAE itself.  
11.1.2 Serious Adverse Event 
During clinical investigations, serious AEs may occur. If the event is suspected to be drug-related, 
the event may be significant enough to lead to important changes in the way the medicinal product 


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is developed (e.g., change in dose, population, needed monitoring, consent forms). This is 
particularly true for reactions, which, in their most severe forms, threaten life or function. A serious 
AE (SAE) or serious adverse drug experience (SADE) is any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening. ‘Life-threatening” refers to an event in which the subject is at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe (ICH E6). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/ incapacity (as per reporter’s opinion) 
• 
Is a congenital anomaly/birth defect 
• 
Is another medically important condition.  Important medical conditions that may not result 
in death, be life-threatening or require hospitalization may be considered as SAEs or 
SADEs when, based upon appropriate medical judgment, they may jeopardize the subject 
or may require intervention to prevent one of the outcomes listed in the definition above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse [Code of Federal 
Regulations Title 21, Volume 5, 21CFR312.32, revised April 1, 2006]. 
 
11.1.2.1 Assigning Relationship of Serious Adverse Event to Study Drug (Causality) 
The Principal Investigator will determine the relationship of each SAE to study drug (i.e., causality) 
by using the classification criteria ‘not related’, ‘possibly related’, or ‘probably related’. 
Descriptions of the three classification categories are as follows: 
Not Related (must include at least the first two features) 
• 
It does not follow a reasonable temporal sequence from administration of the drug.  
• 
It could readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject.  
• 
It does not follow a known pattern to the suspected drug.  
• 
It does not reappear or worsen when the drug is re-administered.  
Possibly Related (must include at least the first two features) 
• 
It follows a reasonable temporal sequence from administration of the drug.  
• 
It could readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject.  
• 
It follows a known response pattern to the suspected drug.  
 
Probably Related (must include at least the first 3 features) 
• 
It follows a reasonable temporal sequence from administration of the drug.  


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• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
subject. 
• 
It disappears or decreases on cessation or reduction of dose. there are exceptions when 
an AE does not disappear upon discontinuation of the drug (e.g., bone marrow 
depression, fixed drug eruptions, tardive dyskinesia).  
• 
It follows a known pattern of response to the suspected drug.  
 
Related (must include all of the following features) 
• 
It follows a reasonable temporal sequence from administration of the drug.  
• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
subject. 
• 
It disappears or decreases on cessation or reduction of dose. there are exceptions when 
an AE does not disappear upon discontinuation of the drug (e.g., bone marrow 
depression, fixed drug eruptions, tardive dyskinesia. 
• 
It follows a known pattern of response to the suspected drug.  
• 
It reappears or worsens if the drug is re-administered.  
All efforts should be made to classify the SAE according to the above categories. After initiation 
of study drug, all SAEs, regardless of relationship to study drug, will be recorded until the 
subject completes his or her last study visit.  
 
11.1.3 Adverse Drug Reaction 
In the pre-approval clinical experience with a new medicinal product or its new usage, particularly 
as the therapeutic dose(s) may not be established, an adverse drug reaction is defined as: All 
noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions (ADR). 
 
11.1.4 Unexpected Adverse Drug Reaction 
An unexpected ADR is: An adverse drug reaction, the nature or severity of which is not consistent 
with the applicable product information, also known as reference safety information. The 
reference safety information is the package insert. 
 
11.2 Monitoring, Recording, and Reporting of Adverse Events 
Serious adverse events related to the use of the study drug (ranolazine) are not expected to occur 
based on extensive previous human experience. Since ranolazine is a marketed drug with a well-
established safety profile, non-serious adverse events will not be subject to expedited reporting 
for this study. For both AEs and SAEs, the Principal Investigator will provide a record of the start 
and stop dates of the event, the action taken with study drug as a result of an AE or SAE as 
applicable (e.g., discontinuation, interruption, or dose reduction of study drug, as appropriate), 
whether any concomitant and/or additional treatments were given for the event, and the outcome 


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of the event. All SAEs that have not resolved upon discontinuation of the subject’s participation 
in the study must be followed until recovered (returned to baseline), recovered with sequelae, or 
death (due to the SAE).  
The study team will review all AE at their regular team meetings. AE will be reported to the IRB 
during annual review.  
Our procedures for reporting the serious adverse events will be as follows: 1. SAEs will be 
recorded in the patient’s study chart and reported to the Principal Investigator within 24 hours of 
the study team’s awareness of the occurrence by email or text message and will be reported to 
Vanderbilt’s IRB according to IRB policies (5 working days). The Principal Investigator will be 
responsible for systematically reviewing SAEs, assigning causality, and evaluating relatedness of 
each event. The Principal Investigator will determine if any necessary actions need to occur as 
result of the event in order to increase the safety of the protocol. 
 
11.3 Pregnancy 
Pregnancy in itself is not regarded as an AE unless there is suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. Pregnancies or suspected 
pregnancies, i.e. positive pregnancy test in a female subject of childbearing potential regardless 
of disease state, occurring while the subject is on study drug, or within 30 to 45 days of the 
subject’s last dose of study drug, are considered immediately reportable events. Study drug is to 
be discontinued immediately and the subject instructed to return any unused portion of study drug 
to the Principal Investigator. 
 
12 DISCONTINUATIONS 
 
12.1 Criteria for Removal from Study 
Participants will be removed from study treatment when any of the criteria listed in the next section 
applies. All patients who initiate protocol treatment will be included in the safety analysis, and all 
patients who initiate protocol treatment and receive the full 24 weeks of treatment (12 weeks 
ranolazine and 12 weeks placebo) will be included in overall evaluation of response. All reasons 
for discontinuation of therapy should be documented clearly in the medical record. 
 
12.2 Discontinuation of Treatment 
The reasons for discontinuation or protocol treatment include, but are not limited to: 
• 
Non-compliance with the study protocol, including, but not limited to not attending the 
scheduled visits. The PI will determine when non-compliance should lead to removal 
from study. Note: These patients will still be included in the overall evaluation of safety.  
• 
Unacceptable major toxicity. Note: These patients will still be included in the overall 
evaluation of safety.  


