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Do Acid Sensing Ion Channels Contribute to Heartburn?

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ClinicalTrials.gov Identifier: NCT01095133
Recruitment Status : Completed
First Posted : March 30, 2010
Last Update Posted : September 20, 2012
Sponsor:
Information provided by (Responsible Party):
Roy Orlando, MD, University of North Carolina, Chapel Hill

Brief Summary:
The purpose of this research study is to learn about whether treating the esophagus with amiloride reduces either the frequency or the time to onset of acid-induced heartburn in patients with nonerosive reflux disease. In particular, we are looking at people who have either had complete relief while using a Proton Pump Inhibitor (PPI) or who have only had some relief of symptoms while on a PPI.

Condition or disease Intervention/treatment Phase
Gastroesophageal Reflux Disease Heartburn Drug: Amiloride Drug: Placebo Phase 1

Detailed Description:

It is now well established that patients with gastroesophageal reflux disease - both erosive and non-erosive forms - have on esophageal biopsy a lesion in esophageal stratified squamous epithelium known as 'dilated intercellular spaces (DIS). This lesion has importance because it reflects an increase in paracellular permeability due to acid damage to the tight junctions [1]. Moreover, the increase in paracellular permeability in non-eroded esophageal epithelium provides a plausible explanation for why heartburn occurs during episodes of acid reflux (or esophageal acid perfusion) in those with nonerosive reflux disease (NERD) but not in healthy subjects, and that is because luminal acid is now able to diffuse between cells in quantities sufficient to acidify the intercellular space [2]. Further, the lowering of intercellular pH is the likely trigger for heartburn by its ability to stimulate pain-sensing neurons (nociceptors) within the esophageal mucosa; with the signal from these neurons being transmitted to the CNS for heartburn perception. Clinical and experimental evidence support these concepts in that antacid ingestion relieves and proton pump inhibitors (PPIs) prevent heartburn in most patients and when PPIs control heartburn, they also lead to resolution of DIS in squamous epithelium [3]. Moreover, it is increasingly likely that many NERD patients classified as PPI-partial responders develop heartburn through the same mechanism as PPI-complete responders with NERD. This is because PPIs only raise gastric pH to ~pH 5, and even such 'weakly-acidic' refluxates have been shown to be associated with heartburn [4]. The reason for this is that in the presence of a broken epithelial barrier, weakly acidic refluxates are still able to acidify the intercellular space to levels sufficient to activate the nociceptors - the latter the case since the nociceptors can be activated even at pHs as modestly acidic as pH 6.0-pH 7.0 (see below).

The esophageal mucosa has two nociceptors that are candidates to mediate heartburn in NERD. These are: a) a capsaicin-sensitive, transient receptor potential vanilloid receptor (TRPV)-1, and b) an amiloride-inhibitable, acid-sensing ion channel (ASIC), subtype 2. Both nociceptor types innervate the esophageal mucosa and are activated by small declines in environmental (intercellular) pH [5,6]. Recently, a role for TRPV-1 was sought in the causation of heartburn during esophageal acid perfusion [7]. This was done by perfusing the esophagus with capsaicin in quantities presumed sufficient to desensitize TRPV-1 and then perfusing with acid to see if it blocked heartburn. The results, however, were negative in that acid still elicited heartburn. From this, one can conclude that heartburn is either not mediated by TRPV-1 or that capsaicin failed to adequately desensitize TRPV-1. We propose to test the hypothesis that capsaicin's failure to block heartburn in these subjects was because the actual nociceptors mediating heartburn are mucosal ASICs rather than TRPV-1. The hypothesis will be tested in a double-blind crossover study designed to determine if esophagal perfusion with the ASIC-inhibitor, amiloride, can block heartburn elicited by acid-perfusion in PPI-complete responders and PPI-partial responders with NERD [8]. The expectation is that, when compared to placebo, amiloride, which readily diffuses across intact esophageal epithelium, will reduce the frequency and both prolong the onset and reduce the severity of heartburn elicitable by esophageal acid perfusion. Such an outcome would provide support for mucosal ASICs, rather than TRPV-1, as mediator of heartburn in NERD, and raise interest in ASICs as a potential therapeutic target for that subset with NERD that are PPI-partial responders.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Do Acid Sensing Ion Channels (ASICs) Contribute to Heartburn in Proton Pump Inhibitor (PPI)-Complete Responders or PPI-Partial Responders With Nonerosive Reflux Disease (NERD)?
Study Start Date : March 2010
Actual Primary Completion Date : September 2011
Actual Study Completion Date : September 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: GERD Heartburn

