supplemental online appendix · scores (drfs) during that week. drfs is defined as the maximum of...

Supplemental Online Appendix IW-3718 for Refractory Gastroesophageal Reflux Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

This appendix has been provided by the authors to give readers additional information about their work.

Contents Description of the Modified Reflux Symptom Questionnaire Electronic

Diary (mRESQ-eD) Employed in the Current Trial 2 Description of Key End Points 3 eFigure 1. IW-3718 Description and Hypothesized Mode of Action 4 eFigure 2. CONSORT Diagram of Patient Disposition 5 eTable 1: Summary of the Results of the Secondary and Additional

End Point Analyses (mITT Population) 6 eTable 2: Incidence of Treatment-emergent Adverse Events Occurring

in ≥3% Patients Receiving IW-3718 (Safety Population) 26 eTable 3: Acceptable Dose Levels of the Various PPIs for Participation

in the Trial 27

IW-3718 for Refractory Gastroesophageal Reflux Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

Description of the Modified Reflux Symptom Questionnaire Electronic Diary (mRESQ-eD) Employed in the Current Trial

During the pretreatment and treatment periods, patients completed the mRESQ-ed, entering the following once daily before going to bed each night.

The following 6 items were assessed on a 0-to-5 severity scale: (0=Did not have, 1=Very mild, 2=Mild, 3=Moderate, 4=Moderately severe, 5=Severe)

1. Heartburna 2. Burning feeling behind breastbone or in the center of the upper stomacha 3. Pain behind the breastbone or in the center of the upper stomacha 4. Difficulty swallowing 5. Hoarseness 6. Cough

The following 4 items were assessed on a 0-to-4 frequency scale: (0=Never, 1=Rarely, 2=Sometimes, 3=Often, 4=Very often)

1. Regurgitation (liquid or food) moving upwards toward your throat or mouthb 2. An acid or bitter taste in the mouthb 3. Burping 4. Coughing

a Items included in the Weekly Heartburn Severity Score (WHSS) and Overall Heartburn Responder end points.

b Items included in the Weekly Regurgitation Frequency Score (WRFS) and Overall Regurgitation Responder end points.


Description of Key End Points

Weekly Heartburn Severity Score (WHSS):

The WHSS for an analysis week was defined as the average of available daily heartburn severity scores

(DHSS) during that week. DHSS was defined as the maximum of the 3 items measuring heartburn from

the mRESQ-ed (“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.

Overall Heartburn Responder:

An Overall Heartburn Responder was defined as a patient who was a Weekly Heartburn Responder for at

least 4 of the 8 treatment weeks and for at least 1 of the final 2 treatment weeks (ie, week 7 and week 8).

In the prospective analysis, a Weekly Heartburn Responder was defined as a patient with a decrease of

≥30% from baseline in WHSS. However, based on the findings on a patient-reported psychometric debrief

assessment that was incorporated into the study, it was determined that symptom improvements of ≥45%

were considered clinically meaningful. Thus, data from the analysis incorporating this more rigorous

threshold are also reported herein.

Weekly Regurgitation Frequency Score (WRFS):

The WRFS for an analysis week was defined as the average of available daily regurgitation frequency

scores (DRFS) during that week. DRFS is defined as the maximum of the 2 items measuring regurgitation

from the mRESQ-ed (“Regurgitation [liquid or food moving upward toward your throat or mouth]” and “An

acid or bitter taste in the mouth”) from a particular day. This analysis was prospectively conducted in

subjects with a baseline WRFS ≥2 (N = 145). A post hoc analysis with subjects with a baseline WRFS >0

(N = 276) was conducted. This is considered more robust because it includes nearly all of the subjects.

Thus, these data are reported herein.

