Gastroesophageal Reflux Disease (GERD)
Conditions
Keywords
Gastroesophageal Reflux Disease, GERD, Proton Pump Inhibitors, IW-3718
Brief summary
The objective of this study is to evaluate the safety and efficacy of IW-3718 administered to patients with GERD who continue to have persistent symptoms, such as heartburn and regurgitation, while receiving once-daily (QD), standard-dose PPIs.
Interventions
Sponsors
Ironwood Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each patient must meet all of the following criteria to be eligible for enrollment in this study: * Patient is an ambulatory male or female (if female, nonpregnant) and is at least 18 years old at the Screening Visit. * Patient has a diagnosis of GERD and reports experiencing GERD symptoms (heartburn or regurgitation) while taking standard PPI therapy. * Patient has evidence of pathological acid reflux. * Female patients must not be pregnant and must agree to avoid pregnancy for the duration of the study. * Patient must comply with study procedures.
Exclusion criteria
Patients who meet any of the following criteria will not be eligible to participate in the study: * Patient has a history of complete lack of GERD symptom response to PPI therapy. * Patient has a significant medical or surgical history including conditions that would impact drug absorption or metabolism (such as bowel obstruction, poorly controlled diabetes, gastroparesis, hiatal hernia). * Patient reports pain or burning behind the breastbone or in the center of the upper stomach as his or her predominant symptom at the Screening Visit. * Patient has received an investigational drug during the 30 days before the Screening Visit, or is planning to receive another investigational drug or use an investigational device at any time during the study. NOTE: Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in WHSS at Week 8 | Baseline, Week 8 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weekly Regurgitation Frequency Score (WRFS) at Week 8 | 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. |
| Percentage of Participants Who Were Overall Heartburn Responders During the 8-Week Treatment Period | 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 |
| Proportion of Heartburn-Free Days During the 8-Week Treatment Period | 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 |
Countries
Canada, United States
Participant flow
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Placebo BID + PPI 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. | 246 |
| 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. | 247 |
| Total | 493 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 7 |
| Overall Study | Lost to Follow-up | 7 | 2 |
| Overall Study | Non-Compliance With Study Drug | 2 | 0 |
| Overall Study | Other Not Specified | 0 | 2 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Randomized by Mistake | 1 | 1 |
| Overall Study | Study Terminated by Sponsor | 10 | 15 |
| Overall Study | Withdrawal by Subject | 7 | 7 |
Baseline characteristics
| Characteristic | 1500 mg IW-3718 BID + PPI | Total | Placebo BID + PPI |
|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 12.61 | 47.6 years STANDARD_DEVIATION 12.89 | 47.2 years STANDARD_DEVIATION 13.17 |
| Erosive Esophagitis (EE) Status, as Randomized EE Not Present | 124 Participants | 251 Participants | 127 Participants |
| Erosive Esophagitis (EE) Status, as Randomized EE Present | 103 Participants | 204 Participants | 101 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 55 Participants | 107 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 188 Participants | 375 Participants | 187 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 11 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 16 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 33 Participants | 65 Participants | 32 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 5 Participants | 8 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 203 Participants | 404 Participants | 201 Participants |
| Sex: Female, Male Female | 145 Participants | 309 Participants | 164 Participants |
| Sex: Female, Male Male | 102 Participants | 184 Participants | 82 Participants |
| Weekly Heartburn Severity Score (WHSS) Category, as Randomized WHSS Score < 3 | 87 Participants | 179 Participants | 92 Participants |
| Weekly Heartburn Severity Score (WHSS) Category, as Randomized WHSS Score >/= 3 | 140 Participants | 276 Participants | 136 Participants |