Arm Intervention/treatment
Experimental: Amiloride Drug: Amiloride
dosage form: intraesophageal amiloride infusion dosage: liquid 1 mM amiloride concentration duration: 5 minute infusion given once frequency: 1 time
Other Name: Midamor

Placebo Comparator: Placebo Drug: Amiloride
dosage form: intraesophageal amiloride infusion dosage: liquid 1 mM amiloride concentration duration: 5 minute infusion given once frequency: 1 time
Other Name: Midamor

Drug: Placebo
dosage form: intraesophageal saline infusion dosage: normal Saline (0.91% w/v of NaCl) duration: 5 minutes given once frequency: 1 time




Primary Outcome Measures :
  1. Bernstein test to measure Initial Onset of Heartburn Symptoms [ Time Frame: 15 minutes after start of Bernstein test ]
    Subjects have esophageal perfusion with active agent or placebo followed by esophageal perfusion with HCl until heartburn occurs or 15 min is reached without heartburn. Time to onset of heartburn is compared for each arm of the study. There is no months or years issue here. It is an acute study with a time frame of minutes to heartburn during acid perfusion. The study begins and ends with the acid perfusion test, there is durable treatment other than two five minute perfusions of the esophagus with placebo or active drug.


Secondary Outcome Measures :
  1. Bernstein test to measure onset of Heartburn Symptoms after receipt of medication or placebo [ Time Frame: 35 Minutes after start of first Bernstein test ]
    The patient has esophageal perfusion with active agent or placebo and each followed by perfusion of the esophagus with HCl until heartburn occurs or 15 min occurs without heartburn. The severity of heartburn after its onset is compared for the two arms of the study.



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Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults, 18-59 years old
  • moderate heartburn at least 3 days/week
  • males and non-pregnant/non-lactating females
  • Complete relief while using a PPI or only some relief of symptoms while on a PPI

Exclusion Criteria:

  • erosive esophagitis
  • unable or unwilling to undergo endoscopy and biopsy or Bernstein testing
  • eosinophilic esophagitis
  • negative Bernstein test
  • known hypersensitivity to amiloride
  • renal disease
  • diabetes
  • hypotension
  • electrolyte imbalance
  • contraindication to diuretics, including taking lithium or ACE inhibitors. -history of gastric or esophageal surgery
  • history of ZE syndrome
  • bleeding disorder
  • UGI bleeding
  • esophageal motor disorder
  • esophageal stricture
  • Barrett's esophagus
  • UGI malignancy
  • esophageal varices
  • subjects with current malabsorption
  • inflammatory bowel disease
  • severe heart-lung-liver-renal-cerebrovascular disease
  • subjects post-transplant
  • diabetes
  • actively taking the following medications: tricyclic antidepressants, quinidine, quinine, dilantin, warfarin, narcotic analgesics, antineoplastic agents, salicylates (except a baby aspirin for cardiovascular protection); steroids, NSAIDs (including COX-2 inhibitors), KCl, anti-tuberculosis medication, bisphosphonates, and triamterene, cyclosporine, tacrolimus, and other potassium sparing drugs like spironolactone
  • serum potassium of 5.5 mEq/L or higher

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): NCT01095133


Locations
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United States, North Carolina
The Clinical and Translational Research Center
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Investigators
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Principal Investigator: Roy Orlando, MD University of North Carolina, Chapel Hill

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Responsible Party: Roy Orlando, MD, M.D., University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01095133     History of Changes
Other Study ID Numbers: 09-0289
First Posted: March 30, 2010    Key Record Dates
Last Update Posted: September 20, 2012
Last Verified: September 2012

Keywords provided by Roy Orlando, MD, University of North Carolina, Chapel Hill:
Gastroesophageal reflux disease
Heartburn

Additional relevant MeSH terms:
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Gastroesophageal Reflux
Esophagitis, Peptic
Heartburn
Esophageal Motility Disorders
Deglutition Disorders
Esophageal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Esophagitis
Gastroenteritis
Peptic Ulcer
Duodenal Diseases
Intestinal Diseases
Stomach Diseases
Signs and Symptoms, Digestive
Signs and Symptoms
Amiloride
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Acid Sensing Ion Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Epithelial Sodium Channel Blockers
Diuretics, Potassium Sparing