Alimentary Pharmacology and Therapeutics

Clinical trial: esomeprazole for moderate-to-severe nighttime heartburn and gastro-oesophageal reux disease-related sleep disturbances
D. Johnson*, J. A. Crawley, C. Hwang & K. Brown

*Gastroenterology Division, Eastern Virginia Medical School, Norfolk, VA, USA. Clinical Research, AstraZeneca LP, Wilmington, DE, USA.

SUMMARY Background Nighttime heartburn, common among patients with gastro-oesophageal reux disease (GERD), is associated with substantial clinical effects. GERDrelated sleep disturbances are underappreciated and undertreated. Aim To evaluate the efcacy of esomeprazole on GERD-related nighttime heartburn and associated sleep disturbances. Methods In this multicentre, randomized, double-blind, placebo-controlled study, patients with moderate-to-severe nighttime heartburn and GERD-related sleep disturbances (endoscopies not required) received esomeprazole 20 mg or placebo each morning for 4 weeks. Heartburn symptoms and GERD-related sleep disturbances were evaluated using the validated Pittsburgh Sleep Quality Index and validated Work Productivity and Activity Impairment Questionnaire. Results The analysis included 262 patients (esomeprazole, n = 137; placebo, n = 125). Signicantly more patients receiving esomeprazole achieved nighttime heartburn relief (primary end point) than those receiving placebo (34.3% vs. 10.4%; P < 0.0001). Secondary end points such as relief of GERD-related sleep disturbances (P = 0.006), days without GERD-related sleep disturbances (P = 0.0003) and complete resolution of sleep disturbances (P < 0.0001) favoured esomeprazole over placebo. Sleep quality, work productivity and regular daily activities also improved signicantly with esomeprazole vs. placebo. Conclusions Esomeprazole 20 mg is effective for patients with moderate-to-severe nighttime heartburn and GERD-related sleep disturbances, improving heartburn symptoms, sleep quality, work productivity and functionality. Aliment Pharmacol Ther 2010; 32: 182190

Correspondence to: Dr D. Johnson, Eastern Virginia Medical School, Gastroenterology Division, 885 Kempsville Rd, Suite 114, Norfolk, VA 23502, USA. E-mail: DAJEVMS@aol.com

Publication data Submitted 25 January 2010 First decision 26 February 2010 Resubmitted 23 April 2010 Accepted 26 April 2010 Epub Accepted Article 29 April 2010

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2010 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2010.04339.x