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• 
Intercurrent illness or condition that would, in the judgment of the treating investigator, 
affect assessment of clinical status to a significant degree or require discontinuation 
of study treatment 
• 
At subject’s own request. Note: The reason for discontinuation from the study must be 
documented. These patients will be included in the overall evaluation of safety and 
response if the full protocol therapy was administered prior to withdrawal. 
• 
Study is closed for any reason (e.g. new information shows that the patient’s welfare 
would be at risk if she continued study treatment) 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator 
 
12.3 Replacement of Patients Who Discontinue Early 
The study intends that patients will complete the full 24 weeks of study drug administration. If a 
patient discontinues study treatment for reasons clearly not related to study treatment, after 
completing fewer than the full 24-week course of study drug, then that patient will be considered 
not evaluable for efficacy analysis (will still be included in the safety analysis though) and may be 
replaced with a new patient.  
  
12.4 Withdrawal from Study 
Subjects may voluntarily withdraw from the study at any time. The Principal Investigator will 
provide written explanation in the source documentation to be entered on the appropriate eCRF 
page describing the reason for discontinuation. No study data from patients who withdraw consent 
at any time will be used in analysis.  
The criteria for enrollment are to be followed explicitly.  
Reasons for discontinuation include, but are not limited to, the following: 
• 
Physician decision: The Principal Investigator must discontinue study drug if is determined 
that it is not safe or in the subject’s best interest to receive further treatment.  
• 
Noncompliance with study drug: A subject may be discontinued from the study for failure 
to comply with the dosing regimen as specified by the protocol.  
• 
Noncompliance with protocol/protocol deviation: A subject fails to follow protocol 
procedures, or other event or decision that stands in contrast to the guidelines set in the 
protocol.  
• 
Adverse event: A subject must be discontinued from study drug if, in the judgment of the 
Principal Investigator or if specified in the protocol, the subject develops an AE such as 
an intercurrent illness or complication that justifies discontinuation from study drug.   
 
 
13 REGULATORY CONSIDERATIONS 
 


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13.1 Investigational New Drug (IND) 
According to the guidance published by the FDA (as outlined in § 312.2(b)(1)) clinical 
investigations of marketed drugs are exempt from the IND requirements if all of the below criteria 
are met; notes on this study are included: 
1. The drug product is lawfully marketed in the United States 
a. Ranolazine is FDA approved for chronic angina. We are proposing to test this 
lawfully marketed drug product for a new indication.  
2. The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other significant 
change in the labeling of the drug.  
a. Data resulting from this small-scale pilot trial in 20 adults will be used to support 
the next phase of development (e.g., preliminary data for future grant proposals, 
informing the design of future trials, attracting commercial interest) and will NOT 
be reported to the FDA in direct support of a new indication/label change.  
3. In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising of the drug.  
a. Data resulting from this small-scale pilot trial in 20 adults will not be used to support 
any change in advertising. See notes above on #2 for detail about how resulting 
data will be used.  
4. The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreased the acceptability of the risk) 
associated with the use of the drug product.  
a. This investigation will use the FDA approved dose and route of administration for 
ranolazine. Ranolazine has a good safety profile and its use in the Crohn’s patient 
population is not anticipated to significantly increase risk.  
5. The investigation is conducted in compliance with the requirement for review by an IRB 
and with the requirements for informed consent.  
a. A full clinical protocol, informed consent document, and other materials will be 
submitted to the VUMC Human Research Protections Program in order to obtain 
IRB approval to conduct this trial at VUMC. If the IRB requests that an IND is filed, 
one will be filed with the FDA, and the ‘may proceed’ letter will be submitted to the 
IRB in order to gain approval to conduct the trial at VUMC.  
6. The investigation is not intended to promote or commercialize the drug product.  
a. Data resulting from this small-scale pilot trial in 20 adults is not intended to promote 
or commercialize the drug product. See notes above on #2 for detail about how 
resulting data will be used.  
 


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13.2 Good Clinical Practice 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
• 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 
• 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations) 
• 
Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996) 
The investigator agrees to adhere to the instructions and procedures described in it and thereby 
to adhere to the principles of Good Clinical Practice to which it conforms. 
 
13.3 Privacy/Confidentiality 
Data will be maintained in paper and computer files that will be locked and password-protected. 
Only the study team will have access to identifying information. Information will be maintained 
indefinitely by the Principal Investigator.  
 
13.4 Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards. Any changes to the protocol will be made in 
the form of an amendment and must be approved by the IRB of each institution prior to 
implementation at that institution. 
 
13.5 Compliance with Trial Registration and Results Posting Requirements 
This study will be registered with clinicaltrials.gov prior to initiation of enrollment of study 
subjects. 
 
14 DATA AND SAFETY MONITORING 
 
14.1 Overall Framework 
The Principal Investigator, study coordinator, and clinical research data monitor will be 
responsible for real-time monitoring of all trial-related activities. They will assure that the study is 
conducted according to Good Clinical Practice Guidelines and according to FDA requirements. 
The study team will meet monthly to review recruitment, enrollment, retention, status of each 
participant currently enrolled, adverse events.  Targets will be established for enrollment and 
completion and reviewed at each meeting where strategies will be discussed to assure that the 
study is on track. Adverse and serious adverse events reports will be monitored in real-time by 
the Principal Investigator, study coordinator, and project manager. All final data will be stored on 
case report forms in REDCap with all source documents uploaded into REDCap then shredded. 
 


