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

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.

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)