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The Effect of Dexlansoprazole MR on Nocturnal Heartburn and GERD-Related Sleep Disturbances in Patients With Symptomatic GERD
Ronnie Fass, MD1, David A. Johnson, MD2, William C. Orr, PhD3, Cong Han, PhD4, Reema Mody, PhD5, Kathleen N. Stern, PhD6, Betsy L. Pilmer, RN, BSN6 and M. Claudia Perez, MD6 OBJECTIVES:

Nocturnal heartburn and related sleep disturbances are common among patients with gastroesophageal reux disease (GERD). This study evaluated the efcacy of dexlansoprazole MR 30 mg in relieving nocturnal heartburn and GERD-related sleep disturbances, improving work productivity, and decreasing nocturnal symptom severity in patients with symptomatic GERD. Patients (N = 305) with frequent, moderate-to-very severe nocturnal heartburn and associated sleep disturbances were randomized 1:1 in a double-blind fashion to receive dexlansoprazole MR or placebo once daily for 4 weeks. The primary end point was the percentage of nights without heartburn. Secondary end points were the percentage of patients with relief of nocturnal heartburn and of GERD-related sleep disturbances over the last 7 days of treatment. At baseline and week 4/nal visit, patients completed questionnaires that assessed sleep quality, work productivity, and the severity and impact of nocturnal GERD symptoms. Dexlansoprazole MR 30 mg (n = 152) was superior to placebo (n = 153) in median percentage of nights without heartburn (73.1 vs. 35.7%, respectively; P < 0.001). Dexlansoprazole MR was signicantly better than placebo in percentage of patients with relief of nocturnal heartburn and GERD-related sleep disturbances (47.5 vs. 19.6%, 69.7 vs. 47.9%, respectively; P < 0.001), and led to signicantly greater improvements in sleep quality and work productivity and decreased nocturnal symptom severity. Adverse events were similar across treatment groups. placebo in providing relief from nocturnal heartburn, in reducing GERD-related sleep disturbances and the consequent impairments in work productivity, and in improving sleep quality/quality of life.

METHODS:

RESULTS:

CONCLUSIONS: In patients with symptomatic GERD, dexlansoprazole MR 30 mg is signicantly more efcacious than

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg

Am J Gastroenterol 2011; 106:421431; doi:10.1038/ajg.2010.458; published online 11 January 2011

INTRODUCTION
Approximately 1420% of US adults experience gastroesophageal reflux disease (GERD) weekly (1,2), which translates to more than 60 million adults (3). Among those reporting GERD symptoms, up to 89% report nocturnal symptoms (1,46), resulting in impairment in health-related quality of life (HRQoL) and significantly worse sleep quality (7,8). Because continued sleep disruption leads to increased daytime sleepiness (9), nocturnal heartburn can reduce productivity while patients are present
1

at work, as well as reduce function when performing normal daily activities (7,8,10,11). The continued presence of nocturnal heartburn despite routine medical treatment is strongly associated with decreases in HRQoL (12). In addition, the majority of GERD patients participating in a Gallup survey were not completely satisfied with their over-the-counter or prescription medication due to persistent nocturnal symptoms (6). The aims of this study were to assess, in patients with symptomatic GERD, the efficacy and safety of dexlansoprazole MR 30 mg

Southern Arizona VA Health Care System, Section of Gastroenterology (111G-1), Tucson, Arizona, USA; 2Eastern Virginia Medical School, Division of Gastroenterology, Norfolk, Virginia, USA; 3The Lynn Health Science Institute, Oklahoma City, Oklahoma, USA; 4Takeda Global Research & Development Center, Inc, Department of Statistics, Deereld, Illinois, USA; 5Takeda Pharmaceuticals International, Inc, Department of Global Health Economics and Outcomes Research, Deereld, Illinois, USA; 6Takeda Global Research & Development Center, Inc, Department of Clinical Sciences, Deereld, Illinois, USA. Correspondence: Ronnie Fass, MD, Southern Arizona VA Health Care System, Section of Gastroenterology (111G-1), 3601 S. 6th Avenue, Tucson, Arizona 85723, USA. E-mail: ronnie.fass@med.va.gov Received 16 July 2010; accepted 3 November 2010
2011 by the American College of Gastroenterology

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once daily compared with placebo for relief of nocturnal heartburn, and improvement of GERD-related sleep disturbances by utilizing electronic diaries. The study included patient-reported outcome measures to assess the impact of dexlansoprazole MR (compared with placebo) on sleep quality, nocturnal GERD symptom severity, and work productivity. To date, there are no studies evaluating the effects of proton pump inhibitor (PPI) treatment efficacy specifically in symptomatic GERD patients with moderate-to-very severe nocturnal heartburn and GERD-related sleep disturbances and no esophageal erosions based on endoscopy before randomization.