Clinical trial: esomeprazole for heartburn and sleep disturbances INTRODUCTION Nighttime heartburn is common among patients with gastro-oesophageal reux disease (GERD) and has a clinically signicant impact on patients lives. Data suggest that approximately three-fourths of patients with symptoms of GERD experience heartburn at night.1, 2 Patients who experience nocturnal GERD have a signicantly greater impairment of health-related quality of life compared with those who do not experience nocturnal symptoms.1, 3, 4 In a survey of 1000 US patients with heartburn, 75% reported that nighttime heartburn affects their sleep, 63% indicated that heartburn negatively affects their ability to sleep well and 40% believed that sleep difculties caused by nighttime heartburn impair their ability to function the next day.2 In another study, European patients (N = 2202) showed that gastrooesophageal reux symptoms were associated with increased risks for difculties in sleep induction, nightmares and nocturnal and early morning awakenings.5 Furthermore, productivity at work and during regular activities is reduced in patients with GERD symptoms compared with those without GERD symptoms6, 7 and the effect is greater in those with nocturnal symptoms compared with those with minimal or no nocturnal symptoms.3 In addition to negatively affecting work productivity, daytime sleepiness has been associated with an increased risk of cardiovascular mortality, especially in women.8 Moreover, nocturnal reux symptoms are associated with an increased risk of oesophageal adenocarcinoma,9 asthma and respiratory symptoms and symptoms of obstructive sleep apnoea syndrome.10 In most patients with symptomatic GERD, reux events occur during daytime and nighttime. While daytime reux events occur frequently, reux events that occur during sleep are less frequent but last longer than those that occur during daytime.11 Reux events can disturb sleep, and sleep also can negatively inuence reux events. During sleep, a dramatic decline occurs in saliva production, the frequency of swallowing and the rate of gastric emptying, leading to a decreased ability to neutralize reux events and a prolonged acid contact time.11 Patients with GERD with sleep complaints may have a more severe form of reux disease. A study demonstrated that patients who have signicant nighttime heartburn and sleep complaints have a greater number of reux events lasting longer than 5 min and a greater duration of time with acidic oesophageal pH (pH <4) than patients without nighttime heartburn.12 Increased severity or frequency of GERD symptoms is associated
with more concomitant diseases, lower health-related quality of life, reduced work productivity, impairment in daily activities and increased health care utilization.6, 13 Previous studies have suggested that effective acid suppressive treatment can ameliorate the negative clinical impact of nocturnal symptoms.1419 Although several of these studies were uncontrolled and or observed only a small number of patients, one placebo-controlled study that observed 650 patients with moderate-to-severe nighttime heartburn and GERD-associated sleep disturbances has been published; Johnson et al.14 showed that signicantly more patients receiving esomeprazole 40 mg and 20 mg (53.1% and 50.5%, respectively) achieved relief of nighttime heartburn symptoms (primary end point) compared with patients receiving placebo (12.7%; P < 0.0001). Additionally, secondary end points, including resolution of GERD-related sleep disturbances, improvements in sleep quality and work hours saved per week per patient compared with baseline, all signicantly (P < 0.0001) favoured both esomeprazole groups over placebo.14 The present study was conducted to conrm the ndings of Johnson et al.14 for esomeprazole 20 mg once daily, which is the dosage approved by the US Food and Drug Administration for the healing of erosive oesophagitis and symptomatic GERD.20 The primary objective was to assess the difference in effects between esomeprazole 20 mg once daily taken in the morning before breakfast for 4 weeks and placebo on the relief of GERD-related nighttime heartburn. Secondary objectives included assessments of the impact of esomeprazole 20 mg on GERD-related sleep disturbances, daytime and 24-h heartburn, work productivity and functionality during regular daily activities.

METHODS
Study design and patient protocols This multicentre, randomized, double-blind, placebocontrolled, prospective study (D9612L00122; NCT00660660) was conducted between 7 April 2008 and 10 July 2008 in the United States in accordance with Good Clinical Practice, the Declaration of Helsinki and applicable regulatory requirements. Approval from appropriate Institutional Review Boards for the participating centres and written informed consent were obtained before initiation of study procedures. Men, and nonpregnant, nonlactating women aged 18 85 years with GERD were eligible for study entry if they had episodes of heartburn or acid regurgitation for

