Esophageal Hypersensitivity Study in Patients With Gastroesophageal Reflux Disease (GERD)

A Phase IIa, Double-blind, Randomized, 2-way Cross-over Study to Evaluate the Effect of a Single Dose of AZD1386 95 mg Compared to Placebo in a Multimodal Experimental Pain Model on Esophageal Sensitivity in GERD Patients With a Partial Response to PPI Treatment

The purpose of the study is to compare sensitivity of visceral pain in the esophagus using different pain stimuli.

Study Overview

• Status: Completed
• Conditions: Sensitivity in Esophagus
• Intervention / Treatment: Drug: AZD1386; Drug: Placebo to AZD1386

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Århus C, Denmark
    • Research Site
• Sweden
  • Vastra Gotaland
    • Goteborg, Vastra Gotaland, Sweden
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of signed informed consent form
• BMI 18.5-35.0, inclusive
• Continuous PPI treatment for GERD during the last 4 weeks

Exclusion Criteria:

• Patients that have not experienced any GERD symptoms improvement at all after PPI treatment
• Unstable or clinically significant disorders including cardiovascular, respiratory, renal, hepatic, metabolic, psychiatric, other gastrointestinal and esophageal disorders besides GERD
• Prior surgery of the upper GI tract

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: First AZD1386, then washout, then placebo	Drug: AZD1386; 95 mg, oral solution, single dose; Drug: Placebo to AZD1386; Placebo, oral solution, single dose
Experimental: First placebo, then washout, then AZD1386	Drug: AZD1386; 95 mg, oral solution, single dose; Drug: Placebo to AZD1386; Placebo, oral solution, single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Visual Analogue Scale 7 (VAS7) During Thermal Stimulation at 1.5 Hours Post-Dose.	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES). Heat stimuli were applied by recirculation of heated water in the bag. Prior to recirculation the bag is filled with 7mL to ensure adequate mucosal contact. Water was heated up to a maximum of 63° C and the stimulation was continued until VAS 7 was reached. The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	1.5 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Visual Analogue Scale 7 (VAS7) During Thermal Stimulation at 0.5 Hours Post Dose	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES). Heat stimuli were applied by recirculation of heated water in the bag. Prior to recirculation the bag is filled with 7mL to ensure adequate mucosal contact. Water was heated up to a maximum of 63° C and the stimulation was continued until VAS 7 was reached. The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	0.5 hours post dose
Time to Visual Analogue Scale 7 (VAS7) During Thermal Stimulation at 2.5 Hours Post Dose	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES). Heat stimuli were applied by recirculation of heated water in the bag. Prior to recirculation the bag is filled with 7mL to ensure adequate mucosal contact. Water was heated up to a maximum of 63° C and the stimulation was continued until VAS 7 was reached. The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	2.5 hours post dose
Volume at Visual Analogue Scale 7 (VAS7) During Mechanical Stimulation at 0.5 Hours Post Dose	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES). Volume change in the bag was recorded continuously at each level of the visual analogue scale (VAS) and up to VAS7 (Volume at Visual Analogue Scale 7). The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	0.5 hours post dose
Volume at Visual Analogue Scale 7 (VAS7) During Mechanical Stimulation at 1.5 Hours Post-Dose	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES). Volume change in the bag was recorded continuously at each level of the visual analogue scale (VAS) and up to VAS7 (Volume at Visual Analogue Scale 7). The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	1.5 hours post dose
Volume at Visual Analogue Scale 7 (VAS7) During Mechanical Stimulation at 2.5 Hours Post-Dose.	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES). Volume change in the bag was recorded continuously at each level of the visual analogue scale (VAS) and up to VAS7 (Volume at Visual Analogue Scale 7). The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	2.5 hours post dose
Current at Visual Analogue Scale 7 (VAS7) During Electrical Stimulation 0.5 Hours Post Dose	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES) and stimulations were performed at approximately 8 cm above the LES. The intensity of the stimuli is increased steadily in steps of 0.5 to 1 mA and the intensity corresponding to the VAS levels 1, 3, 5 and 7 were recorded. The current will be increased until the patient report moderate pain (VAS 7) or max 80 mA. The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	0.5 hours post dose
Current at Visual Analogue Scale 7 (VAS7) During Electrical Stimulation at 1.5 Hours Post Dose	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES) and stimulations were performed at approximately 8 cm above the LES. The intensity of the stimuli is increased steadily in steps of 0.5 to 1 mA and the intensity corresponding to the VAS levels 1, 3, 5 and 7 were recorded. The current will be increased until the patient report moderate pain (VAS 7) or max 80 mA. The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	1.5 hours post dose
Current at Visual Analogue Scale 7 (VAS7) During Electrical Stimulation at 2.5 Hours Post Dose	A probe (bag) was inserted 7cm above the lower esophageal sphincter (LES) and stimulations were performed at approximately 8 cm above the LES. The intensity of the stimuli is increased steadily in steps of 0.5 to 1 mA and the intensity corresponding to the VAS levels 1, 3, 5 and 7 were recorded. The current will be increased until the patient report moderate pain (VAS 7) or max 80 mA. The intensities of the non-painful sensations were scored with the following descriptors added to facilitate the scoring: = vague perception of mild sensation; = definite perception of mild sensation; = vague perception of moderate sensation; = definite perception of moderate sensationFor painful sensations the patients will use the scale from 5-10 anchored at:; = pain detection; = slight pain; = moderate pain; = medium pain intensity; = intense pain; = unbearable pain	2.5 hours post dose
AUCt	Area under the plasma concentration curve from time zero to the last quantifiable concentration	0 to 4 hours post dose
Cmax	Maximum plasma concentration	0 to 4 hours post dose
Tmax	Time of maximum plasma concentration	0 to 4 hours post dose
SBP	Supine Systolic Blood Pressure at 1.5 hours post dose	1.5 hours post dose
DBP	Supine Diastolic Blood Pressure at 1.5 hours post dose	1.5 hours post dose
Pulse	Supine Pulse at 1.5 hours post dose	1.5 hours post dose
QTcF	QT interval corrected for heart rate using Fredericia formula(QTcF) at 1.5 hours post dose	1.5 hours post dose
Body Temperature	Oral Body Temperature at 1.5 hours post dose	1.5 hours post dose
Clinically Relevant Change of Laboratory Variables	Number of participants with clinically relevant change of laboratory variables(clinical chemistry, haematology and urinalysis parameters)	Pre-entry to follow-up

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Marie Sundin, AstraZeneca R&D, Mölndal, Sweden; Principal Investigator: Peter Funch-Jensen,, MD, PhD, Aarhus Hospital, Dept of Surgical Gastroenterology, Aarhus, Denmark

Publications and helpful links

General Publications

• Krarup AL, Ny L, Gunnarsson J, Hvid-Jensen F, Zetterstrand S, Simren M, Funch-Jensen P, Hansen MB, Drewes AM. Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain. Scand J Gastroenterol. 2013 Mar;48(3):274-84. doi: 10.3109/00365521.2012.758769. Epub 2013 Jan 16.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: November 20, 2009
• First Submitted That Met QC Criteria: November 24, 2009
• First Posted (Estimate): November 25, 2009

Study Record Updates

• Last Update Posted (Estimate): November 9, 2012
• Last Update Submitted That Met QC Criteria: October 10, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: pain; GERD; patient; esophagus
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity
• Other Study ID Numbers: D9127C00002; 2008-007420-26