Insurance Portability Accountability Act authorization forms before any study-related procedure was performed.
Patients

METHODS
Study design

This was a prospective, randomized, double-blind, placebo-controlled, parallel-group study of 4 weeks duration (ClinicalTrials. gov identifier NCT00627016). The study population included patients with a history of nocturnal heartburn and GERDrelated sleep disturbances who had previously responded to acidsuppression therapy (PPIs, histamine 2-receptor antagonists, or any other antacid treatment). Patients with a history of symptomatic GERD with or without history of erosive esophagitis diagnosed > 6 months before screening were allowed to participate. The primary objective was to assess the efficacy of dexlansoprazole MR 30 mg compared with placebo for relief of nocturnal heartburn symptoms. The secondary objectives were to assess the safety and efficacy of dexlansoprazole MR 30 mg compared with placebo for improvement of GERD-related sleep disturbances and HRQoL outcomes. After a screening period of up to 21 days, all patients underwent an upper endoscopy within 4 days before day 1 to exclude patients with esophageal erosions. Eligible patients were then randomized on day 1, at which time study drug and rescue medication were dispensed. Throughout the 4-week treatment period, patients reported symptoms in their daily electronic diaries. At day 1 and week 4/final visit, patients underwent an investigator assessment of GERD symptoms and completed three patient-reported outcome questionnaires: the Pittsburgh Sleep Quality Index (PSQI) questionnaire to assess sleep quality (13), the Nocturnal Gastroesophageal Reflux Disease Symptom Severity and Impact Questionnaire (N-GSSIQ) to assess the severity and impact of nocturnal GERD symptoms (14), and the Work Productivity and Activity Impairment (WPAI): Special Health Problem questionnaire to measure the impairment of work productivity due to GERD-related sleep disturbances (1517). Diary entries were accessed and reviewed at weeks 1, 2, and 4/final visit to ensure compliance. At baseline and week 4/final visit, all patients underwent a physical examination, including vital signs and body weight, a 12-lead electrocardiogram, and routine laboratory evaluation. Also at baseline, all female patients took a required urine pregnancy test. Patients who withdrew prematurely underwent the final visit procedures. This study was approved by the independent institutional review boards at the participating study centers and was conducted according to the ethical principles stated in the Declaration of Helsinki. Each patient signed informed consent and Health
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Males and females, 1866 years of age, were included if they met both of the following qualification criteria during 3 of 7 nights by daily diary entries: (i) experienced nocturnal heartburn with a severity of moderate, severe, or very severe and (ii) experienced GERD-related sleep disturbances. The upper age limit of 66 years was used to avoid enrolling a population with increased prevalence of comorbidities, which might interfere with restful sleep. All female subjects who were not nursing, pregnant, postmenopausal, or surgically sterile were to be using an approved form of contraception. Patients were to have normal esophageal mucosa upon screening endoscopy. Patients were excluded for the following: pregnancy or lactation; known hypersensitivity to any PPI, any component of dexlansoprazole, or antacid; endoscopy finding of erosive esophagitis (performed within 4 days before randomization); active gastric or duodenal ulcers, gastrointestinal bleeding, coexisting diseases affecting the esophagus, history of trauma or radiation or ablative therapy, and need for dilation of esophageal strictures; any condition other than GERD that could be the primary cause of sleep disturbance; presence of any comorbidities that may impact participation and results; nightshift work; anticipated travel beyond three time zones during the study; a history of alcohol abuse; use of any PPI 14 days before randomization; use of histamine 2receptor antagonists, or antacids (except for study-supplied rescue medication) during the screening period; chronic use of nonsteroidal anti-inflammatory drugs ( > 12 doses/month), including COX-2 inhibitors, within 30 days before randomization (low-dose aspirin use, up to 325 mg daily, was allowed); use of sucralfate, misoprostol, corticosteroids, prokinetics, anticoagulants, antiseizure medications (other than stable dose), psychotropic medications (other than stable dose), bisphosphonates, and narcotics (occasional use allowed) 14 days before screening; use of sleep medications, first-generation antihistamines, benzodiazepines, modified tricyclic antidepressants, anti-anxiety medications, or any other drugs affecting the central nervous system that could mask perception of symptoms unless on a stable regimen for 90 days before randomization and remained on this regimen for the duration of study; abnormal laboratory values that suggested significant underlying disease; or at investigator discretion.
Treatment assignment/masking

On day 1, patients were randomized using a centralized, computer-directed interactive voice response system or interactive website response system in a 1:1 ratio to receive dexlansoprazole MR 30 mg (Dexilant Takeda Pharmaceutical Company, Osaka, Japan) daily or placebo. During the 4-week treatment period, patients self-administered the study drug once daily by mouth, in the morning, without regard to the timing of food intake from blinded study-drug blister cards. Open-label Gelusil (aluminum/ magnesium hydroxide, simethicone; Pfizer, New York, NY) was provided as rescue medication (up to 6 tablets/day).
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Efcacy end points

The primary efficacy end point was the percentage of nights without heartburn over 4 weeks. The secondary efficacy end points were the percentage of patients with relief of nocturnal heartburn (defined as 6 of 7 nights with no heartburn and allowing for 1 night with mild heartburn) over the last 7 days of treatment, and the percentage of patients with relief of GERD-related sleep disturbances (defined as 6 of 7 nights with no GERD-related sleep disturbances) over the last 7 days of treatment. Additional efficacy end points included mean severity of nocturnal heartburn during treatment, percentage of nights with GERD-related sleep disturbances, percentage of nights with each type of sleep disturbance, severity of GERD symptoms at week 4 as assessed by the investigator, percentage of 24-h heartburn-free days, change from baseline to week 4 in sleep quality assessed by PSQI score, change from baseline to week 4 in N-GSSIQ scores, and change from baseline to week 4 in WPAI scores.
Efcacy assessments