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3 months or history of erosive oesophagitis and nighttime GERD symptoms averaging at least two episodes in a 7-day period before enrolment. Patients must have had a history of GERD-related sleep disturbances (e.g. trouble falling asleep, frequent awakenings, overall poor sleep quality) for 1 month before enrolment. In addition, patients must have had GERD-related sleep disturbances and moderate or severe nighttime heartburn on at least three of the last seven nights of the 1- to 2week run-in period. Patients were excluded if they had conditions other than GERD known to affect sleep (e.g. sleep apnoea, obstructed airway, severe depression), were shift workers who worked between the hours of 12 AM (midnight) and 6 AM or had active gastrointestinal bleeding. The study protocol did not require endoscopic evaluations, so the study population was expected to include patients with and without erosive oesophagitis. Sleep medication was allowed if use was stable (3 months) and was expected to remain stable throughout the study. Proton pump inhibitor (PPI) use was not allowed within 1 week before screening. Gelusil antacid tablets (Pzer Inc., New York, NY, USA) were allowed as rescue medication throughout the study (6 tablets during 24-h period and 21 tablets over any 7-day period). Assignment. After a 1- to 2-week run-in period, patients were randomized (from a centralized centre using a computerized randomization schedule) to esomeprazole 20 mg (Nexium; AstraZeneca LP, Wilmington, DE, USA) once daily or placebo taken before breakfast for 4 weeks. Masking. Patients who met all study entry criteria and who provided written informed consent were randomized in a double-blind fashion and assigned an allocation number in sequential order within each study centre. At the randomization visit, patients received a bottle of investigational product with the assigned allocation number. A single-dummy design (identical appearance of study drug and placebo capsules) was used to ensure continued blinding. Symptoms. Daytime and nighttime heartburn symptom severity (none, mild, moderate, severe) was assessed each morning using a daily diary card. The primary end point, relief of nighttime heartburn, was dened as a daily diary response of none on 6 of the last 7 days of the study, allowing for one mild response. Complete
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resolution of heartburn was dened as a daily diary response of none for 7 consecutive days of the study. Relief of GERD-related sleep disturbances. Relief of GERD-related sleep disturbances was assessed by a yes or no response to the question, Did you have trouble sleeping last night due to your heartburn or other symptoms of GERD? each morning using a daily diary card. Relief of GERD-related sleep disturbance was dened as a daily diary response of no on 5 of the last 7 consecutive days of the study. Complete resolution of GERDrelated sleep disturbance was dened as a daily diary response of no for 7 consecutive days of the study. Days to complete resolution of GERD-related sleep disturbances was dened as the number of days until the rst day of the 7-consecutive-day period during which the daily diary response was no. Sleep quality. The Pittsburgh Sleep Quality Index (PSQI) Questionnaire is a validated, disease-independent instrument that assesses seven areas of sleep (sleep quality, sleep latency, sleep duration, habitual sleep efciency, sleep disturbance, use of sleep medication and daytime dysfunction) retrospectively over 1 month. Patients completed the PSQI Questionnaire at randomization and nal visit. Scores for each of the seven areas of sleep are based on a 4-point scale (0 = no difculty to 3 = severe difculty). The sum of the seven component scores yield the global PSQI score, which ranges from 0 to 21 with higher scores indicating worse sleep quality. A global PSQI score above 5 indicates that a patient has sleep disturbances (i.e. severe difculties in at least two areas or moderate difculties in at least three areas). Meanwhile, good sleep is dened as a global PSQI score of 5.21 Work productivity. Patients who were employed at the time of the study completed the Work Productivity and Activity Impairment Questionnaire: Sleep DisturbanceGERD (WPAI-SLEEP-GERD) at randomization and nal visits. The WPAI-SLEEP-GERD is a validated six-item questionnaire6, 22 that assesses hours missed from work because of GERD-related sleep disturbance, hours missed from work for other reasons, hours actually worked, the degree (010 scale, with higher scores indicating greater impairment) that sleep disturbance secondary to GERD symptoms affected productivity while working and the degree that sleep disturbance due to GERD symptoms affected regular activities. Answers were based on the previous 7 days. Overall work hours lost because of
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Clinical trial: esomeprazole for heartburn and sleep disturbances

