Buspirone for Weak or Absent Esophageal Peristalsis

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, cross-over clinical trial of buspirone in patients with complaints of dysphagia due to poor esophageal motility. The goal of this clinical trial is to study the effect of buspirone on esophageal motility by performing high resolution impedance manometry (HRiM).

Detailed Description
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Esophageal motility disorders can be characterized by poor esophageal motility with impaired clearance of the esophagus. Examples are Ineffective Esophageal Motility (IEM, >70% of the swallows are ineffective or ≥50% are failed) and Absent Contractility (100% failed peristalsis). Both might be the underlying cause for dysphagia. Several studies have shown that poor esophageal motility can be manipulated by pharmacological means. Buspirone, a 5-HT1A agonist, is able to significantly increase distal esophageal wave amplitude and duration in healthy volunteers, suggesting it may be effective in IEM. At the moment, findings in patients with IEM are not consistent and depend on the dose and treatment duration. This cross-over trial will examine the use of buspirone in patients with dysphagia, with the intent of using a higher dose. We will use impedance/manometry and pressure flow analysis to liquid, viscous and solid boluses to evaluate the symptomatic and manometric effect of buspirone.

Official Title
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The Effect of Oral Buspirone Hydrochloride on Esophageal Motility, Bolus Transit and Symptoms of Dysphagia, in Patients With Poor Esophageal Motility: A Randomized, Double-blind, Placebo Controlled, Cross-over Trial With HRiM

Conditions
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Dysphagia, Esophageal