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14.2 Data Management and Reporting 
All study data, including those captured from the EHR and other hospital databases, will be 
transferred into the study database via standardized electronic case report forms (eCRFs) which 
will reside in a centralized REDCap database located on Vanderbilt’s secure servers. REDCap is 
a secure, web-based application for building and managing online databases. Vanderbilt 
University Medical Center, with collaboration from a consortium of institutional partners, including 
the Vanderbilt Institute for Clinical and Translation Research (VICTR) Informatics Core, 
developed and manages a software toolset and workflow methodology for electronic collection 
and management of research and clinical trial data. Data will be accessed via password protected 
and secured Web-based interface for data entry and data cleaning. REDCap contains an audit 
trail for tracking all activities within the system. REDCap servers are housed in a local data center 
at Vanderbilt and all web-based information transmission is encrypted. REDCap was developed 
specifically around HIPAA Security guidelines and is recommended by both the Vanderbilt 
University Privacy Office and Institutional Review Board. REDCap has been disseminated for use 
locally at other institutions and currently supports more than 3,700 academic/non-profit 
consortium partners and over 1 million research end-users (www.project-redcap.org).  
In addition to the subject database, which will include all study participant data, REDCap will also 
be used for a regulatory and monitoring database.  
To ensure data is accurately and completely collected during the study, periodic monitoring will 
occur by the Project Manager to ensure the study protocol is being followed, protocol changes 
have been implemented appropriately, data are being captured per protocol, and are accurate, 
complete, and current for study subjects. Per best practice guidelines, the monitor will compare a 
representative number of subject records and other supporting documents with the investigator’s 
reports. Specifically, monitoring activities will include: 
[1] A Technical Review annually which will consist of the clinical research data monitor examining 
the quality and accuracy of data, regulatory documents, and other essential documents. Data 
quality and accuracy will be reviewed through a CRF data and source document review. 
Regulatory Document Review will consist of a review of IRB approvals, informed consents, critical 
documents, and protocols/amendments.  
[2] The Scientific Review will occur annually and will consist of a review of the study’s 
organizational structure, patient recruitment, staff training, and quality control procedures by the 
clinical research data monitor. Monitoring progress reports will be submitted to the IRB as 
requested and/or required. This review will serve as a method for identifying systematic problems 
and provide a means in which to institute resolution and follow-up and therefore increase data 
quality. 
 
14.3 Source Verification 
All data entered into the REDCap system must come from an original source. Study coordinators 
will upload all related source documents and medical records that contain information (including 
Protected Health Information for verification purposes) used in completing the eCRFs into the 
secure REDCap system. If original source is given verbally and/or if study procedures were 
documented outside of the medical record, an original source document must be created (which 
includes applicable signatures and dates) that provides an accurate account of the information 


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that was exchanged.  All applicable study source documentation will be uploaded into REDCap 
for monitoring purposes then shredded. 
 
14.4 Meetings 
Study initiation meeting: Once IRB approval is received, an in-person study initiation team 
meeting will be scheduled by the Project Manager. During this meeting, the study team will review 
the following with the Principal Investigator: 
• 
Overall study goals and obligations 
• 
Protocol procedures, with particular attention to inclusion/exclusion criteria, enrollment 
goals, adverse events, and GCP compliance 
• 
Presentation of the REDCap databases 
• 
Informed consent procedure  
• 
AE/SAE reporting 
• 
CRF completion and error/correction/need for adequate source documentation 
• 
Maintenance of the regulatory binder and site visit log, both maintained electronically in 
REDCap 
• 
Any other issue as deemed important to the conduct of the study 
 
Monthly study team meetings: These meetings will include the Principal Investigator, Study 
Coordinator, Statistician, Clinical Research Data Monitor, Project Manager, and relevant staff 
from the Gastroenterology Clinical Research Enterprise (GICRE) to review adverse events and 
unanticipated problems. Determinations will be made whether adverse events and unanticipated 
problems are related to the study. The team will discuss if any change in risk to the patients is 
present that would require a change to the informed consent document.  
 
14.5 Frequency of Monitoring 
• 
Real-time: AE/SAE monitoring by the Principal Investigator and Study Coordinator 
• 
Monthly: Study team meetings including the Principal Investigator, Study Coordinator, 
Statistician, Project Manager, and relevant GICRE staff 
• 
Annual: Institutional IRB 
 
 
14.6 Individual or Group Responsible for Monitoring 
Responsibility for monitoring will occur at multiple levels. The Principal Investigator will ultimately 
be responsible for assuring that all aspects of study conduct comply with GCP guidelines and all 
regulatory body guidelines. The institutional IRB will conduct annual reviews of the study. 
 
14.7 Process for AE, UP and SAE Reporting 
Information on AE will be collected by the study coordinator or other members of the study team 
at each interaction and recorded on case report forms in REDCap. Interactions occur at each of 
the three study visits (Days 0, 84, 168) and during telephone/email interactions. AE will be 
reviewed at each study team meeting with annual reporting to the IRB. UP will be reviewed at 


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each study team meeting and the relationship to the study will be determined.  The team will 
discuss if any change in risk to the patients is present that would require a change to the informed 
consent document. Any SAE will be reported to the Principal Investigator within 24 hours of when 
the study team becomes aware that the SAE occurred. There will be a preliminary determination 
of whether the SAE is study related or not.  The study team will report the SAE to the institutional 
IRB. 
15 REFERENCES 
 