GERD-related sleep disturbance were calculated as the sum of the hours missed because of GERD plus the actual hours worked multiplied by the degree (converted to a percentage) that GERD affected work productivity. The overall work hours saved were the differences between baseline and the week-4 values. Compliance. At each study visit, patients were instructed to return all unused study and rescue medication. Treatment compliance was assessed by reviewing accountability records. Patients who consumed 75125% of study medications were considered compliant. Safety. Adverse events were recorded throughout the study. Clinical laboratory measurements were completed at baseline and nal visits. Vital signs were assessed at baseline and weeks 2 and 4. Statistical analyses Analysis was performed on the modied intention-to-treat (mITT) population to observe a population with prespecied key protocol criteria. The mITT population was dened as patients who received at least one dose of study medication, had post-treatment data beyond day 7, reported a history of heartburn and had moderate or severe nighttime heartburn and GERD-related sleep disturbances on 3 of 7 consecutive days of the run-in period. A sample size of 120 patients per treatment group was determined to provide 90% power to detect a 20% difference in relief rates, assuming a 40% relief rate for the esomeprazole 20 mg group and a 20% relief rate for the placebo group, with a two-sided test at an alpha level of 0.05 using the chi-squared test for proportions. Differences between treatment groups in complete resolution and relief of GERD-related sleep disturbances and daytime, nighttime and 24-h heartburn symptoms were assessed using a chi-squared test. The percentage of days without GERD-related sleep disturbances was analysed with a oneway analysis of variance. The difference in time to rst complete resolution of sleep disturbances between treatment groups was assessed using a log-rank test. Changes from baseline to end of treatment in global PSQI scores and WPAI-SLEEP-GERD end points were analysed using analysis of covariance with baseline score as a covariate. Achievement of good sleep at week 4 was analysed using a Cochran-Mantel-Haenszel test with baseline response as a stratifying factor. Overall work hours saved per patient at week 4 were converted to monetary values using the US Bureau of Labor Statistics labor compensation standard23 from June
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2008 of $28.48 per hour, which included the cost of benets and the mean hourly wage, and were analysed using analysis of variance to compare treatment differences.

RESULTS
Patients Of 276 patients randomized to the study, 262 were included in the mITT population. For inclusion in the study, patients had to have nighttime heartburn graded as moderate or severe on 3 of the last 7 days of the run-in period. The reasons for early discontinuation from the study were voluntary discontinuation of treatment (n = 3), adverse events (n = 1) and other (n = 1) in the esomeprazole group and lost to follow-up (n = 6), lack of therapeutic response (n = 2) and incorrect enrolment (n = 1) in the placebo group (Figure 1). These patients were excluded from the mITT population. Baseline demographics of the 262 patients in the mITT population were similar between the esomeprazole 20 mg and placebo groups (Table 1). Efcacy outcomes Symptoms. The primary end point was the percentage of patients with relief of nighttime heartburn during the last 7 days of the study. Signicantly more patients in the esomeprazole treatment group achieved this end point compared with those receiving placebo (P < 0.0001; Figure 2, Table 2). Esomeprazole treatment also resulted in signicant improvement in several secondary end points, including relief or complete resolution of nighttime, daytime and 24-h heartburn symptoms during the last 7 days of the study (P < 0.0001 vs. placebo for all; Table 2). Sleep disturbances. Relief of GERD-related sleep disturbance was seen signicantly (P = 0.006) more in the esomeprazole group compared with the placebo group during the last 7 days of the study (Table 3). Similarly, patients receiving esomeprazole had signicantly (P = 0.0003) more days without GERD-related sleep disturbances compared with the placebo group (Table 3). Complete resolution of GERD-related sleep disturbances during the last 7 days of the study also was seen signicantly more (P < 0.0001) in the esomeprazole group (48.2%) compared with the placebo group (21.6%). Resolution of sleep disturbances also was faster in the esomeprazole group, with a median number of days to the rst complete resolution of sleep disturbance of 9 days. More than 50% of patients who received placebo did not experience complete resolution during the course
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Screened (n = 431) Failed screening (n = 155) Voluntary by subject (9) Lost to follow-up (6) Sponsor request (106) Other (34) Randomized (n = 276)

Randomized to esomeprazole 20 mg (n = 143) Received esomeprazole 20 mg (n = 142) Discontinuations (n = 4) Adverse event (1) Voluntary by subject (2) Other (1) Completed study (n = 138) Analysis exclusions No study drug or postbaseline measurement (2) No history of heartburn or no nighttime heartburn on 3 days of run-in (4) No GERD-related sleep disturbances on 3 days of run-in (2)

Randomized to placebo (n = 133) Received placebo (n = 132) Discontinuations (n = 8) Incorrect enrollment (1) Lost to follow-up (5) Lack of therapeutic response (2) Completed study (n = 124) Analysis exclusions No study drug or postbaseline measurement (6) No history of heartburn or no nighttime heartburn on 3 days of run-in (1) No GERD-related sleep disturbances on 3 days of run-in (1)

Included in mITT analysis (n = 137)

Included in mITT analysis (n = 125)

Figure 1 | Patient disposition. GERD, gastro-oesophageal reux disease; mITT, modied intention-to-treat.

