Trial Outcomes & Findings for A Trial of IW-3718 for 8 Weeks in Patients With Persistent Gastroesophageal Reflux Disease (GERD) Receiving Proton Pump Inhibitors (PPIs) (NCT NCT03561090)

Last Updated: 2021-08-19

Results Overview

The WHSS is defined as the weekly average of the DHSS. The DHSS for a day is the greater of the 2 items assessing heartburn severity (Item #1 "Burning feeling behind the breastbone or in the center of the upper stomach" and Item #2 "Pain behind the breastbone or in the center of the upper stomach"). The DHSS items are assessed on a 5-point ordinal scale, where 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, and 5=Severe; higher scores indicate worse symptoms. A negative change from baseline indicates improvement.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

495 participants

Primary outcome timeframe

Baseline, Week 8

Results posted on

2021-08-19

Participant Flow

After the screening and pre-treatment periods, participants were stratified by whether they had/did not have erosive esophagitis (EE) on esophagogastroduodenoscopy (EGD), and by their baseline weekly heartburn severity score (WHSS, defined as the average heartburn severity score over the last 7 days prior to randomization of \< 3 vs. ≥ 3), and were randomly assigned 1:1 within each stratum to placebo or 1500 mg IW-3718 twice daily (BID).

Participant milestones

Participant milestones
Measure	Placebo BID + PPI Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose proton pump inhibitors (PPIs) administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI Three 500 mg IW-3718 tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Overall Study STARTED	247	248
Overall Study Randomized and Treated	246	247
Overall Study COMPLETED	207	212
Overall Study NOT COMPLETED	40	36

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo BID + PPI Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose proton pump inhibitors (PPIs) administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI Three 500 mg IW-3718 tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Overall Study Adverse Event	11	7
Overall Study Non-Compliance With Study Drug	2	0
Overall Study Protocol Violation	2	2
Overall Study Withdrawal by Subject	7	7
Overall Study Lost to Follow-up	7	2
Overall Study Study Terminated by Sponsor	10	15
Overall Study Randomized by Mistake	1	1
Overall Study Other Not Specified	0	2

Baseline Characteristics

Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo BID + PPI n=246 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI n=247 Participants Three 500 mg IW-3718 tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	Total n=493 Participants Total of all reporting groups
Age, Continuous	47.2 years STANDARD_DEVIATION 13.17 • n=246 Participants	48.1 years STANDARD_DEVIATION 12.61 • n=247 Participants	47.6 years STANDARD_DEVIATION 12.89 • n=493 Participants
Sex: Female, Male Female	164 Participants n=246 Participants	145 Participants n=247 Participants	309 Participants n=493 Participants
Sex: Female, Male Male	82 Participants n=246 Participants	102 Participants n=247 Participants	184 Participants n=493 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	52 Participants n=246 Participants	55 Participants n=247 Participants	107 Participants n=493 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	187 Participants n=246 Participants	188 Participants n=247 Participants	375 Participants n=493 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	7 Participants n=246 Participants	4 Participants n=247 Participants	11 Participants n=493 Participants
Race/Ethnicity, Customized White	201 Participants n=246 Participants	203 Participants n=247 Participants	404 Participants n=493 Participants
Race/Ethnicity, Customized Black or African American	32 Participants n=246 Participants	33 Participants n=247 Participants	65 Participants n=493 Participants
Race/Ethnicity, Customized Asian	10 Participants n=246 Participants	6 Participants n=247 Participants	16 Participants n=493 Participants
Race/Ethnicity, Customized Other, Not Specified	3 Participants n=246 Participants	5 Participants n=247 Participants	8 Participants n=493 Participants
Erosive Esophagitis (EE) Status, as Randomized EE Present	101 Participants n=228 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	103 Participants n=227 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	204 Participants n=455 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.
Erosive Esophagitis (EE) Status, as Randomized EE Not Present	127 Participants n=228 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	124 Participants n=227 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	251 Participants n=455 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.
Weekly Heartburn Severity Score (WHSS) Category, as Randomized WHSS Score >/= 3	136 Participants n=228 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	140 Participants n=227 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	276 Participants n=455 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.
Weekly Heartburn Severity Score (WHSS) Category, as Randomized WHSS Score < 3	92 Participants n=228 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	87 Participants n=227 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	179 Participants n=455 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 04 August 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.
WHSS	3.17 score on a scale STANDARD_DEVIATION 0.66 • n=228 Participants • mITT Population: participants who were randomized prior to or on 04 August 2020, and who received at least 1 dose of study drug and had at least 1 postbaseline primary efficacy assessment.	3.25 score on a scale STANDARD_DEVIATION 0.79 • n=227 Participants • mITT Population: participants who were randomized prior to or on 04 August 2020, and who received at least 1 dose of study drug and had at least 1 postbaseline primary efficacy assessment.	3.21 score on a scale STANDARD_DEVIATION 0.73 • n=455 Participants • mITT Population: participants who were randomized prior to or on 04 August 2020, and who received at least 1 dose of study drug and had at least 1 postbaseline primary efficacy assessment.

