A Trial of IW-3718 for 8 Weeks in Patients With Symptomatic Gastroesophageal Reflux Disease (GERD)

A Phase 2b, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-range-finding Trial of IW-3718 Administered Orally for 8 Weeks to Patients With Symptomatic Gastroesophageal Reflux Disease Not Completely Responsive to Proton Pump Inhibitors

The objectives of this study are to evaluate the safety, efficacy, and dose-response relationship of IW-3718 administered orally to participants who have GERD and continue to experience GERD symptoms while receiving once-daily (QD), standard-dose proton pump inhibitors (PPIs).

Study Overview

• Status: Completed
• Conditions: Gastroesophageal Reflux Disease
• Intervention / Treatment: Drug: Matching Placebo; Drug: IW-3718; Drug: PPI

• Study Type: Interventional
• Enrollment (Actual): 282
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Dothan, Alabama, United States, 36305
      • IW-3718 Investigator
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • IW-3718 Investigator
    • Tucson, Arizona, United States, 85710
      • IW-3718 Investigator
    • Tucson, Arizona, United States, 85712
      • IW-3718 Investigator
    • Tucson, Arizona, United States, 85741
      • IW-3718 Investigator
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • IW-3718 Investigator
  • California
    • Anaheim, California, United States, 92801
      • IW-3718 Investigator
    • Carmichael, California, United States, 95608
      • IW-3718 Investigator
    • Chula Vista, California, United States, 91910
      • IW-3718 Investigator
    • La Mirada, California, United States, 90638
      • IW-3718 Investigator
    • Mission Hills, California, United States, 91345
      • IW-3718 Investigator
    • Newport Beach, California, United States, 92660
      • IW-3718 Investigator
    • Oakland, California, United States, 94612
      • IW-3718 Investigator
    • Sacramento, California, United States, 95821
      • IW-3718 Investigator
    • San Diego, California, United States, 92123
      • IW-3718 Investigator
  • Connecticut
    • Bristol, Connecticut, United States, 06010
      • IW-3718 Investigator
    • Waterbury, Connecticut, United States, 06708
      • IW-3718 Investigator
  • Florida
    • DeLand, Florida, United States, 32720
      • IW-3718 Investigator
    • Hollywood, Florida, United States, 33024
      • IW-3718 Investigator
    • Inverness, Florida, United States, 34452
      • IW-3718 Investigator
    • Jupiter, Florida, United States, 33458
      • IW-3718 Investigator
    • Lauderdale Lakes, Florida, United States, 33319
      • IW-3718 Investigator
    • Miami, Florida, United States, 33126
      • IW-3718 Investigator
    • Miami, Florida, United States, 33135
      • IW-3718 Investigator
    • Miami Lakes, Florida, United States, 33014
      • IW-3718 Investigator
    • Port Orange, Florida, United States, 32129
      • IW-3718 Investigator
  • Iowa
    • Clive, Iowa, United States, 50325
      • IW-3718 Investigator
  • Kentucky
    • Bowling Green, Kentucky, United States, 42101
      • IW-3718 Investigator
  • Louisiana
    • Monroe, Louisiana, United States, 71201
      • IW-3718 Investigator
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • IW-3718 Investigator
    • Baltimore, Maryland, United States, 21215
      • IW-3718 Investigator
    • Chevy Chase, Maryland, United States, 20815
      • IW-3718 Investigator
  • Michigan
    • Chesterfield, Michigan, United States, 48047
      • IW-3718 Investigator
    • Wyoming, Michigan, United States, 49519
      • IW-3718 Investigator
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • IW-3718 Investigator
    • Reno, Nevada, United States, 89511
      • IW-3718 Investigator
  • New Jersey
    • Egg Harbor Township, New Jersey, United States, 08234
      • IW-3718 Investigator
  • New York
    • Great Neck, New York, United States, 11021
      • IW-3718 Investigator
    • Great Neck, New York, United States, 11023
      • IW-3718 Investigator
    • Kew Gardens, New York, United States, 11415
      • IW-3718 Investigator
    • New York, New York, United States, 10065
      • IW-3718 Investigator
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • IW-3718 Investigator
    • Raleigh, North Carolina, United States, 27612
      • IW-3718 Investigator
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • IW-3718 Investigator
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • IW-3718 Investigator
    • Columbus, Ohio, United States, 43213
      • IW-3718 Investigator
    • Lima, Ohio, United States, 45806
      • IW-3718 Investigator
  • Oklahoma
    • Norman, Oklahoma, United States, 73071
      • IW-3718 Investigator
    • Oklahoma City, Oklahoma, United States, 73104
      • IW-3718 Investigator
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15243
      • IW-3718 Investigator
  • South Carolina
    • Charleston, South Carolina, United States, 29412
      • IW-3718 Investigator
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • IW-3718 Investigator
    • Germantown, Tennessee, United States, 38138
      • IW-3718 Investigator
    • Nashville, Tennessee, United States, 37232
      • IW-3718 Investigator
  • Texas
    • El Paso, Texas, United States, 79905
      • IW-3718 Investigator
    • Houston, Texas, United States, 77098
      • IW-3718 Investigator
    • San Antonio, Texas, United States, 78209
      • IW-3718 Investigator
    • San Antonio, Texas, United States, 78229
      • IW-3718 Investigator
  • Utah
    • Sandy, Utah, United States, 84092
      • IW-3718 Investigator
    • South Ogden, Utah, United States, 84405
      • IW-3718 Investigator
  • Virginia
    • Christiansburg, Virginia, United States, 24073
      • IW-3718 Investigator
    • Lynchburg, Virginia, United States, 24502
      • IW-3718 Investigator