Characteristic Women, n (%) Mean age (s.d.), years Mean BMI (range), kg m2 Race, n (%) White Black Asian Other Mean nighttime heartburn severity score (s.d.) during run-in period* Mean number of days (s.d.) without heartburn during run-in period BMI, body mass index.

Esomeprazole 20 mg (n = 137) 89 (65) 47.0 (11.7) 30.3 (17.365.6)

Placebo (n = 125) 85 (68) 46.8 (12.9) 30.9 (18.363.1)

Table 1 | Patient demographic and baseline clinical characteristics

105 (77) 25 (18) 3 (2) 4 (3) 2.0 (0.5) 0.6 (1.2)

104 (83) 13 (10) 2 (2) 6 (5) 2.0 (0.5) 0.7 (1.5)

* Mean score in the last 7 days of the run-in period (0 = none; 1 = mild; 2 = moderate; 3 = severe).

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Clinical trial: esomeprazole for heartburn and sleep disturbances

100
Patients with relief of nighttime heartburn (%)

80 60 40 20 0
Esomeprazole 20 mg (n = 137) Placebo (n = 125)

Table 2 | Percentages of patients with complete resolution and relief of heartburn

Symptom Esomeprazole 20 mg (n = 137) Placebo (n = 125)

* 34.3
10.4

Daytime heartburn Relief* Complete resolution Nighttime heartburn Relief* Complete resolution 24-H heartburn Relief* Complete resolution 32.8 27.0 7.2 4.0 34.3 30.7 10.4 6.4 40.1 32.8 11.2 7.2

Figure 2 | Percentage of patients with relief of nighttime heartburn. Daily diary response of none on 6 of last 7 days of the study, allowing for one night with mild heartburn. *P < 0.0001 vs. placebo.

* Daily diary response of none on 6 days of the last 7 days of the study, allowing for one mild response.

of the study (P = 0.0001 for comparison of the time to complete resolution curves), and the median number of days to the rst complete resolution of sleep disturbance was >21 days for these patients. Sleep quality. Patients receiving esomeprazole 20 mg had signicantly (P = 0.003) greater least squares mean (LSM) changes from baseline to end of treatment in PSQI global score compared with the placebo group (Table 3). The mean changes from baseline to end of treatment (week 4) in each of the PSQI domains except sleep disturbance (i.e. global score, sleep quality, sleep latency, sleep duration, habitual sleep efciency, use of sleep medication, daytime dysfunction) were consistently greater with esomeprazole 20 mg once daily than with placebo. Improvements in sleep quality seen in the esomeprazole group occurred regardless of baseline sleep quality. More patients treated with esomeprazole 20 mg who had good sleep (PSQI 5) or sleep disturbances (PSQI >5) at baseline experienced good sleep after 4 weeks compared with patients who received placebo, although the difference did not reach statistical signicance (P = 0.07; Table 3). Work productivity. Employed patients who received esomeprazole (n = 83) reported a signicantly larger change in the overall work hours lost from baseline to end of study attributed to GERD-related sleep disturbances ()9.5 vs. )4.9 h) compared with those who received placebo (n = 78) [LSM difference, )4.64; 95% condence interval (CI): )7.2 to )2.1; P = 0.0005]. The impact of GERD-related sleep disturbances on work productivity also was signicantly lower in the esomeprazole
Aliment Pharmacol Ther 2010; 32: 182190 2010 Blackwell Publishing Ltd

P < 0.0001 vs. placebo. Daily diary response of none for the last 7 consecutive days of the study.