Intervention / Treatment
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* Drug: Buspirone Hydrochloride 10 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients can participate in this study if: A minimum of 18 years old; Ineffective Esophageal Motility (IEM) or absent contractility, as determined on HRM in the last three months before inclusion in the study, using the Chicago classification v4.0 (1). IEM is defined as >70% ineffective or ≥50% failed swallows with a normal integrated relaxation pressure (IRP4). IEM includes a weak contraction (DCI ≥ 100 mmHg·s·cm and <450 mmHg·s·cm), failed peristalsis (DCI < 100 mmHg·s·cm), or fragmented peristalsis (a large break (>5 cm length) in the 20-mmHg isobaric contour with DCI > 450 mmHg·s·cm). Absent contractility is defined as 100% failed swallows (DCI < 100 mmHg·s·cm), with a normal IRP4. Have completed a gastro-duodenoscopy, within 12 months, showing no anatomical abnormality of the stomach or esophagus, which can explain the patients' symptoms. History of dysphagia for at least 2 months, at least twice per week in the last month. Sexually active women of childbearing potential participating in the study must be using an appropriate form of contraception. Medically acceptable forms of contraception include oral contraceptives, injectable or implantable methods, intrauterine devices, or properly used barrier contraception. If the female patient has not been on oral, injectable, implantable or intrauterine contraception, a urinary pregnancy test will be performed prior to administration of Buspirone/Placebo. Subjects must be capable of understanding and be willing to provide signed and dated written voluntary informed consent before any protocol-specific screening procedures are performed. Exclusion Criteria: Patients cannot participate in this study if: Endoscopic signs of severe erosive esophagitis (grade C or D, Los Angeles classification) on endoscopy performed off PPI treatment in the 12 months prior to screening, or ≥ grade B when endoscopy is performed during PPI treatment. Systemic diseases, known to affect esophageal motility (i.e. systemic sclerosis) Surgery in the thorax or in the upper part of the abdomen (appendectomy and cholecystectomy are allowed). Hiatal hernia ≥3 cm QT c>450 ms. Use of medication that effect cholinergic function such as anticholinergics, tricyclic antidepressants. Concomitant promotility agents such as prucalopride or domperidone. Concomitant use of more than one benzodiazepine. Significant neurological, respiratory, hepatic, renal, hematological, cardiovascular, metabolic or gastrointestinal cerebrovascular disease as judged by the investigator. Major psychiatric disorder. Pregnancy or breastfeeding. History of poor compliance. History of/or current psychiatric illness that would interfere with ability to comply with protocol requirements or give informed consent. History of alcohol or drug abuse that would interfere with ability to comply with protocol requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Patients with IEM or absent contractility and symptoms of dysphagia will participate in this study. They will be randomized on a 1:1 basis: Patients will be randomized to take buspirone for 4 weeks or placebo for 4 weeks. After a 2-week washout period the randomized groups will cross over into the alternate treatment.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Buspirone => Washout => Placebo<br>Patients will take Buspirone hydrochloride 10mg oral once a day (in the evening) for 3 days, twice a day (morning and evening) for 4 days, three times a day for 2 weeks and 20mg oral three times a day for one week. Esophageal motility will be assessed with high resolution impedance manometry (HRiM) after 4 weeks of treatment. Patients will also report their perceived symptoms of dysphagia during the HRiM. A washout period of two weeks will take place. Afterwards, the second treatment period starts. Patients will take Placebo oral once a day (in the evening) for 3 days, twice a day (morning and evening) for 4 days, three times a day for 2 weeks and 20mg oral three times a day for one week. Esophageal motility will also be assessed with high resolution impedance manometry (HRiM) after 4 weeks of treatment. Patients will again report their perceived symptoms of dysphagia during the HRiM. | Drug: Buspirone Hydrochloride 10 MG<br>* 4 weeks of treatment with buspirone<br>* Other names: Buspiron;Drug: Placebo<br>* 4 weeks of treatment with placebo<br>|
| Experimental: Placebo => Washout => Buspirone<br>Patients will take Placebo oral once a day (in the evening) for 3 days, twice a day (morning and evening) for 4 days, three times a day for 2 weeks and 20mg oral three times a day for one week. Esophageal motility will be assessed with high resolution impedance manometry (HRiM) after 4 weeks of treatment. Patients will also report their perceived symptoms of dysphagia during the HRiM. A washout period of two weeks will take place. Afterwards, the second treatment period starts. Patients will take Buspirone hydrochloride oral once a day (in the evening) for 3 days, twice a day (morning and evening) for 4 days, three times a day for 2 weeks and 20mg oral three times a day for one week. Esophageal motility will also be assessed with high resolution impedance manometry (HRiM) after 4 weeks of treatment. Patients will again report their perceived symptoms of dysphagia during the HRiM. | Drug: Buspirone Hydrochloride 10 MG<br>* 4 weeks of treatment with buspirone<br>* Other names: Buspiron;Drug: Placebo<br>* 4 weeks of treatment with placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HRiM Manometric Features: DCI 5ml supine | Changes in distal contractile integral (DCI, in mmHg*s*cm) between buspirone and placebo. DCI is established on HRiM. As primary endpoint, we will focus on the values for DCI for the liquid bolus, 5 ml in supine position. | During manometric assessment after 4 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bolus passage score | Patients will evaluate the perception of each swallow during the manometric assessment via the following Likert score: 1-Normal, 2-Slow passage of bolus, 3-Stepwise passage, 4-Partial Blockage, 5-Complete Blockage. | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: PCI | Pharyngeal Esophageal Contractile Integral (PCI es., mm.Hg.s.cm) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: DCI | Distal Esophageal Contractile Integral (DCI, mmHg.s.cm) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: Largest Break Size | Largest Break Size (cm) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: DL | Distal Latency (DL, s) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: IRP4s | Integrated Relaxation Pressure EGJ 4sec (IRP4s, mmHg) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: PFI | Pressure Flow Index (PFI, -) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: IR | Impedance Ratio (IR, -) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: DPA | Distension Pressure Accommodation Phase (DPA, mmHg) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: DPE | Distension Pressure Emptying Phase (DPE, mmHg) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: RP | Distal Ramp Pressure (RP, mmHg/s) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: CSI | Contractile Segment Impedance (CSI, Ohm) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: BPT | Bolus Presence Time (BPT, s) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: BFT | Bolus Flow Time (BFT, s) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: EGJ Rest.P | EGJ Resting Pressure (EGJ Rest.P, mmHg) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: EGJCI | EGJ Contractile Integral (EGJCI, mmHg.cm) | During manometric assessment after 4 weeks of treatment | 
| HRiM Manometric Features: LES-CD | Lower Esophageal Sphincter - Crural Diaphragm (LES-CD, mm) | During manometric assessment after 4 weeks of treatment | 
| Mayo Dysphagia Questionnaire | Symptom questionnaire | At baseline and after 4 weeks of treatment | 
| Overall Treatment Evaluation (OTE) | Symptoms questionnaire | At baseline and after 4 weeks of treatment | 
| Overall Symptom Severity (OSS) | Symptom questionnaire | At baseline and after 4 weeks of treatment |