Overall Regurgitation Responder:

An Overall Regurgitation Responder was defined as a patient who is a Weekly Regurgitation Responder

for at least 4 of the 8 treatment weeks and for at least 1 of the final 2 treatment weeks (ie, week 7 and

week 8). A Weekly Regurgitation Responder was defined as a patient with a decrease of ≥30% from

baseline in WRFS. However, based on the findings on a patient-reported psychometric debrief

assessment that was incorporated into the study, it was determined that symptom improvements of ≥45%

were considered clinically meaningful. This analysis was also prospectively conducted in subjects with a

baseline WRFS ≥2 (N = 145). A post hoc analysis with subjects with a baseline WRFS >0 (N = 277) was

conducted. This is considered more robust because it includes nearly all of the subjects. Thus, these data

are reported herein.


eFigure 1. IW-3718 Description and Hypothesized Mode of Action

IW-3718 is a gastric-retentive, extended-release formulation (tablet) containing the bile acid sequestrant (BAS) colesevelam. Figure 1 shows IW-3718 in the stomach.

A.

B.

Panel A shows bile acid in the stomach, which can reflux into the lower esophagus. Panel B shows IW-3718 in the stomach. Using Acuform® technology, the IW-3718 tablet expands in the stomach and slowly releases the bile acid sequestrant (BAS) over time. The released BAS is proposed to bind and sequester bile acids that are en route to esophagus, thereby reducing detrimental effects on esophagus.


eFigure 2. CONSORT Diagram of Patient Disposition


eTable 1: Summary of the Results of the Secondary and Additional End Point Analyses (mITT Population) IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68

WHSS

Percent change from baseline to week 4 (No.) 69 71 71 68

Mean percent change from baseline (95% CI)a –38.9

(–46.2 to –31.5)

–42.6 ( –49.8 to –35.4)

–41.6 ( –48.9 to –34.4)

–47.5

( –54.9 to –40.1)

Mean difference (IW-3718 – Placebo; [95% CI])a -- –3.7 ( –14.0 to 6.6)

–2.7 ( –13.1 to 7.6)

–8.6 ( –19.0 to 1.8)

Change from baseline to week 8 (No.) 69 71 71 68

Mean percent change from baseline (95% CI)a –1.5 ( –1.7 to –1.2)

–1.5 ( –1.8 to –1.3)

–1.7 ( –2.0 to –1.5)

–1.9 ( –2.1 to –1.6)


–0.3 ( –0.6 to 0.1)

–0.4 ( –0.8 to –0.1)

Change from baseline to week 4 (No.) 69 71 71 68

Mean percent change from baseline (95% CI)a –1.3 ( –1.5 to –1.0)

–1.3 ( –1.5 to –1.1)

–1.30 ( –1.5 to –1.1)

–1.5 ( –1.7 to –1.3)


0.0 ( –0.4 to 0.3)

–0.3 ( –0.6 to 0.1)

Overall Heartburn Responders

Proportion of Overall Heartburn Responders based on ≥30% decrease (No.) 70 71 71 68

Proportion of responders (95% CI for Responder Rate)b 54.3 (41.9 to 66.3)

52.1 (39.9 to 64.1)

62.0 (49.7 to 73.2)

66.2 (53.7 to 77.2)

Difference in responder rate (IW-3718 – Placebo [95% CI])c -- –2.2 ( –18.6 to 14.3)

7.7 ( –8.6 to 23.9)

11.9 ( –4.3 to 28.1)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68

DHSS

Proportion of patients with a DHSS of no more than very mild (≤1) on any day during week 8 (No.) 70 71 71 68


18.3 (10.1 to 29.3)

29.6 (19.3 to 41.6)

38.2 (26.7 to 50.8)

Difference in responder rate (IW-3718 – Placebo [95% CI])c -- –10.3 ( –24.2 to 3.6)

1.0 ( –14.0 to 16.0)

9.7 ( –6.0 to 25.3)

Proportion of patients with a DHSS of no more than very mild (≤1) on any day during week 4 (No.) 70 71 71 68


15.5 (8.0 to 26.0)

22.5 (13.5 to 34.0)

22.1 (12.9 to 33.8)

Difference in responder rate (IW-3718 – Placebo [95% CI])c -- 2.6 ( –8.9 to 14.1)

9.7 ( –2.8 to 22.2)

9.2 (–3.4 to 21.8)

Number of days where DHSS was no more than very mild (≤1) during week 8 62 66 63 62

Mean change from baseline (95% CI)a 3.0

(2.3 to 3.7)

2.7

(2.0 to 3.4) 3.3

(2.6 to 3.9) 3.5

(2.8 to 4.2)