group (n = 83) compared with the placebo group (n = 78) (LSM difference, )1.24; 95% CI: )1.9 to )0.6; P = 0.0002; Figure 3a). In addition, regular activities outside of work (e.g. work around the house, shopping, childcare, exercising, studying) were signicantly less impaired by GERD-related sleep disturbances in patients who received esomeprazole (n = 87) compared with those who received placebo (n = 78) (LSM difference, )1.00; 95% CI: )1.7 to )0.3; P = 0.003; Figure 3b). Finally, the monetary value of work hours saved per patient was signicantly greater in the esomeprazole group (n = 76) compared with the placebo group (n = 74) at week 4 ($280.21 vs. $156.61, respectively). The LSM difference for the monetary value (for 1 week) of work hours saved per patient at week 4 between esomeprazole treatment and placebo ($123.60) was statistically signicant (95% CI: $41.41)205.78; P = 0.0035). Compliance. Treatment compliance was determined with drug accountability records. Three patients in the esomeprazole group and two patients in the placebo group were noncompliant with treatment. Safety Esomeprazole treatment was well tolerated. The overall incidence of adverse events was 21% (30 of 143) in the esomeprazole group and 18.2% (24 of 133) in the placebo group. Nine events (6.3%) in 143 patients in the
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Esomeprazole 20 mg (n = 137) GERD-related sleep disturbances Patients with relief, %* Days without disturbances, mean %* PSQI Global score, LSM change from baseline Patients with score 5, % Patients with score >5, % )2.93 90.5 44.2 )1.80 82.8 33.0 0.0034 NS NS 71.5 73.0 55.2 59.3 0.0060 0.0003 Placebo (n = 125)

P value

Table 3 | Relief of GERDrelated sleep disturbances and improvement in sleep quality

GERD, gastro-oesophageal reux disease; LSM, least squares mean; NS, not signicant; PSQI, Pittsburgh Sleep Quality Index. * Last 7 consecutive days of the study. Baseline (randomization) to week 4. n = 134. n = 123.

esomeprazole group and four events (3.0%) in 133 patients in the placebo group were considered treatmentrelated by the investigator. The most common adverse events with esomeprazole treatment were nausea (n = 5), headache (n = 4), diarrhoea (n = 3) and vomiting (n = 3) and the most common adverse events in the placebo group were abdominal pain (n = 2), atulence (n = 2), nasopharyngitis (n = 2) and pneumonia (n = 2). No serious adverse events were reported with esomeprazole treatment during the study.

DISCUSSION In the present study, treatment with esomeprazole 20 mg once daily for 4 weeks relieved moderate-to-severe nighttime heartburn and GERD-related sleep disturbances. Resolution of sleep disturbances (i.e. 7 consecutive days of no sleep disturbance) occurred signicantly earlier and in more patients with esomeprazole treatment. The economic benets of increased work productivity associated with esomeprazole ($123.60 per patient at week 4) are likely to substantially offset the costs of therapy to the employer who is providing prescription benets as part of health insurance coverage to the employees. Although the savings attributed to improved work productivity from a 1-week analysis should extrapolate to other weeks of therapy, further study is warranted to conrm whether this type of intervention would provide expanded benet. The inclusion and exclusion criteria in the present study were designed to enrol patients experiencing sleep disturbances associated with GERD and not other medical conditions, work schedules or excessive caffeine
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intake. As previously noted, esomeprazole 20 mg was used because it is the dose approved for the healing of erosive oesophagitis and symptomatic GERD.20 Additionally, a 4-week study period was selected because it is the approved treatment period for patients with symptomatic GERD20 and because a majority of patients with erosive oesophagitis are healed with PPI treatment within 48 weeks.20, 24 Because of the association of nighttime heartburn with poor sleep quality and next-day functionality in GERD patients, one can reasonably assume that treatment of nighttime heartburn may improve sleep and daytime functioning. However, the efcacy of acid suppressive therapy in patients with nighttime GERD is not well established. A randomized, placebo-controlled study,14 a study of self-treating subjects25 and several other small or uncontrolled studies1519 have suggested that acid suppression can provide benets in patients with nighttime heartburn or GERD-related sleep disturbances. A placebo-controlled study of 864 subjects with nighttime heartburn found that lansoprazole 15 mg or 30 mg once daily reduced nights with heartburn; however, no outcome measures or assessments of sleep were evaluated.25 In a large prospective, uncontrolled study in 6215 patients with GERD who were receiving routine care, esomeprazole 40 mg or 20 mg daily was associated with improvements from baseline in the sleep subscale of the Quality of Life in Reux and Dyspepsia questionnaire at 2 weeks.18 The previously described randomized, doubleblind, placebo-controlled trial by Johnson et al.14 specically was conducted to focus on GERD-associated sleep disturbances and moderate-to-severe nighttime
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Clinical trial: esomeprazole for heartburn and sleep disturbances