Patients were provided with and trained to use electronic daily diaries on the first day of the screening period. Diary entries were to be completed twice daily, every morning upon waking and every evening before bedtime. Although patients were to complete electronic diary entries in the morning and in the evening, if they missed an entry, they were permitted to complete up to two entries immediately before the scheduled entry, but not beyond. Nocturnal was defined as the time at which the patient lay down to fall asleep through the time when the patient woke up and began daily activities. Diaries were used throughout the screening and treatment periods to document the presence and severity of nocturnal heartburn symptoms, the presence of GERD-related sleep disturbances and sleep disturbances due to other causes (i.e., stress, illness (other than GERD or heartburn), environment in which patients slept, or urge to urinate), and rescue medication use. Patients rated the heartburn severity according to the following 5-point scale: 0 = none, 1 = mild (occasional heartburn that could be ignored and did not influence sleep), 2 = moderate (heartburn that could not be ignored and occasionally influenced sleep), 3 = severe (heartburn that was present most of the night and regularly influenced sleep), and 4 = very severe (constant heartburn that markedly influenced sleep). Similar 5-point scales have been used in other GERD studies (1821). Patients completed the PSQI, N-GSSIQ, and WPAI questionnaires at day 1 and week 4/final visit. Only results for those patients who completed the questionnaires at both baseline and week 4 are reported. The PSQI questionnaire comprises 19 selfrated items that provide a valid, reliable, standardized measure of sleep quality over the past month (13). Overall score ranges from 0 to 21; a lower score indicates better sleep quality. The N-GSSIQ is a validated instrument to assess nocturnal GERD symptom severity and its impact on the next morning during the past 2 weeks. This questionnaire includes 20 items covering three subscales: Nocturnal GERD Symptom Severity (13 items; score range of 065), Morning Impact of Nocturnal GERD (2 items; score range of 010), and Concern about Nocturnal
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GERD (5 items; score range of 020) (14). Morning Impact relates to how the patient feels upon waking because of GERD symptoms they may have experienced during the night, including feeling tired or irritable. Concern about Nocturnal GERD relates to the patients level of concern about their condition, including concern about severity and worsening of symptoms, the need to monitor diet close to bedtime to prevent symptoms, and general impact of symptoms on everyday life. For the purpose of this study, the total N-GSSIQ score was calculated as the sum of the scores of all items. For each subscale, item scores were summed when at least 50% of the items were non-missing, with the missing items imputed by the mean of the non-missing items. Higher scores represent greater severity of symptoms, greater symptom impact, and greater concern. The WPAI-Special Health Problem, a validated six-item, selfadministered questionnaire, was adapted to assess the impact of GERD-related sleep disturbances on work productivity and regular daily activities during the past 7 days (1517). The questionnaire assesses the numbers of hours missed from work due to GERDrelated sleep disturbances (absenteeism), and the degree to which (on a scale of 010) GERD-related sleep disturbances affected productivity at work (presenteeism) and during other non-work activities. Outcomes are expressed as percentage impairments in overall work productivity, impairment while working, and impairment of daily activities, with higher numbers indicating greater impairment. Work hours missed due to sleep disturbance were calculated as the sum of the hours missed due to GERD plus the actual hours worked multiplied by the degree (in percentage impairment) to which GERD affected work productivity. Economic savings were calculated as the mean change in work hours missed from baseline to week 4 multiplied by the average total employee compensation cost obtained for December 2009 from the Bureau of Labor Statistics (22).
Safety assessments

Safety assessments, including vital signs, electrocardiograms, laboratory evaluations, physical exams, and evaluation of adverse events (AEs), were performed at day 1 and week 4/final visit, and during any unscheduled visit. All AEs which occurred after the patient signed the informed consent form were collected (treatment-emergent AEs). The investigator rated the severity of each AE and assessed its relationship to the study drug.
Statistical analyses

The sample size was 150 patients/treatment and provided at least 95% power for a two-sided test at the 0.05 significance level to detect a 21% treatment difference between dexlansoprazole MR 30 mg and placebo (61 vs. 40%) for the primary efficacy end point of percentage of nights without heartburn. In addition, this sample size would provide sufficient power to determine significance in the treatment differences for the secondary end points. The SAS system for the UNIX operating system was used to perform the statistical analyses. The significance was 0.05 for demographic, efficacy, and safety variables. All statistical tests were two-sided. All efficacy and safety analyses were performed on the
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intent-to-treat population (all randomized patients who received 1 dose of study drug). The primary efficacy variable of the percentage of nights without heartburn was compared between dexlansoprazole MR and placebo using a Wilcoxon rank-sum test. Because of the non-parametric statistical method used and the skewed nature of individual results within each treatment group, the primary efficacy end point is reported using the median within each treatment group. Subgroup analyses for the primary efficacy variable were conducted for various factors, including the baseline mean severity of nocturnal heartburn. Comparisons between the treatment groups were made using the van Elteren test with the subgroup as the stratification factor. If the dexlansoprazole MR 30 mg group was statistically superior to the placebo group for the primary efficacy variable, comparisons between dexlansoprazole MR 30 mg and placebo for the secondary efficacy variables would be made with a Fishers exact test and the multiplicity between the two secondary variables would be controlled by HommelSimes method. For the additional efficacy end points, the treatment groups were compared using Wilcoxon rank-sum tests for frequency and severity of heartburn and frequency of sleep disturbances, and one-way analysis of covariance adjusting for baseline score for the patient-reported outcome questionnaires. Differences in the treatment-emergent AEs for the treatment groups receiving dexlansoprazole MR 30 mg and placebo were compared using Fishers exact test.