Mean difference (IW-3718 – Placebo; [95% CI])a -- –0.3 (–1.3 to 0.7)

0.3 (–0.7 to 1.2)

0.5 (–0.5 to 1.5)

Number of days where DHSS was no more than very mild (≤1) during week 4 (No.) 64 70 67 68

Mean change from baseline (95% CI)a 2.3 (1.6 to 2.9)

2.3 (1.7 to 2.9)

2.7 (2.0 to 3.3)

2.7 (2.1 to 3.4)

Mean difference (IW-3718 – Placebo; [95% CI])a -- 0.0 (–0.9 to 0.9)

0.4 (–0.5 to 1.3)

0.5 (–0.5 to 1.4)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68

Heartburn-free Days

Proportion of heartburn-free days during week 8 (No.) 61 66 62 62

Mean change from baseline (95% CI) * 0.3 (0.2 to 0.4)

0.3 (0.2 to 0.3)

0.3 (0.2 to 0.4)

0.3 (0.3 to 0.4)

Mean difference (IW-3718 – Placebo [95% CI])a -- 0.0 (–0.2 to 0.1)

0.0 (–0.1 to 0.2)

0.1

(–0.1 to 0.2)

Proportion of heartburn-free days during week 4 (No.) 64 70 66 68

Mean change from baseline (95% CI)a 0.1 (0.1 to 0.2)

0.1 (0.1 to 0.2)

0.1 (0.1 to 0.2)

0.2 (0.2 to 0.3)


0.0 (–0.1 to 0.1)

0.1 (0.0 to 0.2)

mRESQ-eD Individual Items

Heartburn Severity

Change in the weekly average from baseline to week 1 (No.) 69 71 71 68

Mean change from baseline (95% CI)a –0.655 (-0.832 to -0.477)

–0.632 (-0.807 to -0.457)

–0.531 (-0.706 to -0.356)

–0.673 (-0.852 to -0.495)

Mean difference (IW-3718 – placebo [95% CI])a – 0.023 (-0.226 to 0.272)

0.124 (-0.126 to 0.373)

-0.019 (-0.270 to 0.233)


Mean change from baseline (95% CI)a -0.994 (-1.195 to -0.793)

-0.974 (-1.172 to -0.776)

-0.977 (-1.175 to -0.779)

-1.102 (-1.304 to -0.899)

Mean difference (IW-3718 – placebo [95% CI])a -- 0.020 (-0.262 to 0.303)

0.017 (-0.266 to 0.299)

-0.108 (-0.393 to 0.177)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-1.141 (-1.352 to -0.930)

-1.153 (-1.364 to -0.942)

-1.350 (-1.565 to -1.134)

Mean difference (IW-3718 – placebo [95% CI])a -- -0.049 (-0.350 to 0.251)

-0.062 (-0.362 to 0.239)

-0.258 (-0.562 to 0.045)



-1.281 (-1.497 to -1.064)

-1.259 (-1.475 to -1.042)

-1.498 (-1.719 to -1.277)


0.004 (-0.304 to 0.313)

-0.235 (-0.546 to 0.077)



-1.301 (-1.534 to -1.068)

-1.339 (-1.573 to -1.106)

-1.677 (-1.916 to -1.439)


-0.055 (-0.388 to 0.278)

-0.393 (-0.729 to -0.057)



-1.343 (-1.578 to -1.109)

-1.467 (-1.702 to -1.233)

-1.744 (-1.984 to -1.504)


-0.071 (-0.406 to 0.263)

-0.348 (-0.686 to -0.010)



-1.350 (-1.595 to -1.104)

-1.436 (-1.682 to -1.191)

-1.693 (-1.944 to -1.441)


-0.044 (-0.394 to 0.306)

-0.300 (-0.654 to 0.053)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-1.482 (-1.729 to -1.234)

-1.666 (-1.913 to -1.418)

-1.807 (-2.060 to -1.555)


-0.262 (-0.614 to 0.091)

-0.403 (-0.759 to -0.048)

Burning feeling behind breastbone or center of upper stomach severity



-0.536 (-0.708 to -0.364)

