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Mirabegron in Achalasia: A Clinical and Manometric Proof of Concept Pilot Study

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ClinicalTrials.gov Identifier: NCT03411252
Recruitment Status : Recruiting
First Posted : January 26, 2018
Last Update Posted : January 29, 2018
Sponsor:
Collaborator:
Astellas Pharma Inc
Information provided by (Responsible Party):
Jeff GI, Thomas Jefferson University

Brief Summary:
This study evaluates whether a medication called mirabegron is better than placebo (sugar pill) in helping patients with achalasia swallow better. Each patient will receive either mirabegron or the placebo for 4 weeks followed by the opposite medication. Each patient will complete several surveys and undergo several tests to determine if the mirabegron is helping reduce the pressures in the esophagus (swallowing tube).

Condition or disease Intervention/treatment Phase
Achalasia Drug: Mirabegron 50 MG Drug: Placebo Early Phase 1

Detailed Description:
Achalasia is characterized by incomplete or absent relaxation of the lower esophageal sphincter (LES) and loss of esophageal peristalsis which leads to dysphagia. Standard of care for achalasia includes endoscopic management (dilation and injection of injection of botulinum toxin) and surgery, however both of these options carry procedural risks, may lose efficacy over time and many patients are not appropriate candidates for these treatment options. Unfortunately, there are limited oral medications for patients with achalasia. Mirabegron is an oral beta-3 agonist currently FDA approved for overactive bladder that works by relaxing the bladder muscles. Beta-3 receptors have also been identified in the LES with stimulation leading to LES relaxation in preclinical studies. Through a proof of concept pilot study, the investigators aim to evaluate the effect of mirabegron in patients with achalasia via high resolution manometry and a validated dysphagia scale.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Mirabegron in Achalasia: A Clinical and Manometric Proof of Concept Pilot Study
Estimated Study Start Date : February 15, 2018
Estimated Primary Completion Date : December 15, 2018
Estimated Study Completion Date : December 15, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Mirabegron

Arm Intervention/treatment
Experimental: Mirabegron
Patients will receive 50 mg of oral Mirabegron daily for 4 weeks and then switch to placebo by mouth daily for an additional 4 weeks.
Drug: Mirabegron 50 MG
Myrbetriq (Mirabegron) tablet
Other Name: Myrbetriq

Drug: Placebo
Sugar pill manufactured to mimic Mirabegron
Other Name: Placebo (for Mirabegron)

Placebo Comparator: Placebo
Patients will receive placebo by mouth daily for 4 weeks and then switch to oral Mirabegron 50 mg daily for an additional 4 weeks.
Drug: Mirabegron 50 MG
Myrbetriq (Mirabegron) tablet
Other Name: Myrbetriq

Drug: Placebo
Sugar pill manufactured to mimic Mirabegron
Other Name: Placebo (for Mirabegron)




Primary Outcome Measures :
  1. Changes in lower esophageal sphincter pressures [ Time Frame: Change in lower esophageal sphincter pressure from baseline after 4 weeks of placebo or Mirabegron ]
    Evaluation of changes in lower esophageal sphincter pressures using high resolution manometry


Secondary Outcome Measures :
  1. Eckardt Achalasia Score (EAS) [ Time Frame: Patients will complete the EAS on study day -14, 0, 7, 28, 42, 49, 70, 84. We will evaluate changes in patient's EAS between day 0 and all of these time points. ]
    Patients will complete the Eckardt Achalasia score which is a simple written scale evaluating dysphagia, regurgitation, retrosternal pain and weight loss. Patients report their symptoms from a 0 to 3. Weight loss (0-none, 1: < 5 kg, 2: 5-10 kg, 3: > 10 kg), Dysphagia (0-none, 1-occasional, 2-daily, 3-each meal), Retrosternal pain (0-none, 1-occasional, 2-daily, 3-each meal), Regurgitation (0-none, 1-occasional, 2-daily, 3-each meal). The value for each of the 4 categories is added together to give the EAS. This EAS will be reported for each time point below. A higher score is consistent with worse achalasia and worse outcomes. A lower score is consistent with less severe achalasia and better outcomes. The total range is 0 (no symptoms) to 12 (severe symptoms). There are no subscales.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18 years old < Age < 75 years old with prior diagnosis of achalasia via manometry and/or radiographically

Exclusion Criteria:

  • < 18 years old or > 75 years old
  • History of hypertension not controlled on oral medications (blood pressure > 160/100 mm Hg)
  • No prior history of hypertension with a blood pressure > 160/100 mm Hg
  • History of bladder outlet obstruction
  • History of angioedema
  • Pregnant or breast-feeding women: Women between 18 and 40 years old who are enrolled in the study will be required to use a form of birth control during the study
  • Patients currently receiving certain medications (digoxin, warfarin, any overactive bladder medications, thioridazine, flecainide, propafenone, phosphodiesterase inhibitors)
  • Patients with prolonged QTc interval or risk factors to develop it:

    • Baseline QTc on EKG of > 450 milliseconds
    • History of additional risk factors for Torsades de Pointes (heart failure, family history of long QT syndrome)
    • Concomitant medications that prolong the QTc interval: ranolazine, sotalol, dofetilide, procainamide, disopyramide, propafenone, azole antifungals, fluoroquinolones, macrolide antibiotics, HIV antiretrovirals, chemotherapy, beta-2 agonists, tricyclic antidepressants, selective serotonin reuptake inhibitors
  • Prior surgeries for achalasia
  • < 2 months since last endoscopic botulinum toxin injection into LES or endoscopic dilation
  • Stage 4 Chronic kidney disease (severe renal impairment with GFR 15-29 ml/min), Stage 5 Chronic Kidney disease (GFR < 15 ml/min or on dialysis)
  • Childs Pugh B (moderate) or C (severe) Cirrhotic (hepatic impairment)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03411252


Contacts
Contact: Cynthia Miller, RN 215-955-8108 cynthia.l.miller.3@jefferson.edu

Locations
United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Anthony J DiMarino, MD    215-955-2728    anthony.dimarino@jefferson.edu   
Contact: cynthia miller, RN    215.955.8108    cynthia.miller@jefferson.edu   
Principal Investigator: Anthony J DiMarino, MD         
Sub-Investigator: Sidney Cohen, MD         
Sponsors and Collaborators
Thomas Jefferson University
Astellas Pharma Inc

Responsible Party: Jeff GI, Dr Anthony J DiMarino, Chair, Division of Gastroenterology, Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT03411252     History of Changes
Other Study ID Numbers: 17P.054
First Posted: January 26, 2018    Key Record Dates
Last Update Posted: January 29, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Esophageal Achalasia
Esophageal Motility Disorders
Deglutition Disorders
Esophageal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Mirabegron
Adrenergic beta-3 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Urological Agents