Efcacy analyses

RESULTS
Demographics and baseline characteristics

Of the 777 patients screened, 305 patients from 33 sites met the inclusion criteria and thus were randomized and received at least one dose of the study drug; 153 patients received placebo and 152 received dexlansoprazole MR 30 mg daily (Figure 1). Six patients in each treatment group discontinued prematurely. The most common reasons for premature discontinuation were withdrew consent and other, with no significant differences in reasons between treatment groups. Compliance with study drug use of 90% was reported for 92.1% of all patients. In addition, 86.6% of patients were 90% compliant with their daily diary entries. Patient demographics and baseline characteristics by treatment group are provided in Table 1. Overall, the majority of patients were female (63.9%) and white (85.2%). There were no significant differences between treatment groups for any of the demographics or baseline characteristics. At baseline, 96% of all patients reported 47 nights with heartburn, while 76% reported sleep disturbances due to GERD-related symptoms on 47 nights during the 7-day period before randomization. The median number of nights with heartburn was 7 and median mean severity of nocturnal heartburn was 2 (moderate). The two treatment groups were comparable in baseline frequency and severity of nocturnal heartburn, with no significant differences observed. Baseline mean use of rescue medication during the night was 5.2 nights/week, with the majority (77%) of patients requiring rescue medication 4 nights/week during screening.
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The primary efficacy end point of the percentage of nights free of heartburn, as assessed by daily diary, was significantly greater in patients receiving dexlansoprazole MR 30 mg daily than in those receiving placebo (median of 73.1 vs. 35.7%; P < 0.001; Table 2). After adjusting for various subgroup factors, including age, race, gender, body mass index, neck circumference, smoking status, alcohol use, caffeine use, baseline number of days with daytime or nocturnal heartburn, baseline number of days with nocturnal heartburn, baseline mean severity of daytime or nocturnal heartburn, baseline mean severity of nocturnal heartburn, baseline GERD Symptom Investigator Assessment of heartburn, and prior PPI usage, dexlansoprazole MR 30 mg remained significantly superior to placebo in controlling nocturnal heartburn. Patients with more severe baseline nocturnal heartburn experienced greater therapeutic gain (Figure 2). The therapeutic gain for patients with mild-to-moderate, moderate-to-severe, and severe-to-very severe baseline heartburn was 30.2, 32.1, and 65.6%, respectively. The secondary efficacy end pointspercentage of patients with relief of nocturnal heartburn and GERD-related sleep disturbances during the last 7 days of treatmentare also provided in Table 2. A significantly greater percentage of patients in the dexlansoprazole MR 30 mg group than in the placebo group reported relief of nocturnal heartburn or GERD-related sleep disturbances (47.5 vs. 19.6% and 69.7 vs. 47.9%, respectively; P < 0.001 for both variables). During treatment, patients in the dexlansoprazole MR group had significantly less severe nocturnal heartburn than patients in the placebo group (median mean severity score of 0.48 vs. 1.15, respectively; P < 0.001). Figure 3 illustrates the median percentage of nights with any GERD-related sleep disturbances, nights with specific types of sleep disturbances, mornings impacted by sleep disturbances, and nights with sleep disturbance due to other reasons, as assessed by daily diary. Patients receiving dexlansoprazole MR reported a significantly lower percentage of nights with sleep disturbance due to GERD compared with placebo (median of 11.1 vs. 36.8%; P < 0.001). In addition, patients in the dexlansoprazole MR group experienced significantly fewer nights with each specific GERDrelated sleep disturbance (P < 0.001) and significantly fewer mornings impacted by sleep disturbances (P < 0.001), as shown in Figure 3. The percentage of 24-h heartburn-free days was significantly greater in patients receiving dexlansoprazole MR 30 mg daily than in those receiving placebo (median of 53.3 vs. 14.3%; P < 0.001; Supplementary Table online). Both groups experienced sleep disturbances attributed to other causes (stress, illness other than GERD, sleeping environment, or urge to urinate) infrequently and at similar rates (median of 4.0 vs. 3.8% of nights; P = 0.377). Improvements from baseline to week 4 in sleep quality as assessed by the PSQI questionnaire were significantly greater in the dexlansoprazole MR 30 mg group vs. the placebo group (mean of 2.70 vs. 1.35; P = 0.001; Table 3). Patients in the dexlansoprazole MR 30 mg group also experienced significant improvement in patient-reported outcome measures. Improvements in N-GSSIQ total score, the Nocturnal GERD Symptom Severity, Morning Impact of Nocturnal GERD,
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Patients screened N =777