-0.492 (-0.664 to -0.319)

-0.675 (-0.851 to -0.499)


0.147 (-0.098 to 0.392)

-0.036 (-0.284 to 0.212)



-0.918 (-1.118 to -0.719)

-0.970 (-1.170 to -0.770)

-1.116 (-1.320 to -0.912)


0.028 (-0.256 to 0.312)

-0.118 (-0.405 to 0.169)



-1.074 (-1.284 to -0.865)

-1.112 (-1.323 to -0.902)

-1.385 (-1.599 to -1.170)


-0.073 (-0.372 to 0.226)

-0.345 (-0.647 to -0.043)



-1.246 (-1.466 to -1.026)

-1.316 (-1.536 to -1.096)

-1.497 (-1.722 to -1.272)


-0.117 (-0.430 to 0.196)

-0.298 (-0.615 to 0.019)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-1.287 (-1.519 to -1.054)

-1.323 (-1.557 to -1.090)

-1.648 (-1.886 to -1.410)


-0.097 (-0.428 to 0.234)

-0.422 (-0.757 to -0.087)



-1.297 (-1.528 to -1.067)

-1.450 (-1.681 to -1.219)

-1.733 (-1.969 to -1.497)


-0.093 (-0.421 to 0.236)

-0.376 (-0.708 to -0.044)



-1.359 (-1.599 to -1.120)

-1.424 (-1.665 to -1.184)

-1.676 (-1.921 to -1.430)


-0.114 (-0.456 to 0.228)

-0.366 (-0.711 to -0.020)



-1.422 (-1.659 to -1.185)

-1.627 (-1.864 to -1.389)

-1.781 (-2.023 to -1.538)


-0.298 (-0.636 to 0.040)

-0.452 (-0.793 to -0.110)

Pain behind breastbone or center of upper stomach severity



-0.548 (-0.722 to -0.375)

-0.454 (-0.629 to -0.280)

-0.626 (-0.803 to -0.448)


0.148 (-0.100 to 0.396)

-0.023 (-0.273 to 0.227)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.869 (-1.068 to -0.670)

-0.934 (-1.134 to -0.734)

-1.083 (-1.287 to -0.880)

Mean difference (IW-3718 – placebo [95% CI])a -- 0.051

(-0.232 to 0.335)

-0.013

(-0.297 to 0.271)

-0.162

(-0.449 to 0.124)



-1.008 (-1.221 to -0.795)

-1.126 (-1.340 to -0.912)

-1.313 (-1.531 to -1.095)


-0.125 (-0.429 to 0.180)

-0.311 (-0.618 to -0.004)



-1.210 (-1.429 to -0.991)

-1.244 (-1.464 to -1.024)

-1.439 (-1.664 to -1.215)


-0.059 (-0.372 to 0.254)

-0.254 (-0.570 to 0.062)



-1.230 (-1.462 to -0.999)

-1.299 (-1.531 to -1.066)

-1.578 (-1.815 to -1.341)


-0.020 (-0.350 to 0.310)

-0.299 (-0.633 to 0.034)



-1.257 (-1.487 to -1.028)

-1.367 (-1.597 to -1.136)

-1.665 (-1.900 to -1.430)


-0.024 (-0.352 to 0.303)

-0.323 (-0.653 to 0.008)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-1.303 (-1.541 to -1.065)

-1.302 (-1.541 to -1.064)

-1.638 (-1.881 to -1.395)

Mean difference (IW-3718 – placebo [95% CI])a -- -0.051

(-0.389 to 0.287)

-0.050

(-0.389 to 0.289)

-0.386

(-0.728 to -0.043)



-1.333 (-1.567 to -1.099)

-1.525 (-1.760 to -1.290)

-1.674 (-1.914 to -1.434)

Mean difference (IW-3718 – placebo [95% CI])a -- -0.044

(-0.378 to 0.289)

-0.236

(-0.570 to 0.098)

-0.385

(-0.722 to -0.048)

Difficulty Swallowing Severity



-0.405 (-0.550 to -0.259)

-0.309 (-0.455 to -0.163)

-0.519 (-0.668 to -0.370)


0.189 (-0.020 to 0.397)

