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

Early Phase 1

Terminated

• Conditions: Achalasia
• Interventions: Drug: Mirabegron 50 MG; Drug: Placebo

• Registration Number: NCT03411252
• Lead Sponsor: 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).

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 Timeline

• Study First Submitted: 2017-12-11
• Study First Submitted QC: 2018-01-18
• Study First Posted: 2018-01-26
• Study Start: 2018-02-15
• Primary Completion: 2019-12-15
• Study Completion: 2019-12-15
• Status Verified: 2021-03
• Last Update Submitted: 2021-03-22
• Last Update Posted: 2021-03-24

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 5

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Mirabegron	Mirabegron 50 MG	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.
Placebo	Mirabegron 50 MG	Patients will receive placebo by mouth daily for 4 weeks and then switch to oral Mirabegron 50 mg daily for an additional 4 weeks.
Placebo	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.
Mirabegron	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Changes in lower esophageal sphincter pressures	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

Name	Time	Method
Eckardt Achalasia Score (EAS)	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.

Trial Locations

Locations (1)

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States