Randomization and receipt of study drug N =305

Other (n=45) Withdrew consent (n=26) Non-compliance (n=10) Scheduling conflicts (n=4) Personal reasons (n=2) Lost to follow-up (n=2) Sponsor decision (n=1)

Dexlansoprazole MR 30 mg N =152

Placebo N =153

Completed N =146

Prematurely discontinued N =6

Completed N =147

Prematurely discontinued N =6

Adverse event (n=1) Protocol violation (n=2) Lost to follow-up (n=1) Withdrew consent (n=1) Inclusion/exclusion criteria not met (n=1)

Adverse event (n=1) Withdrew consent (n=2) Other (n=3)

Figure 1. Flow of patients through the study.

and Concern about Nocturnal GERD subscale scores were all greater in the active therapy group (P < 0.001; Table 3). From baseline to week 4, the dexlansoprazole MR group showed a significantly greater decrease in overall work productivity impairments (Table 3). In addition, significantly greater decreases in impairment while working and impairment of regular activities (such as work around the house, shopping, childcare, and studying) were observed in the dexlansoprazole MR group. The number of impaired work hours decreased by 8.25 h/patient (as measured for the last week assessed) among patients in the dexlansoprazole MR group and by 6.89 h/patient among patients receiving placebo (P = 0.036; Table 3). Based on the average hourly employee compensation cost of $27.49 in December 2009 (22), the mean cost saved for the last week of treatment for patients treated with dexlansoprazole MR ($227) was greater compared with placebo ($189), based on mean hours worked.
2011 by the American College of Gastroenterology

Safety analyses

Rates of AEs were similar between treatment groups. The most frequently reported treatment-emergent AE (5% of patients) was upper respiratory tract infection, reported by 7 patients (5%) in the dexlansoprazole MR group, and 3 (2%) in the placebo group. The majority of patients who experienced AEs had events that were mild or moderate in severity. Two patients discontinued prematurely due to an AE; one patient in the dexlansoprazole MR group withdrew due to headaches, and one patient in the placebo group withdrew due to nausea. Both instances were considered to be related to the study drug, and occurred during the first 2 days of treatment. The only serious AEs experienced were in the placebo group; 1 patient had a spontaneous abortion and another developed an incisional hernia. No deaths occurred during the study.
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Screening failures (N =472) Did not meet inclusion/exclusion criteria (n=427)

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Table 1. Demographics and baseline characteristicsa

Table 2. Results of the primary and secondary end points

Overall, N = 305 Dexlansoprazole MR 30 mg, N =152 73.1 47.5 (67/141) Placebo, N =153 35.7 19.6 (29/148)

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Characteristic

Dexlansoprazole MR 30 mg, N =152

Placebo, N =153 n (%)

Efcacy end point Median percentage of nights without heartburn Percentage of patients with relief of nocturnal heartburn during the last 7 days of treatment Percentage of patients with relief of GERDrelated sleep disturbances during the last 7 days of treatment

P value < 0.001 < 0.001

Female Caucasian Age at baseline (years) MeanSD Range Weight (kg) MeanSD Range Height (cm) MeanSD Range BMI (kg/m2) MeanSD Range PPI use within 6 months of randomization Alcohol drinker Smoker Caffeine user

97 (63.8) 129 (84.9)

98 (64.1) 131 (85.6)

195 (63.9) 260 (85.2)

44.611.29 2166

43.912.45 1866

44.211.87 1866

69.7 (99/142)

47.9 (69/144)

< 0.001

85.020.39 49158

86.823.89 44150

85.922.20 44158

GERD, gastroesophageal reux disease.

168.69.61 144193

167.810.44 132193

168.210.02

Median percentage of nights without heartburn

132193

100 90 80 70 60 50 40 30 20 10 0

98.1 77.6 60.7 47.4 28.6 65.6

73.9

29.86.48 1754 79 (52.0)

30.77.78 1858 79 (51.6)

30.37.17 1758 158 (51.8)

86 (56.6) 35 (23.0) 126 (82.9)

81 (52.9) 42 (27.5) 126 (82.4)

167 (54.8) 77 (25.2) 252 (82.6)

0.0
ve r se e-to ve -v re er y M m ildod to er - < at e ild <M -to M se od ve era re te -<

BMI, body mass index; PPI, proton pump inhibitor. a There was no signicant difference in the distribution of demographics and baseline characteristic between the treatment groups. n=2, 7

n=60, 63

n=55, 59

DISCUSSION
Dexlansoprazole MR 30 mg daily was significantly better than placebo in improving symptoms of nocturnal heartburn in symptomatic GERD patients with frequent, moderate-to-very severe nocturnal heartburn leading to improved sleep quality, and decreased symptom severity and impact on morning activities. Dexlansoprazole MR 30 mg was also effective in increasing work productivity and reducing activity impairment. It should be noted that patients enrolled in this study had to be responsive to acid-suppression therapy. This inclusion criterion was used to limit the number of functional heartburn patients enrolled in the study. During this study, the median percentage of nights without heartburn over 4 weeks for the intent-to-treat patients receiving dexlansoprazole MR 30 mg was 73.1%. In a previous dexlansoprazole MR phase 3 study, which assessed efficacy and safety among patients with non-erosive reflux disease, this value was 80.8% (vs. 51.7% for placebo; P < 0.00001) (23), supporting the results of our study. Furthermore, the therapeutic gain, or the difference between active study drug and placebo, seen in this current nocturnal heartburn study was greater than that observed in a previous phase 3 symptomatic GERD trial (37 vs. 29%) (23).
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Figure 2. Median percentage of nights without heartburn, by baseline nocturnal heartburn severity. P < 0.001 for overall comparison between treatment groups.