-0.021 (-0.232 to 0.189)



-0.566 (-0.736 to -0.396)

-0.611 (-0.782 to -0.440)

-0.714 (-0.888 to -0.541)


0.007 (-0.237 to 0.251)

-0.096 (-0.342 to 0.149)



-0.675 (-0.856 to -0.494)

-0.817 (-0.998 to -0.635)

-1.022 (-1.207 to -0.837)


-0.146 (-0.405 to 0.114)

-0.351 (-0.612 to -0.089)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.763 (-0.952 to -0.574)

-0.810 (-0.999 to -0.621)

-1.061 (-1.254 to -0.868)


-0.073 (-0.344 to 0.198)

-0.324 (-0.596 to -0.051)



-0.850 (-1.039 to -0.660)

-0.846 (-1.036 to -0.656)

-1.156 (-1.350 to -0.963)


-0.022 (-0.293 to 0.250)

-0.332 (-0.605 to -0.059)



-0.805 (-1.002 to -0.609)

-0.961 (-1.159 to -0.764)

-1.174 (-1.375 to -0.973)


-0.078 (-0.360 to 0.204)

-0.291 (-0.575 to -0.007)



-0.756 (-0.964 to -0.548)

-0.906 (-1.114 to -0.698)

-1.166 (-1.378 to -0.953)


-0.057 (-0.355 to 0.241)

-0.317 (-0.616 to -0.017)



-0.822 (-1.029 to -0.615)

-0.989 (-1.196 to -0.782)

-1.197 (-1.409 to -0.986)


-0.125 (-0.422 to 0.171)

-0.333 (-0.632 to -0.035)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68

Hoarseness severity



-0.292 (-0.435 to -0.149)

-0.400 (-0.543 to -0.256)

-0.406 (-0.553 to -0.260)


-0.071 (-0.275 to 0.133)

-0.077 (-0.283 to 0.129)


Mean change from baseline (95% CI)a -0.483

(-0.660 to -0.305)

-0.416

(-0.591 to -0.241)

-0.605

(-0.780 to -0.430)

-0.544

(-0.723 to -0.366)


-0.122 (-0.372 to 0.127)

-0.062 (-0.313 to 0.190)



-0.574 (-0.759 to -0.389)

-0.796 (-0.981 to -0.610)

-0.778 (-0.967 to -0.589)


-0.270 (-0.534 to -0.006)

-0.252 (-0.519 to 0.014)



-0.631 (-0.830 to -0.433)

-0.842 (-1.040 to -0.643)

-0.833 (-1.036 to -0.631)


-0.336 (-0.620 to -0.053)

-0.328 (-0.614 to -0.043)



-0.684 (-0.892 to -0.476)

-0.870 (-1.078 to -0.662)

-0.842 (-1.055 to -0.630)


-0.282 (-0.579 to 0.015)

-0.255 (-0.554 to 0.045)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.677 (-0.889 to -0.464)

-0.990 (-1.203 to -0.777)

-0.962 (-1.180 to -0.745)


-0.373 (-0.677 to -0.069)

-0.345 (-0.652 to -0.039)



-0.626 (-0.841 to -0.411)

-0.860 (-1.075 to -0.645)

-1.054 (-1.274 to -0.835)


-0.290 (-0.596 to 0.017)

-0.484 (-0.793 to -0.175)



-0.683 (-0.893 to -0.473)

-0.954 (-1.165 to -0.744)

-1.086 (-1.301 to -0.871)


-0.350 (-0.650 to -0.050)

-0.482 (-0.785 to -0.180)

Cough severity



-0.283 (-0.433 to -0.133)

-0.353 (-0.504 to -0.203)

-0.389 (-0.542 to -0.235)


0.072 (-0.143 to 0.288)

0.037 (-0.181 to 0.254)



-0.501 (-0.684 to -0.318)

-0.608 (-0.791 to -0.425)

-0.589 (-0.776 to -0.402)


-0.034 (-0.296 to 0.228)

-0.015 (-0.280 to 0.249)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.614 (-0.791 to -0.437)

-0.745 (-0.923 to -0.568)

-0.890 (-1.071 to -0.709)


-0.212 (-0.466 to 0.042)

