Clinical trial NCT02674412
Conditions: Functional Dysphagia Ineffective Esophageal Motility
Sponsor: The Cleveland Clinic
Start date: 2016-02-01; Completion date: 2017-04-12
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study evaluates the utility of buspirone in patients who have a diagnosis of functional dysphagia. All participants will be randomized to receive either a placebo pill or buspirone. Subsequently, we will evaluate whether their swallowing is improved. Participants who were randomized to receive placebo will then receive buspirone and those who were receiving buspirone will receive placebo. We will again evaluate whether their swallowing improved.

Detailed description:
Buspirone helps to modulate molecules which can affect the activity of the muscles in the esophagus. Studies in the past have shown that in healthy people, buspirone can improve the vigor with which the esophagus squeezes to propel food into the stomach. In patients with functional dysphagia, the esophagus muscles may be weak (as defined by manometry).

Our two phase study will evaluate both symptoms of difficulty swallowing and the vigor with which the esophagus propels a bolus in patients after they 1) receive placebo pills and 2) receive buspirone pills.

We hypothesize that the placebo pills will not affect the vigor of the muscles or the symptoms of difficulty swallowing, but that buspirone will improve both outcomes.

Arms: arm 1: Buspirone 10 mg PO TID for two weeks, followed by a washout period for two weeks and placebo for two weeks arm 2: Placebo Tablet TID for two weeks, followed by a washout period for two weeks and Buspirone 10mg TID for two weeks.
Interventions: intervention 1: Buspirone intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: Placebo Pill Manufactured by the Investigational Pharmacy at Cleveland Clinic

Protocol documents:
Prot_SAP_000.pdf: 
NCT: 02674412 
 
 
Version Date:  08/10/2016 
Buspirone for Functional Dysphagia - Protocol 
 
 
 
Introduction   
 
Functional Dysphagia has been defined by the Rome Criteria as a syndrome in which patients report symptoms of dysphagia 
without evidence of GERD and without any histopathology-based esophageal motility disorder.  (Rome Criteria) Ineffective 
Esophageal Motility is a manometric diagnosis (based on the Chicago Classification) without a histopathology correlate which 
has been shown to cause dysphagia.  (Kahrilas, PJ)  Data related to treatment of this disorder are limited.  Buspirone is a 
serotonin modulating anxiolytic and antidepressant medication with a reliable safety profile, which has been shown to improve 
esophageal motility.  (Blonski W)  We plan to perform a prospective randomized double-blind crossover style placebo 
controlled trial of the effect of buspirone on patients with functional dysphagia and ineffective esophageal motility. 
 
Background and Significance 
 
Functional Dysphagia has been defined by the Rome Criteria as a syndrome in which patients report symptoms of dysphagia 
without evidence of GERD and without any histopathology-based esophageal motility disorder.  (Rome Criteria) Ineffective 
Esophageal Motility (IEM) is a manometric diagnosis (based on the Chicago Classification) without a histopathology correlate 
which has been shown to cause dysphagia.  (Kahrilas, PJ) 
 
While the etiology of functional dysphagia is widely debated, there are data that argue that ineffective esophageal motility is 
the manometric correlate of functional dysphagia.  In a study of about 200 patients, Roman, et al. showed that patients with 
history of dysphagia without any other structural abnormalities were 3-6 times more likely to have ineffective esophageal 
motility.  (Roman S 2011).  Furthermore, the prevalence of IEM in functional dysphagia increases with age and has been found 
to be up to seven times as high in patients above the age of 70 compared to patients below 70. (Ratuapli, SK) 
IEM may also be partially responsible for the pathogenesis of Gastro-esophageal Reflux Disease (GERD) because of poor acid 
clearance from the esophagus.  (Martinucci I et al, Ribolsi M et al, Savarino E et al, and Fouad YM et al).  
Data about treatment of IEM are limited.  Bethanechol has been tested in this patient population.  Agrawal, et al studied seven 
patients diagnosed with IEM were treated with 50 mg of bethanechol before repeat manometry was performed by providers 
who were blinded to the experiment.  Bethanecol in this population caused an increase in the contractility of the esophagus as 
well as complete bolus clearing.  (Agrawal A)  In addition, one study showed that buspirone, pyridostigmine, or bethanechol 
administration in healthy volunteers causes enhances contractility in the distal esophagus.  (Blonski W) 
While there are no data which have studied medical management of functional dysphagia, functional gastrointestinal disorders 
of the upper gastrointestinal tract have been treated extensively with antidepressants and anxiolytics, especially buspirone.  
Functional dyspepsia, for example, is a disorder of gastric motility without histopathologic abnormality on endoscopy.  A 
double-blind randomized controlled crossover style trial of buspirone in this disorder showed increased gastric 
accommodation, which was correlated with symptom improvement in patients with functional dyspepsia.  (Tack J) There are 
no consensus guidelines for the treatment of functional dysphagia or ineffective esophageal motility.  However, various experts 
argue for the utility of antidepressants and anxiolytic medications for treatment of these disorders.  Dr. Ronnie Fass, Chairman 
of the Functional Esophageal Disorders Committee for Rome Criteria IV, says, “..antidepressants are likely to remain the 
mainstay of treatment of  functional esophageal disorders…” (Weijenborg RA et al and Maradey-Romero C) 
Based on the above observations, we suspect that patients with IEM treated with buspirone will experience improvement in 
esophageal motility, dysphagia, and GERD.   
 