Stratification of the primary end point by baseline mean nocturnal symptom severity reveals that patients with the most severe symptoms experience the greatest therapeutic gain. Although the median percentage of nights free of nocturnal heartburn declined with increasing baseline severity, the therapeutic gain increased. The therapeutic gain experienced by patients receiving dexlansoprazole MR with severe-to-very severe baseline nocturnal symptoms is more than twice that experienced by patients with mild-to-moderate or moderate-to-severe baseline nocturnal symptoms. Patients in the severe-to-very severe group who received placebo experienced a median of 0% heartburn-free nights, while the 34 patients in the dexlansoprazole MR group reported a median of 66% of their nights as heartburn free during the 4 weeks of the trial. This could be explained by the finding that patients with more severe non-erosive reflux disease (NERD; as determined by
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Se

n=34, 24

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40

36.8
35

Dexlansoprazole MR 30 mg Placebo

30

Median percentage

26.1
25

22.2
20

22.2

16.7
15

16.7

11.1
10

9.7 6.9 7.7 6.2 6.1 4.0 3.8

Nights with GERD-related sleep disturbances

Nights with difficulty falling asleep

Nights with waking

Nights with Mornings difficulty waking too getting back to early sleep

Mornings waking up feeling tired

Nights with sleep disturbances due to other reasons

Figure 3. Median percentage of nights with sleep disturbances, mornings impacted by sleep disturbances, or nights with other (non-gastroesophageal reux disease (non-GERD) associated) sleep disturbances, as assessed by daily diary. P < 0.001 for all comparisons between treatment groups except for the percentage of nights with sleep disturbances due to other reasons (P = 0.377). Other reasons for sleep disturbances were stress, illness other than GERD, sleeping environment, or urge to urinate.

pH testing) are more responsive to PPI therapy than patients with less severe NERD (24). This is in contrast to the response of erosive esophagitis patients receiving anti-reflux treatment (25). During the last 7 days of the study, 48 and 70% of patients receiving dexlansoprazole MR reported relief of nocturnal heartburn and GERD-related sleep disturbances, respectively, which were significantly greater than with placebo (P < 0.001 for each comparison). A similar pattern was observed by Johnson et al. (26), where patients receiving esomeprazole, 20 or 40 mg, reported higher rates of relief from GERD-related sleep disturbances from nocturnal heartburn during the last 7 days of a 4-week study. A significantly lower frequency of GERD-related sleep disturbances was observed in the dexlansoprazole MR group. Dexlansoprazole MR resulted in a significantly lower frequency of the different types of sleep disturbances attributed to nocturnal heartburn. Of note, the percentage of nights with sleep disturbances due to other causes did not differ significantly between treatment groups. Taken together, these results suggest that patients taking dexlansoprazole MR 30 mg can expect a reduction in or relief from nocturnal heartburn symptoms and therefore better sleep quality. Recording daily symptoms via diaries is common in clinical trials where symptom relief is a primary outcome (27). However, the limitations of this approach, particularly with paper diaries, include non-adherence (skipping entries) and hoarding (the retrospective completion of entries), which can lead to recall errors (28,29). Objective analyses of paper diary use have shown high rates of both non-adherence and hoarding (29). Electronic diaries, such as those used during this study, do not allow for hoarding

beyond 24 h before the scheduled entry. Compliance with diary entries was high: 90% in 87% of patients. The efficacy of dexlansoprazole MR for the relief of nocturnal heartburn and relief from GERD-related sleep disturbances is further supported by the improvements seen in the patient-reported outcomes. Patients receiving dexlansoprazole MR reported significantly greater improvements from baseline in sleep quality compared with placebo, which manifested as greater decreases in PSQI scores. Decreases in overall and subscale N-GSSIQ scores also showed greater efficacy for dexlansoprazole MR 30 mg compared with placebo in decreasing symptom severity, next morning impact of nocturnal symptoms, and concern regarding nocturnal GERD among the patients, thus demonstrating improvements in HRQoL. Significant improvements in HRQoL due to treatment of heartburn, both daytime and nocturnal, have been documented previously (23,26,30,31). Accompanying these improvements in sleep quality, decreased symptom severity, and reduced impact the following morning were decreases in impairments in work productivity, as demonstrated by decreases in the WPAI scores. Treatment with dexlansoprazole MR was more effective than placebo in decreasing impairment while working and improving overall work productivity and functionality during regular activities. Furthermore, this treatment was more effective in reducing the number of work hours missed due to GERD-related sleep disturbances. These results are not unexpected when one considers the connection between repeated lack of sleep during the night and daytime sleepiness (9), as well as reduced HRQoL and work productivity (11). The