-0.357 (-0.613 to -0.100)



-0.657 (-0.847 to -0.467)

-0.878 (-1.068 to -0.687)

-0.914 (-1.109 to -0.720)


-0.348 (-0.621 to -0.075)

-0.384 (-0.660 to -0.109)



-0.692 (-0.897 to -0.487)

-0.840 (-1.045 to -0.634)

-0.972 (-1.181 to -0.762)


-0.223 (-0.518 to 0.071)

-0.355 (-0.652 to -0.058)



-0.671 (-0.878 to -0.465)

-0.953 (-1.160 to -0.746)

-1.026 (-1.237 to -0.814)


-0.319 (-0.616 to -0.023)

-0.392 (-0.691 to -0.093)



-0.688 (-0.903 to -0.472)

-0.971 (-1.187 to -0.755)

-1.063 (-1.283 to -0.842)


-0.377 (-0.687 to -0.068)

-0.469 (-0.781 to -0.157)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.706 (-0.913 to -0.500)

-0.949 (-1.156 to -0.743)

-1.158 (-1.369 to -0.947)


-0.336 (-0.632 to -0.040)

-0.545 (-0.843 to -0.246)

Regurgitation (liquid or food moving upwards toward your throat or mouth) frequency



-0.385 (-0.516 to -0.255)

-0.340 (-0.470 to -0.210)

-0.511 (-0.644 to -0.379)


0.143 (-0.042 to 0.328)

-0.028 (-0.216 to 0.159)



-0.637 (-0.797 to -0.478)

-0.597 (-0.756 to -0.438)

-0.774 (-0.937 to -0.612)


0.051 (-0.176 to 0.277)

-0.127 (-0.356 to 0.102)



-0.784 (-0.947 to -0.620)

-0.791 (-0.955 to -0.628)

-0.879 (-1.046 to -0.712)


-0.210 (-0.443 to 0.022)

-0.298 (-0.534 to -0.063)



-0.855 (-1.028 to -0.683)

-0.838 (-1.010 to -0.666)

-0.984 (-1.160 to -0.809)


-0.068 (-0.313 to 0.176)

-0.215 (-0.463 to 0.033)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.869 (-1.038 to -0.700)

-0.866 (-1.035 to -0.698)

-1.028 (-1.200 to -0.856)


-0.108 (-0.348 to 0.131)

-0.270 (-0.512 to -0.027)



-0.936 (-1.110 to -0.761)

-0.939 (-1.113 to -0.765)

-1.093 (-1.271 to -0.915)


-0.105 (-0.353 to 0.144)

-0.259 (-0.510 to -0.008)


Mean change from baseline (95% CI)a -0.796

(-0.974 to -0.618)

-0.899

(-1.075 to -0.723)

-0.867

(-1.042 to -0.691)

-1.081

(-1.260 to -0.902)


-0.071 (-0.321 to 0.179)

-0.285 (-0.538 to -0.033)



-0.951 (-1.129 to -0.772)

-1.029 (-1.207 to -0.851)

-1.191 (-1.373 to -1.008)


-0.218 (-0.472 to 0.035)

-0.380 (-0.637 to -0.123)

Acid or bitter taste frequency



-0.374 (-0.508 to -0.240)

-0.401 (-0.535 to -0.267)

-0.530 (-0.667 to -0.393)


0.100 (-0.091 to 0.292)

-0.028 (-0.221 to 0.165)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.640 (-0.802 to -0.477)

-0.676 (-0.838 to -0.514)

-0.784 (-0.949 to -0.618)


0.062 (-0.169 to 0.293)

-0.045 (-0.279 to 0.188)



-0.806 (-0.966 to -0.647)

-0.842 (-1.001 to -0.683)

-0.874 (-1.036 to -0.711)


-0.151 (-0.378 to 0.076)

-0.183 (-0.412 to 0.046)



-0.847 (-1.020 to -0.673)

-0.893 (-1.066 to -0.719)

-0.952 (-1.130 to -0.775)


-0.096 (-0.343 to 0.152)

-0.155 (-0.405 to 0.095)



-0.920 (-1.092 to -0.748)

-0.929 (-1.101 to -0.757)