1.  Schwartz DA, Loftus EV, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, 
Sandborn WJ. The natural history of fistulizing Crohn’s disease in Olmsted County, 
Minnesota. Gastroenterology. 2002 Apr;122(4):875–880. PMID: 11910338 
2.  Boyapati R, Satsangi J, Tzer Ho G. Pathogenesis of Crohn’s disease. F1000Prime Rep 
[Internet]. 
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3.  Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical 
Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018 
Apr;113(4):481–517.  
4.  Crohn’s and Colitis Foundation of America. The Facts About Inflammatory Bowel Disease 
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5.  Pulley JM, Shirey-Rice JK, Lavieri RR, Jerome RN, Zaleski NM, Aronoff DM, Bastarache L, 
Niu X, Holroyd KJ, Roden DM, Skaar EP, Niswender CM, Marnett LJ, Lindsley CW, Ekstrom 
LB, Bentley AR, Bernard GR, Hong CC, Denny JC. Accelerating Precision Drug Development 
and Drug Repurposing by Leveraging Human Genetics. ASSAY Drug Dev Technol. 2017 
Apr;15(3):113–119.  
6.  Reference GH. SCN5A gene [Internet]. Genetics Home Reference. [cited 2018 Mar 12]. 
Available from: https://ghr.nlm.nih.gov/gene/SCN5A 
7.  Beyder A, Farrugia G. Ion channelopathies in functional GI disorders. Am J Physiol - 
Gastrointest Liver Physiol. 2016 Oct 1;311(4):G581–G586. PMCID: PMC5142191 
8.  Neshatian L, Strege PR, Rhee P-L, Kraichely RE, Mazzone A, Bernard CE, Cima RR, Larson 
DW, Dozois EJ, Kline CF, Mohler PJ, Beyder A, Farrugia G. Ranolazine inhibits voltage-gated 
mechanosensitive sodium channels in human colon circular smooth muscle cells. Am J 
Physiol-Gastrointest Liver Physiol. 2015 Sep 15;309(6):G506–G512.  
9.  Clinicaltrials.gov. Search of: ranolazine - List Results [Internet]. [cited 2018 Aug 28]. Available 
from: 
https://clinicaltrials.gov/ct2/results?cond=&term=ranolazine&cntry=&state=&city=&dist= 
10.  Reddy BM, Weintraub HS, Schwartzbard AZ. Ranolazine: a new approach to treating an old 
problem. Tex Heart Inst J. 2010;37(6):641–647. PMCID: PMC3014127 


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11.  FDA. Package Insert: RANEXA (ranolazine) extended-release tablets [Internet]. FDA Access 
Data. 
Available 
from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021526s029lbl.pdf 
12.  Malykhina AP, Akbarali HI. Inflammation-induced “channelopathies” in the gastrointestinal 
smooth muscle. Cell Biochem Biophys. 2004;41(2):319–330. PMID: 15475616 
13.  Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, 
Strichartz GR. The role of sodium channels in chronic inflammatory and neuropathic pain. J 
Pain Off J Am Pain Soc. 2006 May;7(5 Suppl 3):S1-29. PMID: 16632328 
14.  Deshmukh SH, Patel SR, Pinassi E, Mindrescu C, Hermance EV, Infantino MN, Coppola JT, 
Staniloae CS. Ranolazine improves endothelial function in patients with stable coronary artery 
disease: Coron Artery Dis. 2009 Aug;20(5):343–347.  
15.  El Amrani F, Guerra S, Aguirre-Rueda D, Mauricio M, Marchio P, Vila J, Vallés S, Fernández 
F, Aldasoro M. Anti-inflammatory and antioxidant effects of ranolazine on primary cultured 
astrocytes. Crit Care. 2014;18(Suppl 1):P447.  
16.  Teng S, Ren Z, Zhao K. Vagal Stimulation Facilitates Improving Effects of Ranolazine on 
Cardiac Function in Rats with Chronic Ischemic Heart Failure. Curr Mol Med. 2018;18(1):36–
43. PMID: 29879885 
17.  Aldasoro M, Guerra-Ojeda S, Aguirre-Rueda D, Mauricio MD, Vila JM, Marchio P, Iradi A, 
Aldasoro C, Jorda A, Obrador E, Valles SL. Effects of Ranolazine on Astrocytes and Neurons 
in Primary Culture. PloS One. 2016;11(3):e0150619. PMCID: PMC4780741 
18.  Terruzzi I, Montesano A, Senesi P, Vacante F, Benedini S, Luzi L. Ranolazine promotes 
muscle differentiation and reduces oxidative stress in C2C12 skeletal muscle cells. 
Endocrine. 2017;58(1):33–45. PMCID: PMC5608860 
19.  Black JA, Liu S, Waxman SG. Sodium channel activity modulates multiple functions in 
microglia. Glia. 2009 Aug 1;57(10):1072–1081. PMID: 19115387 
20.  Principi M, Mastrolonardo M, Scicchitano P, Gesualdo M, Sassara M, Guida P, Bucci A, Zito 
A, Caputo P, Albano F, Ierardi E, Di Leo A, Ciccone MM. Endothelial function and 
cardiovascular risk in active inflammatory bowel diseases. J Crohns Colitis. 2013 
Nov;7(10):e427–e433.  
21.  Cromer WE, Mathis JM, Granger DN, Chaitanya GV, Alexander JS. Role of the endothelium 
in inflammatory bowel diseases. World J Gastroenterol. 2011 Feb 7;17(5):578–593. PMCID: 
PMC3040330 
22.  Hatoum OA, Binion DG, Otterson MF, Gutterman DD. Acquired microvascular dysfunction in 
inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation. Gastroenterology. 
2003 Jul;125(1):58–69. PMID: 12851871 
23.  Cibor D. Endothelial dysfunction in inflammatory bowel diseases: Pathogenesis, assessment 
and implications. World J Gastroenterol. 2016;22(3):1067.  