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Table 3. Mean change from baseline to week 4 in PSQI, N-GSSIQ, and WPAI questionnaire scores

Table 3. Continued
Questionnaire outcome P value Dexlansoprazole MR 30 mg, N =152 Placebo, N =153

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Questionnaire outcome PSQI Sleep quality na Baseline Week 4 Changeb N-GSSIQ Total score n Baseline Week 4 Change

Dexlansoprazole MR 30 mg, N =152

Placebo, N =153

P value

Degree of impairment on regular activities (%) n Baseline 140 43.1426.34 16.2922.64 26.8629.77 136 46.3227.02 26.4725.92 19.8528.47 0.001

137 9.303.57 6.603.71 2.703.08

133 8.873.64 7.523.70 1.353.23

0.001

Week 4 Change

Degree of impairment while working (%) n Baseline Week 4/nal visit 93 36.9927.93 12.2619.00 24.7328.38 84 40.3627.26 23.3325.43 17.0224.92 0.001

139 46.5517.71 18.1719.34 28.3820.26

136 48.2416.95 30.2322.11 18.0118.78

< 0.001

Change

Nocturnal GERD Symptom Severity subscale n Baseline Week 4 Change 139 29.2012.13 10.8513.03 18.3513.51 136 30.3311.29 18.4514.67 11.8813.01 < 0.001

GERD, gastroesophageal reux disease; N-GSSIQ, Nocturnal Gastroesophageal Reux Disease Symptom Severity and Impact Questionnaire; PSQI, Pittsburgh Sleep Quality Index; WPAI, Work Productivity and Activity Impairment. a For each score, only patients with baseline and week 4/nal visit data available were included in each analysis. Negative change indicates improvement or decreased impairment. Only patients who were employed at the time they completed the WPAI were included in the responses regarding work, while all patients, regardless of employment status, were included in responses regarding impact on regular activities. Results are presented as means.d.
c b

Morning Impact of Nocturnal GERD subscale n Baseline Week 4 Change 138 5.722.70 2.592.81 3.133.30 136 5.862.65 4.093.01 1.772.62 < 0.001

Concern about Nocturnal GERD subscale n Baseline Week 4 Change WPAI c Work hours lost/week/patient n Baseline Week 4 Change 93 13.2111.89 4.957.74 8.2512.28 83 16.6414.22 9.7515.27 6.8914.90 0.036 138 11.724.78 4.755.12 6.965.52 136 12.055.09 7.696.10 4.365.08 < 0.001

Degree of impairment on work productivity (%) n Baseline Week 4 Change 91 38.0829.03 13.0419.94 25.0429.08 78 40.9927.77 23.9326.47 17.0626.49 0.003

negative impact of nocturnal GERD on HRQoL and work productivity is well recognized (7,8,10). A recent survey of over 600 GERD patients on various PPI therapies found that the majority of patients continued to experience heartburn, with 83% experiencing nocturnal symptoms and almost a quarter of these patients reporting severe or very severe nocturnal symptoms (32). Daily dosing of dexlansoprazole MR 30 mg may reduce the likelihood of persistent nocturnal symptoms due to its extended duration of plasma drug levels (33); however, additional studies are needed to determine if this property equates to improved clinical outcomes. In the above-mentioned survey (32), only approximately onehalf of the patients surveyed took their PPI within the recommended 1 h to 30 min before breakfast. Poor compliance with PPI therapy is likely the most common cause for PPI failure (25). In this study, patients were to take the study drug in the morning, without regard to food. Comparable acid suppression with dexlansoprazole MR dosing has been demonstrated regardless of the timing of food intake (fasting, before or after breakfast) (34) or the time of day (before breakfast, lunch, dinner, or evening snack) (35). Although additional studies are needed to assess the impact of various dosing timings of dexlansoprazole MR on GERD symptoms, it is not unreasonable to suggest that increased flexibility in administration, and therefore increased compliance, would lead to reduced symptoms, particularly at night. Dexlansoprazole MR 30 mg was well tolerated by patients in this current trial. Rates of treatment-emergent AEs were low and

