Trial Outcomes & Findings for Trial of IW-3718 for 8 Weeks in Patients With Persistent Gastroesophageal Reflux Disease (GERD) Receiving Proton Pump Inhibitors (PPIs) (NCT NCT03561883)

Last Updated: 2021-08-18

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

COMPLETED

Study phase

PHASE3

Target enrollment

609 participants

Primary outcome timeframe

Baseline, Week 8

Results posted on

2021-08-18

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 + PPIs Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose proton pump inhibitors (PPIs) administered once-daily (QD) approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPIs 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	305	304
Overall Study COMPLETED	259	261
Overall Study NOT COMPLETED	46	43

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo BID + PPIs Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose proton pump inhibitors (PPIs) administered once-daily (QD) approximately 30-60 minutes before the morning meal each day.	1500 mg IW-3718 BID + PPIs 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	10	13
Overall Study Non-Compliance With Study Drug	1	2
Overall Study Protocol Violation	2	3
Overall Study Withdrawal by Subject	14	6
Overall Study Lost to Follow-up	2	6
Overall Study Study Terminated by Sponsor	12	11
Overall Study Physician Decision	1	0
Overall Study Randomized by Mistake	1	0
Overall Study Other, Not Specified	3	2

Baseline Characteristics

Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 05 June 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 + PPIs n=304 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 + PPIs n=304 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=608 Participants Total of all reporting groups
Age, Continuous	49.9 years STANDARD_DEVIATION 12.56 • n=304 Participants	48.7 years STANDARD_DEVIATION 12.61 • n=304 Participants	49.3 years STANDARD_DEVIATION 12.59 • n=608 Participants
Sex: Female, Male Female	186 Participants n=304 Participants	187 Participants n=304 Participants	373 Participants n=608 Participants
Sex: Female, Male Male	118 Participants n=304 Participants	117 Participants n=304 Participants	235 Participants n=608 Participants
Race/Ethnicity, Customized Hispanic or Latino	93 Participants n=304 Participants	107 Participants n=304 Participants	200 Participants n=608 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	208 Participants n=304 Participants	195 Participants n=304 Participants	403 Participants n=608 Participants
Race/Ethnicity, Customized Unknown	3 Participants n=304 Participants	0 Participants n=304 Participants	3 Participants n=608 Participants
Race/Ethnicity, Customized Not Reported	0 Participants n=304 Participants	2 Participants n=304 Participants	2 Participants n=608 Participants
Race/Ethnicity, Customized White	233 Participants n=304 Participants	246 Participants n=304 Participants	479 Participants n=608 Participants
Race/Ethnicity, Customized Black or African American	63 Participants n=304 Participants	49 Participants n=304 Participants	112 Participants n=608 Participants
Race/Ethnicity, Customized Asian	3 Participants n=304 Participants	5 Participants n=304 Participants	8 Participants n=608 Participants
Race/Ethnicity, Customized Other	5 Participants n=304 Participants	4 Participants n=304 Participants	9 Participants n=608 Participants
Erosive Esophagitis (EE) EE Present	66 Participants n=276 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	68 Participants n=277 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	134 Participants n=553 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.
Erosive Esophagitis (EE) EE Not Present	210 Participants n=276 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	209 Participants n=277 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	419 Participants n=553 Participants • Modified Intent-to-Treat (mITT) Population, which included all participants who 1) were randomized prior to or on 05 June 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 WHSS Score ≥ 3	195 Participants n=276 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	201 Participants n=277 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	396 Participants n=553 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 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 WHSS Score < 3	81 Participants n=276 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	76 Participants n=277 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	157 Participants n=553 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.
WHSS	3.32 score on a scale STANDARD_DEVIATION 0.73 • n=276 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	3.31 score on a scale STANDARD_DEVIATION 0.72 • n=277 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.	3.32 score on a scale STANDARD_DEVIATION 0.72 • n=553 Participants • mITT Population, which included all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.

PRIMARY outcome

Timeframe: Baseline, Week 8

Population: mITT Population: all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.

Outcome measures

Outcome measures
Measure	Placebo BID + PPIs n=276 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before morning meal each day.	1500 mg IW-3718 BID + PPIs n=277 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 morning meal each day.
Change From Baseline in WHSS at Week 8	-1.751 score on a scale Standard Error 0.081	-1.814 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 + PPIs n=276 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before morning meal each day.	1500 mg IW-3718 BID + PPIs n=277 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 morning meal each day.
Change From Baseline in Weekly Regurgitation Frequency Score (WRFS) at Week 8	-1.278 score on a scale Standard Error 0.065	-1.287 score on a scale Standard Error 0.065

SECONDARY outcome

Timeframe: Up to Week 8

Population: Modified Intent-to-Treat (mITT) Population: all participants who 1) were randomized prior to or on 05 June 2020, 2) had received at least 1 dose of study drug, and 3) had at least 1 postbaseline primary efficacy assessment.

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 + PPIs n=276 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before morning meal each day.	1500 mg IW-3718 BID + PPIs n=277 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 morning meal each day.
Percentage of Participants Who Were Overall Heartburn Responders During the 8-Week Treatment Period	41.3 percentage of participants	42.6 percentage of participants

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 + PPIs n=276 Participants Three placebo tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before morning meal each day.	1500 mg IW-3718 BID + PPIs n=277 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 morning meal each day.
Proportion of Heartburn-Free Days During the 8-Week Treatment Period	0.200 proportion of days Standard Error 0.030	0.234 proportion of days Standard Error 0.033

Adverse Events

Placebo BID + PPIs

Serious events: 3 serious events

Other events: 6 other events

Deaths: 1 deaths

1500 mg IW-3718 BID + PPIs

Serious events: 2 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo BID + PPIs n=304 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 morning meal each day.	1500 mg IW-3718 BID + PPIs n=304 participants at risk Three IW-3718 tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before morning meal each day.
Cardiac disorders Pulseless electrical activity	0.33% 1/304 • 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.	0.00% 0/304 • 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 Oesophageal stenosis	0.33% 1/304 • 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.	0.00% 0/304 • 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.
General disorders Non-cardiac chest pain	0.33% 1/304 • 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.	0.00% 0/304 • 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% 0/304 • 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.	0.33% 1/304 • 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	0.00% 0/304 • 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.	0.33% 1/304 • 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 Accidental overdose	0.33% 1/304 • 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.	0.00% 0/304 • 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/304 • 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.	0.33% 1/304 • 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.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/304 • 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.	0.33% 1/304 • 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 + PPIs n=304 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 morning meal each day.	1500 mg IW-3718 BID + PPIs n=304 participants at risk Three IW-3718 tablets administered BID immediately after the morning and evening meals. Standard-dose PPIs administered QD approximately 30-60 minutes before morning meal each day.
Gastrointestinal disorders Constipation	1.3% 4/304 • 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.	3.0% 9/304 • 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	0.66% 2/304 • 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.	2.6% 8/304 • 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