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24.  Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-
mediated vasodilatation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging. 2010 
Aug;26(6):631–640. PMID: 20339920 
25.  Wu P, Jia F, Zhang B, Zhang P. Risk of cardiovascular disease in inflammatory bowel 
disease. Exp Ther Med. 2017 Feb;13(2):395–400.  
26.  Verstraelen TE, ter Bekke RMA, Volders PGA, Masclee AAM, Kruimel JW. The role of the 
SCN5A -encoded channelopathy in irritable bowel syndrome and other gastrointestinal 
disorders. Neurogastroenterol Motil. 2015 Jul;27(7):906–913.  
27.  Åkerman A, Månsson S, Fork F-T, Leander P, Ekberg O, Taylor S, Menys A, Ohlsson B. 
Computational postprocessing quantification of small bowel motility using magnetic 
resonance images in clinical practice: An initial experience. J Magn Reson Imaging JMRI. 
2016 Aug;44(2):277–287. PMID: 26801196 
28.  Menys A, Atkinson D, Odille F, Ahmed A, Novelli M, Rodriguez-Justo M, Proctor I, Punwani 
S, Halligan S, Taylor SA. Quantified terminal ileal motility during MR enterography as a 
potential biomarker of Crohn’s disease activity: a preliminary study. Eur Radiol. 2012 
Nov;22(11):2494–2501.  
29.  Koo MWL, Cho CH, Ogle CW. Effects of cold-restraint stress on gastric ulceration and motility 
in rats. Pharmacol Biochem Behav. 1986 Oct 1;25(4):775–779.  
30.  Garrick T, Buack S, Bass P. Gastric motility is a major factor in cold restraint-induced lesion 
formation in rats. Am J Physiol-Gastrointest Liver Physiol. 1986 Feb;250(2):G191–G199.  
31.  Lang J, Price AB, Levi AJ, Burke M, Gumpel JM, Bjarnason I. Diaphragm disease: pathology 
of disease of the small intestine induced by non-steroidal anti-inflammatory drugs. J Clin 
Pathol. 1988 May;41(5):516–526. PMCID: PMC1141503 
32.  Anthony A, Dhillon AP, Nygard G, Hudson M, Piasecki C, Strong P, Trevethick MA, Clayton 
NM, Jordan CC, Pounder RE, Wakefield AJ. Early histological features of small intestinal 
injury induced by indomethacin. Aliment Pharmacol Ther. 1993 Feb 1;7(1):29–40.  
33.  Takeuchi K, Miyazawa T, Tanaka A, Kato S, Kunikata T. Pathogenic Importance of Intestinal 
Hypermotility in NSAID-Induced Small Intestinal Damage in Rats. Digestion. 2002;66(1):30–
41.  
34.  Takeuchi K, Okada M, Niida H, Okabe S. Possible mechanisms involved in gastric 
hypermotility caused by indomethacin in the rat: Role of glycoprivic response. Dig Dis Sci. 
1990 Aug;35(8):984–992.  
35.  Weissenborn U, Maedge S, Buettner D, Sewing K-F. Indometacin-Induced Gastrointestinal 
Lesions in Relation to Tissue Concentration, Food Intake and Bacterial Invasion in the Rat. 
Pharmacology. 1985;30(1):32–39.  
36.  Konaka A, Kato S, Tanaka A, Kunikata T, Korolkiewicz R, Takeuchi K. ROLES OF 
ENTEROBACTERIA, NITRIC OXIDE AND NEUTROPHIL IN PATHOGENESIS OF 
INDOMETHACIN-INDUCED SMALL INTESTINAL LESIONS IN RATS. Pharmacol Res. 1999 
Dec 1;40(6):517–524.  


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37.  Satoh H, Guth PH, Grossman MI. Role of bacteria in gastric ulceration produced by 
indomethacin in the rat: Cytoprotective action of antibiotics. Gastroenterology. 1983 Mar 
1;84(3):483–489.  
38.  Robert A, Asano T. Resistance of germfree rats to indomethacin-induced intestinal lesions. 
Prostaglandins. 1977 Aug;14(2):333–341. PMID: 331401 
39.  Kristinsson JO, Hopman WP, Oyen WJ, Drenth JP. Gastroparesis in patients with inactive 
Crohn’s disease: a case series. BMC Gastroenterol [Internet]. 2007 Dec [cited 2018 Mar 
8];7(1). Available from: http://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-
230X-7-11 
40.  Danciu I, Cowan JD, Basford M, Wang X, Saip A, Osgood S, Shirey-Rice J, Kirby J, Harris 
PA. Secondary use of clinical data: the Vanderbilt approach. J Biomed Inform. 2014 
Dec;52:28–35. PMCID: PMC4133331 
41.  Best WR, Becktel JM, Singleton JW, Kern F. Development of a Crohn’s disease activity index. 
National Cooperative Crohn’s Disease Study. Gastroenterology. 1976 Mar;70(3):439–444. 
PMID: 1248701 
42.  Irvine EJ, Zhou Q, Thompson AK. The Short Inflammatory Bowel Disease Questionnaire: a 
quality of life instrument for community physicians managing inflammatory bowel disease. 
CCRPT Investigators. Canadian Crohn’s Relapse Prevention Trial. Am J Gastroenterol. 1996 
Aug;91(8):1571–1578. PMID: 8759664 
43.  Kroenke K, Spitzer RL, Williams JBW. The PHQ-8: Validity of a brief depression severity 
measure. J Gen Intern Med. 2001 Sep;16(9):606–613.  
44.  Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet Lond Engl. 1980 
Mar 8;1(8167):514. PMID: 6102236 
 
 
 


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16 APPENDIX A: MRAV EMAIL 
 
RE: MyResearch: Study on Crohn’s Disease Symptoms  
From: myresearch@vanderbilt.edu  
 
Hello,  
  
In a survey sent to My Health at Vanderbilt users you agreed to be contacted directly to receive 
information about research studies. Below is a description of a research study at Vanderbilt that 
could possibly match your health profile.  
We are conducting a research study on Crohn’s Disease in order to better understand the 
disease and possible new ways to treat it. The purpose of this study is to learn more about the 
treatment of diarrhea in patients with Crohn’s and to test whether a drug called ranolazine is 
able to reduce or improve those symptoms over the course of three months.   
 
The study will involve three study visits over the course of six months at the IBD Clinic at 
Vanderbilt or through virtual visits. Each visit will last 2-3 hours and will include a number of 
clinical assessments.  
 
If you are eligible and choose to participate, you will be compensated upon study completion. 
 
Whether or not you participate in this study, your care will continue as usual. Your participation 
is voluntary. Our screening process includes a review of your Vanderbilt medical record. If you 
are interested in participating, please follow this link to complete a pre-screening survey.  
 
If our study team determines that you are potentially eligible, you will be contacted by our 
research coordinator, Erin Landry, who can provide more information and schedule a study visit. 
 
Thank you in advance for your participation!  
 