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similar between the dexlansoprazole MR and placebo groups, including the premature discontinuation due to AEs. Recent analyses of pooled safety data from the phase 3 pivotal trials demonstrated that the safety profile of dexlansoprazole MR 30 mg was comparable to that of lansoprazole 30 mg (36). The economic implications of this study are readily apparent. The favorable effect of improvement for work productivity has significant implications to payers and employers. For the patients receiving dexlansoprazole MR compared with placebo, there was an apparent work productivity advantage$38 for the fourth week ($227 vs. $189). If these savings were extrapolated over the 4-week study, the advantage would be $152/treated patient. This type of modeling allows for the development of a business plan for payersemployers to evaluate the cost benefits of effective therapy. By this type of analysis, the investment cost of therapy can be analyzed against the returns of improved work productivity. This study has several limitations, the first being the lack of an active comparator, another PPI. Although direct comparisons of efficacy results from different trials cannot be made, a recent review comparing the efficacy of various PPIs (not including dexlansoprazole MR) in relieving or resolving nocturnal heartburn in a clinical trial setting found no outstanding differences in efficacy between comparable doses (37). Placebo has been the standard comparator used in other studies assessing the efficacy of a PPI for nocturnal heartburn and in all studies of GERD-related sleep disturbances (23,26,38). A second limitation is the lack of pH monitoring to document the level of acid suppression or to distinguish symptomatic nonerosive reflux from functional heartburn. It is difficult to attribute any symptom to reflux without direct esophageal monitoring. The primary reason for no pH monitoring during this study was the potential sleep disruption caused by an intra-esophageal pH electrode. However, to mitigate lack of pH monitoring, inclusion criteria mandated previous response to acid-suppression therapy. We also did not utilize sleep labs for an objective assessment of sleep quality, which could be considered another limitation. Because a sleep lab is an artificial environment, it is likely that many patients would not have slept the same way there as they would at home. Changes in sleep quality are subjective, whether as reported in the daily diaries or in the PSQI and N-GSSIQ. A third limitation is the assessment of response for productivity analysis limited to the fourth week of therapy. Questions remain as to what the effect is on a weekly basis beyond the early therapy effect on these particular measurements. Furthermore, an area of further research is to evaluate whether these favorable effects persist, wane, or continue to improve with extended therapy. In summary, dexlansoprazole MR 30 mg was significantly more efficacious in providing relief from nocturnal heartburn and in reducing GERD-related sleep disturbances compared with placebo in symptomatic GERD patients with moderate-to-very severe nocturnal heartburn. This study also demonstrated significantly greater improvements in sleep quality, HRQoL, and work productivity for patients receiving dexlansoprazole MR compared with those receiving placebo.
2011 by the American College of Gastroenterology

ACKNOWLEDGMENTS

We thank all the investigators who contributed to this study. Writing support was provided by Meryl Gersh, PhD, of AlphaBioCom LLC, Radnor, PA, and was funded by Takeda Pharmaceuticals North America, Inc.

CONFLICT OF INTEREST

Guarantor of the article: M. Claudia Perez, MD. Specific author contributions: Substantial contributions to conception and design/analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, and supervision of manuscript: Ronnie Fass, David A. Johnson, and William C. Orr; substantial contributions to statistical planning, analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, and statistical analysis: Cong Han; substantial contributions to conception and design/analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, and statistical analysis of economic data: Reema Mody; substantial contributions to analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, and administrative/ technical/material support: Kathleen Stern; substantial contributions to analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, administrative/technical/material support, and supervision of manuscript: Betsy Pilmer, and M. Claudia Perez. Financial support: This study was sponsored by Takeda Global Research and Development Center, Inc, Deerfield, IL (TAP Pharmaceutical Products, Lake Forest, IL was the sponsor at the time the study was conducted; TAP is now a part of Takeda Global Research and Development Center, Inc). Potential competing interests: Ronnie Fass has received research grants from Takeda, AstraZeneca, and Wyeth; has served as a consultant to Takeda, Eisai, Vecta, GlaxoSmithKline, and Xenoport; and is a speaker for Takeda. David A. Johnson has received research grants from AstraZeneca and Takeda; has served as a consultant to AstraZeneca, Takeda, Novartis, and Xenoport, and as adjudicator for the clinical trial of Esai. William C. Orr has received research funding from Takeda; is a consultant to Takeda and Xenoport; is a speaker for Takeda. Cong Han, Kathleen N. Stern, Betsy L. Pilmer, and M. Claudia Perez are employees of Takeda Global Research & Development Center, Inc, Deerfield, IL, USA. (At the time of study conduct they were employees of TAP Pharmaceutical Products, Lake Forest, IL, which is now a part of Takeda Global Research & Development Center, Inc.) Reema Mody is an employee of Takeda Pharmaceuticals International, Inc, Deerfield, IL, USA. (At the time of study conduct she was an employee of TAP Pharmaceutical Products, Lake Forest, IL, which
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ESOPHAGUS

Furthermore, there were notable economic implications with favorable advantages evident for patients treated with dexlansoprazole MRallowing for estimates of a calculable rate of return on investment for effective therapy.

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ESOPHAGUS

is now a part of Takeda Pharmaceuticals International, Inc). All authors had access to the data and vouch for the veracity and completeness of the data and the data analysis.

Study Highlights
WHAT IS CURRENT KNOWLEDGE

3Nocturnal gastroesophageal reux disease (GERD)-related 3GERD-related sleep disturbances negatively impact health-related quality of life (HRQoL) and work productivity. 3Proton pump inhibitor (PPI) treatment signicantly improves nocturnal heartburn. 3PPI treatment has also been shown to improve GERDrelated sleep disturbances. symptoms are very common, affecting the majority of GERD patients.

WHAT IS NEW HERE

3Focus on symptomatic non-erosive gastroesophageal reux 3Patients with severe nocturnal heartburn experienced greater therapeutic gain with dexlansoprazole MR than placebo. 3Dexlansoprazole MR improved sleep quality and healthrelated quality of life (HRQoL) compared with placebo. 3Treatment with dexlansoprazole MR improved work productivity compared with placebo. 3There are notable economic implications with favorable
advantages evident for patients treated with dexlansoprazole MR. disease (GERD) patients with GERD-related sleep disturbances.

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