| WHSS | 3.25 score on a scale STANDARD_DEVIATION 0.79 | 3.21 score on a scale STANDARD_DEVIATION 0.73 | 3.17 score on a scale STANDARD_DEVIATION 0.66 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 246 | 0 / 247 |
| other Total, other adverse events | 37 / 246 | 37 / 247 |
| serious Total, serious adverse events | 0 / 246 | 3 / 247 |
Outcome results
Primary
Change From Baseline in WHSS at Week 8
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID + PPI | Change From Baseline in WHSS at Week 8 | -1.774 score on a scale | Standard Error 0.082 |
| 1500 mg IW-3718 BID + PPI | Change From Baseline in WHSS at Week 8 | -1.719 score on a scale | Standard Error 0.082 |
Comparison: Treatment difference calculated as least squares mean (LSM) change from baseline at Week 8; IW-3718 - placebo based on an mixed models repeated measures (MMRM) model with week (categorical), treatment group, week-by-treatment group, and week-by-baseline value interactions, baseline esophagitis status (present vs. not present), and baseline WHSS (\< 3 vs. ≥ 3) as fixed effect terms and baseline value as a covariate, with subject as a random effect. An unstructured covariance structure was used.p-value: 0.634695% CI: [-0.172, 0.281]MMRM
Secondary
Change From Baseline in Weekly Regurgitation Frequency Score (WRFS) at 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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID + PPI | Change From Baseline in Weekly Regurgitation Frequency Score (WRFS) at Week 8 | -1.330 score on a scale | Standard Error 0.067 |
| 1500 mg IW-3718 BID + PPI | Change From Baseline in Weekly Regurgitation Frequency Score (WRFS) at Week 8 | -1.294 score on a scale | Standard Error 0.068 |
Comparison: Treatment difference calculated as LSM change from baseline at Week 8; IW-3718 - placebo based on an MMRM model with week (categorical), treatment group, week-by-treatment group, and week-by-baseline value interactions, baseline esophagitis status (present vs. not present), and baseline WHSS (\< 3 vs. ≥ 3) as fixed effect terms and baseline value as a covariate, with subject as a random effect. An unstructured covariance structure was used.p-value: 0.710195% CI: [-0.151, 0.221]MMRM
Secondary
Percentage of Participants Who Were Overall Heartburn Responders During the 8-Week Treatment Period
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
Time frame: Up to 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo BID + PPI | Percentage of Participants Who Were Overall Heartburn Responders During the 8-Week Treatment Period | 53.1 percentage of participants |
| 1500 mg IW-3718 BID + PPI | Percentage of Participants Who Were Overall Heartburn Responders During the 8-Week Treatment Period | 47.6 percentage of participants |
95% CI: [-14.7, 3.7]
Comparison: Treatment difference was calculated as the difference in the responder rates at Week 8; IW-3718 - placebo. The 95% CI for the difference in the responder rates was obtained using the Newcombe CI. P value was based on the odds ratio for the response rate (IW-3718:placebo) obtained from the CMH tests controlling for baseline esophagitis status and baseline heartburn severity level (\< 3 vs. ≥ 3).p-value: 0.253195% CI: [0.56, 1.17]Cochran-Mantel-Haenszel
Secondary
Proportion of Heartburn-Free Days During the 8-Week Treatment Period
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
Time frame: Up to 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID + PPI | Proportion of Heartburn-Free Days During the 8-Week Treatment Period | 0.232 proportion of days | Standard Error 0.032 |
| 1500 mg IW-3718 BID + PPI | Proportion of Heartburn-Free Days During the 8-Week Treatment Period | 0.218 proportion of days | Standard Error 0.031 |
Comparison: Poisson regression including the fixed categorical effect of treatment, the baseline esophagitis status (present vs. not present) and baseline WHSS (\<3 vs. ≥3), the covariate of baseline proportion of heartburn-free days, and with the diary entry duration (in days) as a weight variable adjusted in the model was applied.p-value: 0.744595% CI: [0.636, 1.382]Negative binomial model
Comparison: Poisson regression including the fixed categorical effect of treatment, the baseline esophagitis status (present vs. not present) and baseline WHSS (\<3 vs. ≥3), the covariate of baseline proportion of heartburn-free days, and with the diary entry duration (in days) as a weight variable adjusted in the model was applied.95% CI: [-0.103, 0.074]