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient is an ambulatory, community-dwelling male or nonpregnant female and is at least 18 years old at the Screening Visit. Lactating females must agree not to breastfeed.
• Patient has a diagnosis of GERD and reports experiencing GERD symptoms (heartburn or regurgitation) on ≥ 4 days per week during the 8 weeks before the Screening Visit while taking standard QD PPI therapy.

Exclusion Criteria:

• Patient may not meet any of the excluded conditions specified in the protocol
• Patient has any alarm symptoms including but not limited to GI bleeding, anemia, vomiting, dysphagia, or unexpected weight loss any time during the Screening or Pretreatment Periods
• Patient has a history of clinically significant hypersensitivity or allergies to any of the excipients contained in the study medication (active or placebo).

NOTE: Additional inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Control; Matching placebo twice daily	Drug: Matching Placebo; Drug: PPI; All participants were taking a standard dose QD PPI (dexlansoprazole, esomeprazole, esomeprazole magnesium, lansoprazole, omeprazole, pantoprazole, pantoprazole sodium sesquihydrate, rabeprazole or rabeprazole sodium) during the study.
EXPERIMENTAL: 500 mg IW-3718; 500 mg IW-3718 twice daily	Drug: IW-3718; Drug: PPI; All participants were taking a standard dose QD PPI (dexlansoprazole, esomeprazole, esomeprazole magnesium, lansoprazole, omeprazole, pantoprazole, pantoprazole sodium sesquihydrate, rabeprazole or rabeprazole sodium) during the study.
EXPERIMENTAL: 1000 mg IW-3718; 1000 mg IW-3718 twice daily	Drug: IW-3718; Drug: PPI; All participants were taking a standard dose QD PPI (dexlansoprazole, esomeprazole, esomeprazole magnesium, lansoprazole, omeprazole, pantoprazole, pantoprazole sodium sesquihydrate, rabeprazole or rabeprazole sodium) during the study.
EXPERIMENTAL: 1500 mg IW-3718; 1500 mg IW-3718 twice daily	Drug: IW-3718; Drug: PPI; All participants were taking a standard dose QD PPI (dexlansoprazole, esomeprazole, esomeprazole magnesium, lansoprazole, omeprazole, pantoprazole, pantoprazole sodium sesquihydrate, rabeprazole or rabeprazole sodium) during the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to Week 8 in Weekly Heartburn Severity Score (WHSS)	The WHSS for an analysis week was defined as the average of available DHSS during that week. DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day. A negative change from Baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to Week 4 in WHSS	The WHSS for an analysis week was defined as the average of available DHSS during that week. DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day. A negative change from Baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Week 4
Change From Baseline to Week 8 in WHSS	The WHSS for an analysis week was defined as the average of available DHSS during that week. DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day. A negative change from Baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Week 8
Change From Baseline to Week 4 in WHSS	The WHSS for an analysis week was defined as the average of available DHSS during that week. DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day. A negative change from Baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Week 4
Percentage of Participants Who Are Overall Heartburn Responders	An overall heartburn responder is a participant who is a weekly heartburn responder for at least 4 of the 8 treatment weeks and for at least 1 of the final 2 treatment weeks (i.e., Week 7 and Week 8). A weekly heartburn responder is a participant with a decrease of >= 30% from baseline in WHSS (see Outcome Measure 1 for description of WHSS). A participant who reported heartburn severity for less than 4 days during a week was not considered a responder for that week.	Week 8
Percentage of Participants With a DHSS of No More Than Very Mild (≤ 1) on Any Day During Week 8	DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day. A participant who reported heartburn severity for less than 4 days during a week was not considered a responder for that week.	Week 8
Percentage of Participants With a DHSS of No More Than Very Mild (≤ 1) on Any Day During Week 4	DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day. A participant who reported heartburn severity for less than 4 days during a week was not considered a responder for that week.	Week 4
Change From Baseline in the Number of Days Where DHSS Was No More Than Very Mild (≤ 1) During Week 8	DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day.	Week 8
Change From Baseline in the Number of Days Where DHSS Was No More Than Very Mild (≤ 1) During Week 4	DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day.	Week 4
Change From Baseline Over Time in the Weekly Average of Modified Reflux Symptom Questionnaire - Electronic Diary (mRESQ-eD) Item 'Heartburn Severity'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the severity of their heartburn over the past 24 hours on a 6-point scale: 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe. Daily scores were averaged each week. A negative change from Baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the Weekly Average of mRESQ-eD Item 'Burning Feeling Behind Breastbone or Center of Upper Stomach Severity'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the severity of their burning feeling behind the breastbone or in the center of the upper stomach over the past 24 hours on a 6-point scale: 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Pain Behind Breastbone or Center of Upper Stomach Severity'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the severity of their pain behind the breastbone or in the center of the upper stomach over the past 24 hours on a 6-point scale: 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Difficulty Swallowing Severity'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the severity of their difficulty swallowing over the past 24 hours on a 6-point scale: 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Hoarseness Severity'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the severity of their hoarseness over the past 24 hours on a 6-point scale: 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Cough Severity'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the severity of their cough over the past 24 hours on a 6-point scale: 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Regurgitation Frequency'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the frequency of their regurgitation (liquid or food moving upwards towards the throat or mouth) over the past 24 hours on a 5-point scale: 0=Never, 1= Rarely, 2=Sometimes, 3=Often, 4=Very often. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Acid or Bitter Taste Frequency'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the frequency of an acid or bitter taste in the mouth over the past 24 hours on a 5-point scale: 0=Never, 1= Rarely, 2=Sometimes, 3=Often, 4=Very often. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Coughing Frequency'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the frequency of their cough over the past 24 hours on a 5-point scale: 0=Never, 1= Rarely, 2=Sometimes, 3=Often, 4=Very often. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline Over Time in the mRESQ-eD Item 'Burping Frequency'	The mRESQ-eD questionnaire assesses the severity and frequency of the symptoms participants experience due to reflux disease. Participants were asked to rate the frequency of their burping over the past 24 hours on a 5-point scale: 0=Never, 1= Rarely, 2=Sometimes, 3=Often, 4=Very often. Daily scores were averaged each week. A negative change from baseline indicates improvement.	Baseline (derived from the eDiary daily data collected from 7 days before randomization up to the time of randomization), Weeks 1, 2, 3, 4, 5, 6, 7, 8
Change From Baseline in the Proportion of Heartburn-Free Days During Week 8	A heartburn free day was a day where DHSS = 0. DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day.	Week 8
Change From Baseline in the Proportion of Heartburn-Free Days During Week 4	A heartburn free day was a day where DHSS = 0. DHSS was defined as the maximum on a 6-point scale (0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) of the 3 items measuring heartburn ( "Heartburn," "Burning feeling behind breastbone or in the center of the upper stomach," and "Pain behind breastbone or in the center of the upper stomach,") from a particular day.	Week 4