 
Study Design 
 
Methods 
Randomized Double-Blind Crossover Placebo controlled prospective trial 
 
Sample 
Inclusion Criteria: >18 years old, diagnosis of IEM, negative EGD or barium swallow, biopsies negative for EOE 
Exclusion Criteria: Have not had any changes to serotonin modulating medications over the last 6 weeks 
This is a cross-over style study and all participants will be both studied in the treatment and control arms. 


NCT: 02674412 
 
 
Version Date:  08/10/2016 
Previous studies have shown up to a 100% improvement in baseline manometric findings in patients treated with 
buspirone.  We hope to show at least a 25% difference with a p<0.05 and power 0.8.  To show this effect, we will 
need 15-20 patients (depending on the standard deviation of the specific marker being tested).  
 
 
Research Procedures – Define the data to be collected to answer the hypothesis/research 
question(s) 
Nurses at the Swallowing Center facilitate the final read by a licensed physician of all manometries performed here.  
For every patient diagnosed with functional dysphagia and IEM who meets the inclusion and exclusion criteria, the 
nurses will notify the investigators.  Review of electronic charts for all patients undergoing manometry is part of the 
routine medical practice and responsibility of the nurses.  The nurses will also seek the patient’s permission to be 
contacted to hear about the details of an ongoing study related to their diagnosis.   
Once the investigators are notified of this diagnosis, one of the investigators will contact the patient to discuss the 
logistics of the study as well as obtain informed consent.  After informed consent is obtained, patients will be 
randomized to either group A or group B.  Both patients and investigators will be blinded to the assignment. 
All patients will be administered a Mayo Dysphagia Questionnaire as well as a validated GERD questionnaire.  
Subsequently, all patients in Group A will receive placebo and Group B will receive buspirone administered by 
pharmacy.   
After two week of treatment, all patients will undergo repeat administration of questionnaires as well as assessment of 
side effects.  They will also undergo repeat manometry.  All participants will be reimbursed with $100 for travel 
expenses.   
Subsequently, all patients will be treatment free for a washout period of two weeks. 
Patients in Group A will then be treated with buspirone and Group B will be treated with placebo for two weeks 
followed by repeat questionnaires and manometry.  All participants will be reimbursed with another $100 for travel 
expenses.   
All participants will be contacted by phone one week after they start their treatments to assess for tolerability and side 
effects related to the medication. 
The two interventions that are part of the study are buspirone as well as the two subsequent manometries.  Both costs 
will be incurred by the investigators.    
 
Data Analysis 
 
Descriptive statistics will be computed for all variables. This includes means, standard deviation and percentiles for continuous 
variables and frequencies and percentages for categorical factors the t test and odds ratio will be calculated for comparison. All 
analyses will be performed using SAS (version 9.2, The SAS Institute, Cary, NC).  
The analysis will be completed by one of the investigators. 
 
Adverse Events and Data Monitoring Committee(DMC) 
 
This project does not require an independent DMC or DSMB because this is an open-label intervention looking 
solely at symptom/sign changes related to buspirone.   
After two weeks of being on the medication, each patient will be questioned about his/her baseline symptoms, new 
symptoms, and any side effects related to the medications (specifically the common side effects of buspirone).   
All Adverse Events will be reported to the IRB using the Adverse Event Form.  
 
Consent 
 
The consent interview will take place in private patient rooms at the Swallowing Center.  
 
The consent interview will take place after patients are diagnosed with functional dysphagia or IEM.  One of the investigators 
will discuss the study in detail and answer all questions.  The patients will then be provided the opportunity to sign the consent 
or take time to think about the study before signing or rejecting the study.   
 
The consent will be documented on the informed consent form attached with the application.