PRIMARY outcome

Timeframe: Baseline, Week 8

Population: mITT Population: participants who were randomized prior to or on 04 August 2020, and who received at least 1 dose of study drug and had at least 1 postbaseline primary efficacy assessment.

Outcome measures

Outcome measures
Measure	Placebo BID + PPI n=228 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI n=227 Participants Three 500 mg IW-3718 tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Change From Baseline in WHSS at Week 8	-1.774 score on a scale Standard Error 0.082	-1.719 score on a scale Standard Error 0.082

SECONDARY outcome

Timeframe: Baseline, Week 8

The WRFS is defined as the average of available daily regurgitation frequency scores (DRFS) during a week. DRFS is defined as the maximum score of the 2 items measuring regurgitation from a particular day (Item #6 "Regurgitation \[liquid or food moving upwards toward your throat or mouth\]" and Item #7 "An acid or bitter taste in the mouth"). The DRFS items are assessed on a 4-point ordinal scale, where 0=Never, 1=Rarely, 2-Sometimes, 3=Often, and 4=Very Often; higher scores indicate worse symptoms. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo BID + PPI n=228 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI n=227 Participants Three 500 mg IW-3718 tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Change From Baseline in Weekly Regurgitation Frequency Score (WRFS) at Week 8	-1.330 score on a scale Standard Error 0.067	-1.294 score on a scale Standard Error 0.068

SECONDARY outcome

Timeframe: Up to Week 8

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 \>/= 45% from baseline in WHSS. A participant who reported heartburn severity for less than 4 days during a week is not considered a responder for that week. The WHSS is defined as the weekly average of the DHSS. The DHSS for a day is the greater of the 2 items assessing heartburn severity (Item #1 "Burning feeling behind the breastbone or in the center of the upper stomach" and Item #2 "Pain behind the breastbone or in the center of the upper stomach"). The DHSS items are assessed on a 5-point ordinal scale, where 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, and 5=Severe; higher scores indicate worse symptoms. A negative change from baseline indicates improvement

Outcome measures

Outcome measures
Measure	Placebo BID + PPI n=228 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI n=227 Participants Three 500 mg IW-3718 tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Percentage of Participants Who Were Overall Heartburn Responders During the 8-Week Treatment Period	53.1 percentage of participants Interval 46.4 to 59.7	47.6 percentage of participants Interval 40.9 to 54.3

SECONDARY outcome

Timeframe: Up to Week 8

Proportion of heartburn-free days is calculated as the number of heartburn-free (DHSS=0) days divided by the number of diary entry days. The DHSS for a day is the greater of the 2 items assessing heartburn severity (Item #1 "Burning feeling behind the breastbone or in the center of the upper stomach" and Item #2 "Pain behind the breastbone or in the center of the upper stomach"). The DHSS items are assessed on a 5-point ordinal scale, where 0=Did Not Have, 1=Very Mild, 2=Mild, 3=Moderate, 4=Moderately Severe, and 5=Severe; higher scores indicate worse symptoms. A negative change from baseline indicates improvement

Outcome measures

Outcome measures
Measure	Placebo BID + PPI n=228 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI n=227 Participants Three 500 mg IW-3718 tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Proportion of Heartburn-Free Days During the 8-Week Treatment Period	0.232 proportion of days Standard Error 0.032	0.218 proportion of days Standard Error 0.031

Adverse Events

Placebo BID + PPI

Serious events: 0 serious events

Other events: 37 other events

Deaths: 0 deaths

1500 mg IW-3718 BID + PPI

Serious events: 3 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo BID + PPI n=246 participants at risk Three placebo tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI n=247 participants at risk Three 1500 mg IW-3718 tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Hepatobiliary disorders Cholecystitis	0.00% 0/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	0.40% 1/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Infections and infestations COVID-19	0.00% 0/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	0.40% 1/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Carbon monoxide poisoning	0.00% 0/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	0.40% 1/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.

Other adverse events

Other adverse events
Measure	Placebo BID + PPI n=246 participants at risk Three placebo tablets administered BID, immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPI n=247 participants at risk Three 1500 mg IW-3718 tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before the morning meal each day.
Gastrointestinal disorders Flatulence	4.1% 10/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	3.6% 9/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	6.9% 17/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	3.2% 8/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Gastrointestinal disorders Constipation	1.2% 3/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	2.4% 6/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	2.4% 6/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	2.4% 6/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	0.81% 2/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	2.0% 5/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Infections and infestations Upper respiratory tract infection	0.41% 1/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	3.2% 8/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Infections and infestations Nasopharyngitis	0.81% 2/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	2.0% 5/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	0.81% 2/246 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.	2.0% 5/247 • From first dose of study drug through the end of treatment (up to Week 8) plus 7 days. Safety Population: Participants who received at least 1 dose of study drug.

Additional Information

Ironwood Study Chair

Ironwood Pharmaceuticals, Inc.

Phone: (617) 621-7722

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI may publish or disclose the results of the study 24 months after final data lock provided that sponsor can review the publication prior to public release, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request a publication delay in order to protect potentially patentable information. Furthermore, if a publication committee is developing an initial publication, PI is to delay disclosure until that publication is published.
Publication restrictions are in place

Restriction type: OTHER