Collaborators and Investigators

• Sponsor: Ironwood Pharmaceuticals, Inc.
• Investigators: Study Director: Lara Lane, Ironwood Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Vaezi MF, Fass R, Vakil N, Reasner DS, Mittleman RS, Hall M, Shao JZ, Chen Y, Lane L, Gates AM, Currie MG. IW-3718 Reduces Heartburn Severity in Patients With Refractory Gastroesophageal Reflux Disease in a Randomized Trial. Gastroenterology. 2020 Jun;158(8):2093-2103. doi: 10.1053/j.gastro.2020.02.031. Epub 2020 Feb 22.
• Andrae DA, Hanlon J, Cala ML, Scippa K, Graham C, Witherspoon B, Shao JZ, Reasner D. Evaluation and Validation of the Modified Reflux Symptom Questionnaire-Electronic Diary in Patients With Persistent Gastroesophageal Reflux Disease. Clin Transl Gastroenterol. 2020 Jan;11(1):e00117. doi: 10.14309/ctg.0000000000000117.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2016
• Primary Completion (ACTUAL): April 26, 2017
• Study Completion (ACTUAL): April 26, 2017

Study Registration Dates

• First Submitted: December 16, 2015
• First Submitted That Met QC Criteria: December 18, 2015
• First Posted (ESTIMATE): December 22, 2015

Study Record Updates

• Last Update Posted (ACTUAL): October 15, 2019
• Last Update Submitted That Met QC Criteria: October 14, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Gastroenteritis; Intestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Esophagitis; Peptic Ulcer; Duodenal Diseases; Gastroesophageal Reflux; Esophagitis, Peptic
• Other Study ID Numbers: ICP-3718-202