-1.024 (-1.200 to -0.849)


-0.061 (-0.306 to 0.184)

-0.156 (-0.403 to 0.091)



-0.966 (-1.145 to -0.787)

-1.009 (-1.188 to -0.830)

-1.098 (-1.281 to -0.915)


-0.139 (-0.394 to 0.116)

-0.228 (-0.485 to 0.030)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.912 (-1.094 to -0.730)

-0.947 (-1.129 to -0.765)

-1.053 (-1.239 to -0.867)


-0.052 (-0.312 to 0.207)

-0.159 (-0.421 to 0.103)



-0.938 (-1.122 to -0.755)

-1.072 (-1.255 to -0.889)

-1.163 (-1.350 to -0.976)


-0.176 (-0.437 to 0.084)

-0.267 (-0.531 to -0.003)

Coughing frequency



-0.286 (-0.409 to -0.162)

-0.290 (-0.413 to -0.166)

-0.352 (-0.478 to -0.225)


0.084 (-0.092 to 0.261)

0.022 (-0.156 to 0.201)



-0.469 (-0.625 to -0.313)

-0.484 (-0.640 to -0.329)

-0.571 (-0.730 to -0.412)


0.087 (-0.135 to 0.310)

0.001 (-0.224 to 0.226)



-0.605 (-0.765 to -0.445)

-0.594 (-0.753 to -0.434)

-0.729 (-0.893 to -0.566)


-0.116 (-0.345 to 0.112)

-0.252 (-0.483 to -0.021)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.667 (-0.839 to -0.494)

-0.685 (-0.858 to -0.513)

-0.793 (-0.969 to -0.617)


-0.188 (-0.434 to 0.058)

-0.295 (-0.544 to -0.046)



-0.659 (-0.842 to -0.475)

-0.648 (-0.832 to -0.464)

-0.812 (-1.000 to -0.624)


-0.142 (-0.405 to 0.121)

-0.306 (-0.571 to -0.040)



-0.653 (-0.830 to -0.476)

-0.700 (-0.877 to -0.523)

-0.872 (-1.053 to -0.691)


-0.106 (-0.359 to 0.148)

-0.278 (-0.534 to -0.021)



-0.656 (-0.842 to -0.469)

-0.713 (-0.900 to -0.526)

-0.872 (-1.063 to -0.681)


-0.152 (-0.419 to 0.115)

-0.311 (-0.581 to -0.041)



-0.647 (-0.830 to -0.463)

-0.718 (-0.902 to -0.534)

-0.988 (-1.175 to -0.800)


-0.164 (-0.427 to 0.099)

-0.433 (-0.699 to -0.168)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68

Burping frequency



-0.416 (-0.553 to -0.279)

-0.309 (-0.446 to -0.172)

-0.416 (-0.557 to -0.275)


0.150 (-0.046 to 0.345)

0.043 (-0.155 to 0.241)



-0.649 (-0.811 to -0.486)

-0.556 (-0.718 to -0.394)

-0.614 (-0.780 to -0.448)


0.113 (-0.118 to 0.344)

0.055 (-0.179 to 0.289)



-0.705 (-0.871 to -0.540)

-0.734 (-0.899 to -0.568)

-0.754 (-0.924 to -0.585)


-0.129 (-0.364 to 0.106)

-0.149 (-0.388 to 0.089)



-0.794 (-0.972 to -0.616)

-0.797 (-0.975 to -0.619)

-0.866 (-1.049 to -0.684)


-0.096 (-0.349 to 0.158)

-0.165 (-0.422 to 0.092)



-0.832 (-1.009 to -0.655)

-0.813 (-0.990 to -0.637)

-0.910 (-1.092 to -0.729)


-0.069 (-0.321 to 0.183)

-0.166 (-0.421 to 0.089)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68



-0.845 (-1.028 to -0.663)

-0.845 (-1.027 to -0.663)

-0.942 (-1.129 to -0.755)


-0.043 (-0.303 to 0.216)

-0.141 (-0.404 to 0.122)



-0.896 (-1.088 to -0.703)

-0.803 (-0.994 to -0.611)

-0.909 (-1.106 to -0.712)


