Clinical trial NCT03411252: Mirabegron in Achalasia: A Clinical and Manometric Proof of Concept Pilot Study
Official title: Mirabegron in Achalasia: A Clinical and Manometric Proof of Concept Pilot Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Achalasia
Lead sponsor: Thomas Jefferson University
Sponsor class: OTHER
Collaborators: name: Astellas Pharma Inc
First posted: 2018-01-26
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility 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)

Primary outcomes:
measure: Changes in lower esophageal sphincter pressures
timeFrame: Change in lower esophageal sphincter pressure from baseline after 4 weeks of placebo or Mirabegron
Secondary outcomes:
measure: Eckardt Achalasia Score (EAS)
timeFrame: 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.
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
Study officials:
References: