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

Thomas Jefferson University

Status and phase: Terminated; Early Phase 1

Conditions: Achalasia

Treatments: Drug: Placebo; Drug: Mirabegron 50 MG

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03411252

17P.054

Details and patient eligibility

About

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).

Full 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.

Enrollment: 5 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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5 participants in 2 patient groups, including a placebo group

Mirabegron

Experimental group

Description:

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.

Treatment:

Drug: Mirabegron 50 MG

Drug: Placebo

Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Mirabegron 50 MG

Drug: Placebo