0.008 (-0.266 to 0.281)

-0.099 (-0.376 to 0.179)



-0.973 (-1.171 to -0.775)

-0.920 (-1.118 to -0.723)

-1.008 (-1.211 to -0.805)


-0.112 (-0.393 to 0.170)

-0.199 (-0.485 to 0.086)

WRFS

Percent change from baseline to week 8 in patients with baseline WRFS ≥2 (n [patients with baseline WRFS ≥2]) 43 55 47 50

Mean change from baseline (95% CI)a –42.1 (–51.1 to –33.0)

–39.5 (–47.5 to –31.5)

–47.4 (–56.0 to –38.8)

–51.3 (–59.7 to –42.9)


–5.4 (–17.8 to 7.1)

–9.2 (–21.6 to 3.1)


IW-3718

End Point Statistic

Placebo BID n = 70

500 mg BID n = 71

1000 mg BID n = 71

1500 mg BID n = 68

Overall Regurgitation Responders

Proportion of Overall Regurgitation Responders based on ≥30% decrease in frequency (n [patients with baseline WRFS ≥2]) 43 55 47 50


52.7 (38.8 to 66.3)

63.8 (48.5 to 77.3)

62.0 (47.2 to 75.3)

Difference in responder rate (IW-3718 – Placebo [95% CI])c -- 3.9 (–16.0 to 23.8)

15.0 (–5.3 to 35.3)

13.2 (–6.9 to 33.3)

CI, confidence interval; DHSS, Daily Heartburn Severity Score; mITT, modified intent-to-treat; No., Number of patients with values both at baseline and during the Treatment Period; WHSS, Weekly Heartburn Severity Score; WRFS, Weekly Regurgitation Frequency Score. a Mean percent changes/changes represent least-squares (LS) means from the ANCOVA model with fixed-effect terms for treatment group and esophagitis status and baseline value

as a covariate. CIs derived from the ANCOVA model; CIs have not been adjusted for multiplicity and inferences drawn from the intervals may not be reproducible. b Proportions of responders were estimated using a Cochran-Mantel-Haenszel (CMH) test controlling for esophagitis status. 95% CIs for Responder Rates are obtained using exact

(Clopper-Pearson) confidence limits. CIs have not been adjusted for multiplicity and inferences drawn from the intervals may not be reproducible. c 95% CIs for Differences in Responder Rates are obtained using the normal approximation to the binomial distribution. CIs have not been adjusted for multiplicity and inferences

drawn from the intervals may not be reproducible.


eTable 2: Incidence of Treatment-emergent Adverse Events Occurring in ≥3% Patients Receiving IW-3718 (Safety Population)

IW-3718

Placebo BID

(n = 70)

500 mg BID

(n = 71)

1000 mg BID

(n = 71)

1500 mg BID

(n = 68)

Overall IW-3718 (N = 210)

No. (%) No. (%) No. (%) No. (%) No. (%)

Patients with at least 1 TEAE 29 (41.4) 30 (42.3) 37 (52.1) 30 (44.1) 97 (46.2)

Individual TEAEs (preferred term)

Constipation 5 (7.1) 6 (8.5) 6 (8.5) 5 (7.4) 17 (8.1)

Nausea 2 (2.9) 3 (4.2) 4 (5.6) 6 (8.8) 13 (6.2)

Flatulence 3 (4.3) 7 (9.9) 4 (5.6) 1 (1.5) 12 (5.7)

Abdominal distension 4 (5.7) 2 (2.8) 4 (5.6) 2 (2.9) 8 (3.8)

Diarrhea 5 (7.1) 2 (2.8) 3 (4.2) 3 (4.4) 8 (3.8)

Upper respiratory tract infection 1 (1.4) 1 (1.4) 3 (4.2) 3 (4.4) 7 (3.3)

Headache -- 3 (4.2) 1 (1.4) 3 (4.4) 7 (3.3) TEAE, treatment-emergent adverse event. Note: Patients were counted only once within each preferred term.


eTable 3: Acceptable Dose Levels of the Various PPIs for Participation in the Trial

supplemental online appendix · scores (drfs) during that week. drfs is defined as the maximum of...

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