 
Dawn Beaulieu, MD 
Associate Professor of Medicine 
Division of Gastroenterology, Hepatology and Nutrition 
Vanderbilt University Medical Center 
 


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17 APPENDIX B: PROVIDER SPONSORED EMAIL 
 
RE: Study on Crohn’s Disease Symptoms 
 
 
Hi [insert name of CD patient/caregiver], 
 
We are conducting a research study on Crohn’s Disease in order to better understand the 
disease and possible new ways to treat it. The purpose of this study is to learn more about the 
treatment of diarrhea in patients with Crohn’s and to test whether a drug called ranolazine is 
able to reduce or improve those symptoms over the course of three months.   
 
The study will involve three study visits over the course of six months at the IBD Clinic at 
Vanderbilt or through virtual visits. Each visit will last 2-3 hours and you will undergo a number 
of clinical assessments.  
 
If you are eligible and choose to participate, you will be compensated upon study completion. 
 
Whether or not you participate in this study, your care will continue as usual. Your participation 
is voluntary. Our screening process includes a review of your Vanderbilt medical record. If you 
are interested in participating, please follow this link to complete a pre-screening survey.  
 
If our study team determines that you are potentially eligible, you will be contacted by our 
research coordinator, Erin Landry, who can provide more information and schedule a study visit. 
 
Thank you in advance for your participation!  
 
 
Dawn Beaulieu, MD 
Associate Professor of Medicine 
Division of Gastroenterology, Hepatology and Nutrition 
Vanderbilt University Medical Center 
 


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18 APPENDIX C: PRE-SCREENING SURVEY 
 
  
 
 


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19 APPENDIX D: RECRUITMENT FLYER 
 
 


20 APPENDIX E: STUDY WEBSITE LANDING PAGE 
 
 
 
 


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21 APPENDIX F: INSTRUCTIONS FOR BLOOD PRESSURE MONITOR 
 
INSTRUCTIONS FOR AT‐HOME BLOOD PRESSURE READINGS 
 
1. Remove any tight clothing from your arm for blood pressure measurement (left arm 
preferred unless there is a reason not to use the left arm). 
2. Sit upright in a chair with both feet uncrossed and flat on the ground; do not talk during 
the recording. 
3. Place cuff around your arm at the same level as your heart and secure Velcro fastener. 
4. Press ‘Start’ Button and remain as still as possible during the recording 
5. 1 blood pressure measurement will be taken automatically. 
6. Record the blood pressure on the next page. 
7. Blood pressure should be measured 7 days after hospital discharge. The study team 
will let you know what days after this, if any, you should repeat your blood pressure. 
 


 
 
Display/Messages for Blood Pressure Monitor 
Movement during a measurement or an error will result in an additional reading. In this case, 
the monitor will deflate and retake a replacement measurement. An error display (see table) 
could appear on the screen to indicate the cause of the error, however the monitor will 
immediately proceed to an additional recording. 
 
Please avoid taking any medications, drinking alcohol or caffeine, eating, smoking or 
exercising at least 30 minutes prior to taking your blood pressure. 
   Record your blood pressure here: 
Date of blood pressure  
/ 
/ 
Blood pressure  
/ 
Please measure your 
blood pressure prior to the study team calling you. 
If you have any issues/questions with your blood pressure monitor, please email Erin Landry at 
erin.vozar@vumc.org for assistance. 
 
 


 
22 APPENDIX G: CROHN’S DISEASE ACTIVITY INDEX 
 
 
 
 
 


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23 APPENDIX H: MYCAP QUESTIONNAIRE 
 
 


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24 APPENDIX I: SHORT INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE 
 
 


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25 APPENDIX J: PATIENT HEATLH QUESTIONNAIRE-8 
 


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26 APPENDIX K: HARVEY BRADSHAW INDEX 
 
Parameter 
Input and score 
1. Patient well-being 
(previous day) 
0 = very well 
1 = slightly below par 
2 = poor 
3 = very poor 
4 = terrible 
2. Abdominal pain 
(previous day) 
0 = none 
1 = mild 
2 = moderate 
3 = severe 
3. Number of liquid or soft 
stools 
(previous day) 
blank field 
possibility to insert an integer, from 1 to 25 
4. Abdominal mass 
0 = none 
1 = dubious 
2 = definite 
3 = definite and tender 
5. Complications 
No (0 points) 
Yes (drop-down menu with multiple selection; each 
selected complication is counted with 1 point) 
arthralgia 
uveitis 
erythema nodosum 
aphthous ulcer 
pyoderma gangrenosum 
anal fissures 
appearance of a new fistula 
abscess 
Calculation formula: sum of the scores of all 5 parameters. 
A score below 5 is generally considered as clinical remission. A reduction of 3 points is 
considered as relevant to define clinical response. 
 
 
 


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ICF_002.pdf: 
Reduce Crohn's-Associated Diarrhea With Sodium Channel Therapy
NCT04456517
October 14, 2020


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
1 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
Name of participant: __________________________________________ Age: ___________ 
 
The following is given to you to tell you about this research study.  Please read this form with care and 
ask any questions you may have about this study.  Your questions will be answered.  Also, you will be 
given a copy of this consent form.   
 
 
 
Key information about this study:  
The purpose of this study is to test the safety and effectiveness of the drug ranolazine in reducing 
Crohn’s disease-associated diarrhea. Ranolazine is approved by the US Food & Drug Administration 
(FDA) for chronic angina (a heart condition). All participants in this study will take ranolazine for 12 
weeks and placebo (pills that do not contain the drug) for 12 weeks, which means that participants will 
be enrolled in the study for a total of 24 weeks. During the 24 weeks, you will come to the Vanderbilt 
IBD Center for three study visits that will each last about 90 minutes. At these visits you will answer 
questions about your Crohn’s symptoms. You will also receive a text message every day during the 24 
weeks prompting you to report daily number of loose stools, any use of antidiarrheal medication, and 
your study medication doses. All participants are allowed to continue taking all of their standard 
medications during the study. There is no cost to you for taking part in this study. 
 
 
 
You are being asked to take part in this research study because you have Crohn’s disease and are 
experiencing frequent diarrhea. The purpose of this study is to compare the safety and effectiveness of 
the drug ranolazine to the safety and effectiveness of placebo (pills that do not contain the drug) in 
reducing Crohn’s disease-associated diarrhea and other symptoms. Ranolazine is approved by the US 
Food & Drug Administration (FDA) for chronic angina (a heart condition), but ranolazine is considered 
investigational for the purposes of this study and some participants may experience side effects. All 
participants in this study will take ranolazine for 12 weeks and placebo for 12 weeks, which means that 
Key Information:  
The first section of this document contains some key points that the research team thought you 
would find important. The study is described in more detail after this section. If you do not 
understand something, please ask someone.  
Detailed Information: 
The rest of this document includes detailed information about this study (in addition to the 
information listed above). 
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
2 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
participants will be enrolled in the study for a total of 24 weeks. During the 24 weeks, you will come to 
the Vanderbilt IBD Center for three study visits. At these visits you will answer questions about your 
Crohn’s symptoms. When all study activities are complete, we will review the results of our testing to 
see if there are similarities among the patients who improved with ranolazine treatment. Approximately 
50 people will be evaluated at Vanderbilt University Medical Center to determine if they are eligible to 
take part in this study. We expect that approximately half of the people we screen will be eligible to 
enter the treatment study. Our goal is to have 20 participants complete the full study: 10 patients with 
active Crohn’s and 10 patients in remission. 
 
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services, or other rights.  You can stop being in this study 
at any time.  If we learn something new that may affect the risks or benefits of this study, you will be 
told so that you can decide whether or not you still want to be in this study.   Your medical record will 
contain a note saying you are in a research study and may contain some research information about 
you.  Anyone you authorize to receive your medical record will also get this information. 
 
Side effects and risks that you can expect if you take part in this study:  
Side effects association with the use of ranolazine: Ranolazine’s safety profile has been established by 
extensive clinical experience. Some drugs are known to interact with ranolazine and may cause adverse 
events. For your safety, you must tell the study doctor or nurse about all the drugs you are taking, 
including over-the-counter drugs and herbals, before you start the study and before taking any new 
drugs while you are on the study. When used properly and not at the same time as other drugs that are 
known to interact with ranolazine, ranolazine has been shown to be safe and well-tolerated. The most 
common side effects include dizziness, nausea, constipation, headache, and asthenia (weakness or lack 
of energy). Other studies have found that less than 2% of patients experience these side effects and 
therefore, these side effects are uncommon. 
 
Ranolazine pregnancy risks: Ranolazine treatment may hurt an unborn child. If you become pregnant 
while you are in this study, you must tell your doctor at once. Also, women must not breastfeed while in 
this study.  If you are a woman and are able to become pregnant, you will have a urine test to make sure 
that you are not pregnant before you receive treatment in this study.   
 
Risks that are not known: 
Because this treatment is investigational, meaning non-FDA approved, there may be risks that we do not 
know about at this time.  
 
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
3 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
Good effects that might result from this study:  
The benefits to science and humankind that might result from this study: A possible benefit to science and 
humankind is that we may learn about using ranolazine as a new treatment for Crohn’s disease-associated 
diarrhea. However, there is no guarantee that participants will benefit from being in this research study.  
 
Procedures to be followed: 
This is a randomized, double-blind, placebo-controlled, crossover study, which means that if you agree 
to be in this study, you will take pills containing the study drug, ranolazine, and placebo pills that look 
like the study drug but do not contain any drug. Crossover means that you will take one of these 
treatments first and then the other second. Randomized means that it is up to chance (like flipping a 
coin) which order you will take ranolazine and placebo. Double-blind means that you, the study doctor, 
and the study team will not know which order you will take ranolazine and placebo.  
 
You will take 1 study pill twice a day.  
 
If you agree to be in this study your involvement will last about 24 weeks (6 months). Below you will find 
information on each of the five study visits and what you can expect if you agree to take part in this 
study.  
 
In-person Visit 1: This visit will last about 1.5 hours. The following will occur at this visit. 
 
The study team will discuss the study with you and answer all of your questions. 
 
The study team will discuss your medical history with you.  
 
If you are a woman who could be pregnant, a urine pregnancy test will be collected to make 
sure you are not pregnant. The study team will also discuss birth control options with you. 
 
You will complete symptom and quality of life questionnaires. 
 
You will be placed into either the ranolazine first/placebo second or placebo first/ranolazine 
second group. 
 
You will receive the first study medication to take home with you. 
 
The study team will discuss mobile phone data collection with you. 
 
Mobile phone data collection (daily): You will receive a text message every day prompting you to report 
daily number of loose stools, any use of antidiarrheal medication, and your study medication doses.  
 
In-person Visit 2 (12 weeks after in-person Visit 1): This visit will last about 1.5 hours. The following will 
occur at this visit. 
 
The study team will discuss how you are feeling. 
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
4 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
The study team will review mobile phone data collection with you.  
 
You will return the empty bottles you were given with your study drug. 
 
You will get a new supply of study drug to last you until your next visit (this is when you switch 
to the second medication).    
 
If you are a woman who could be pregnant, a urine pregnancy test will be collected to make 
sure you are not pregnant. The study team will also discuss birth control options with you. 
 
You will complete symptom and quality of life questionnaires. 
 
Mobile phone data collection (daily): You will receive a text message every day prompting you to report 
daily number of loose stools, any use of antidiarrheal medication, and your study medication doses.  
 
In-person Visit 3 (12 weeks after in-person Visit 2): This visit will last about 1.5 hours. The following will 
occur at this visit. 
 
The study team will discuss how you are feeling. 
 
The study team will review mobile phone data collection with you.  
 
You will return the empty bottles you were given with your study drug. 
 
You will complete symptom and quality of life questionnaires. 
 
Payments for your time spent taking part in this study or expenses: 
If you are eligible and choose to participate, you will receive a $150 compensation upon study 
completion ($50 for each of the three study visits). You will need to provide your social security number 
(SSN) in order for us to pay you. You may choose to participate without being paid if you do not wish to 
provide your SSN for this purpose. You will also need to provide your address so that a check can be 
mailed to you. Your SSN is obtained for payment purposes only and it will not be retained for research 
purposes. It may take up to 4-6 weeks to receive your check following completion or withdrawal from 
the study.  
 
Costs to you if you take part in this study: 
There is no cost to you for taking part in this study. 
 
Payment in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of the 
tests or treatments that are done for research, then you and/or your insurance will not have to pay for 
the cost of immediate medical care provided at Vanderbilt to treat the injury.  
 
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
5 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
There are no plans for Vanderbilt to pay for any injury caused by the usual care you would normally 
receive for treating your illness or the costs of any additional care. There are no plans for Vanderbilt to 
give you money for the injury.  
 
Who to call for any questions or in case you are injured: 
If you should have any questions about this research study or if you feel you have been hurt by being a 
part of this study, please feel free to contact Dr. Dawn Beaulieu at (615) 936-6956 or Erin Landry at (615) 
322-4573. If you cannot reach the research staff, please contact the Director of Clinical Research at (615) 
422-4643. 
 
For additional information about giving consent or your rights as a person in this study, to discuss 
problems, concerns, and questions, or to offer input, please feel free to call the VUMC Institutional 
Review Board Office at (615) 322-2918 or toll free at (866) 224-8273. 
 
Reasons why the study doctor may take you out of this study:  
You will be withdrawn from the study if the study doctors decide it is best for you. If the study doctors 
withdraw you from the study, you will be told the reason. 
 
What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell your study doctor.  Deciding to not be part 
of the study will not change your regular medical care in any way. 
 
Clinical Trials Registry:  
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  This 
website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this Web site at any time. 
 
Confidentiality:   
Data will be maintained in paper and computer files that will be locked and password-protected. Only 
the study team will have access to identifying information. Information will be maintained indefinitely 
by the Principal Investigator.  
This study has support from the National Institutes of Health (NIH). If so, your study information is 
protected by a Certificate of Confidentiality.  This Certificate allows us, in some cases, to refuse to give 
out your information even if requested using legal means.  
  
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
6 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases.  The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help.  
  
Disclosures that you consent to in this document are not protected. This includes putting research data 
in the medical record or sharing research data for this study or future research. Disclosures that you 
make yourself are also not protected.  
 
Privacy: 
Any samples and information about you may be made available to others to use for research.  To 
protect your privacy, we will not release your name.  You will not receive any benefit as a result of the 
tests done on your samples.  These tests may help us or other researchers learn more about the causes, 
risks, treatments, or how to prevent this and other health problems.  
 
Study Results: 
You will have the opportunity to receive results that emerge from the study. Some results will be 
available during the study and some will be available at the conclusion of the study after the results are 
analyzed. Please know that the delay in receiving results may be long.  
 
Screening results: You will receive the results of the screening tests even if you are not eligible to join 
the study. The screening tests include a urine pregnancy test. You will be told your results as soon as 
they are available. You may talk with the study staff about the meaning of your results and if you have 
further questions.  
 
Individual and overall study results: When the results of the study are available to share, we will inform 
you of the overall summary results of the study. We will also share your individual results with you upon 
request. Results will be available within 12 months after the conclusion of the overall study via letter, 
phone call, or visit in our office. Your individual results will include which study group you were in 
(ranolazine-first or placebo-first group) and may include the measurements we took from you (survey 
results, mobile phone data collection results) and, if appropriate, how they compare with other 
participants in the study.  
 
Exploratory results: In the course of research, we may generate results that could be of medical 
significance or personal use to you. In those cases, we reserve the right to contact you and provide the 
option of receiving those results. If you do not hear from us, this does not mean you should not continue 
with regular medical care.  
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
7 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
The researchers do not plan to contact your regular doctors with any study results. If you have any 
questions, you should contact Dr. Dawn Beaulieu at (615) 936-6956.  
 
Authorization to Use/Disclose Protected Health Information 
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information.  By signing 
this document, you agree that your health care providers (including both Vanderbilt University Medical 
Center and others) may release your private health information to us, and that we may use any and all 
of your information that the study team believes it needs to conduct the study.  Your private 
information may include things learned from the procedures described in this consent form, as well as 
information from your medical record (which may include information such as HIV status, drug, alcohol 
or STD treatment, genetic test results, or mental health treatment).    
  
Who will see, use or share the information? 
The people who may request, receive or use your private health information include the researchers and 
their staff.  Additionally, we may share your information with other people at Vanderbilt, for example if 
needed for your clinical care or study oversight.  By signing this form, you give permission to the 
research team to share your information with others outside of Vanderbilt University Medical 
Center.  This may include the sponsor of the study and its agents or contractors, outside providers, study 
safety monitors, government agencies, other sites in the study, data managers and other agents and 
contractors used by the study team.   We try to make sure that everyone who sees your information 
keeps it confidential, but we cannot guarantee that your information will not be shared with others.  If 
your information is disclosed by your health care providers or the research team to others, federal and 
state confidentiality laws may no longer protect it.  
  
Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. 
  
How long will your information be used or shared? 
Your Authorization for the collection, use, and sharing of your information does not expire.  Additionally, 
you agree that your information may be used for similar or related future research studies. 
  
What if you change your mind? 
You may change your mind and cancel this Authorization at any time.  If you cancel, you must contact 
the Principal Investigator in writing to let them know by using the contact information provided in this 
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
REACT Trial: A randomized, double blind, placebo-controlled, crossover study of 
ranolazine for the treatment of Crohn’s Disease-associated diarrhea 
Version Date: 
PI: 
2020.10.08 
Dawn Beaulieu, MD 
  
 
 
 
 
8 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
consent form.  Your cancellation will not affect information already collected in the study, or 
information that has already been shared with others before you cancelled your authorization. 
 
 
If you decide not to take part in this research study, it will not affect your treatment, payment or 
enrollment in any health plans or affect your ability to get benefits. You will get a copy of this form 
after it is signed.  
 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
 
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature of patient/volunteer  
 
 
 
 
 
Consent obtained by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time 
 
 
 
Printed Name and Title  
Date of IRB Approval: 10/14/2020
Date of Expiration: 07/27/2021