(a)

5.0 4.0 3.0 2.0 1.0 0.0 Esomeprazole 20 mg (n = 137) 5.0 4.2 4.0 3.0 2.0 1.0 0.0 Esomeprazole 20 mg (n = 87) 1.7 4.3 Placebo (n = 125) 1.4 4.0 4.0

Baseline Week 4

2.6

Size of effect of GERD-related sleep disturbances on regular activity

(b)

Baseline Week 4

2.6

Placebo (n = 78)

Figure 3 | Mean size of effect of gastro-oesophageal reux disease (GERD)-related sleep disturbances on (a) work productivity (P = 0.0002) and (b) regular activities (P = 0.003). P values are for change from baseline in esomeprazole vs. placebo. For (a), patients answered the question, During the past 7 days, how much did your sleep disturbance due to GERD symptoms affect your productivity while you were working? on a scale of 010, with 0 indicating that GERD-related sleep disturbance had no effect on work and 10 indicating that GERD-related sleep disturbance completely prevented working. For (b), patients answered the question, During the past 7 days, how much did your sleep disturbance due to GERD symptoms affect your ability to do your regular daily activities, other than work at a job? on a scale of 010, with 0 indicating that GERDrelated sleep disturbance had no effect on daily activities and 10 indicating that GERD-related sleep disturbance completely prevented daily activities.

Results of the current study conrm the ndings of Johnson et al.14 and other previous studies. Strengths of this study include the relatively large study population; the multicentre, randomized, doubleblind, placebo-controlled design; and the consistent efcacy observed in a wide range of variables (i.e. heartburn symptoms, sleep disturbances, sleep quality, work productivity). A limitation of the study is that the protocol restricted entry to patients with moderate-to-severe heartburn. Thus, as in the study by Johnson et al.,14 the effect on sleep disturbances in patients with less severe and less frequent heartburn remains to be established and the observed magnitude of benets in the present study should not be presumed to extend to patients with less severe symptoms. In addition, the study population was expected to include patients with and without erosive oesophagitis. However, endoscopies were not required for inclusion in the study, so the proportion (if any) of patients who had erosive oesophagitis remains unknown. Therefore, it also remains unclear whether esomeprazole is benecial in improving nighttime heartburn and sleep disturbances in patients with erosive oesophagitis, without erosive oesophagitis or both. In summary, sleep disturbance is a common complication in patients with GERD. Recent evidence on the prevalence and negative impact of sleep disorders argue for the inclusion of improved sleep quality as an important treatment goal for patients with GERD. Results of this study demonstrate that esomeprazole is an effective treatment for patients with moderate-to-severe nighttime heartburn and GERD-related sleep disturbances.

Size of effect of GERD-related sleep disturbances on work productivity

heartburn. In that study, treatment with esomeprazole 40 mg or 20 mg once daily reduced nighttime heartburn, reduced GERD-related sleep disturbances, improved work productivity, improved productivity in regular activities and decreased work hours lost compared with placebo.14 The inclusion criteria and end points of the present conrmatory study for the esomeprazole 20 mg once daily dosage were the same as those in the Johnson et al. study, with the exception of an additional analysis on time to relief of symptoms in the present study.
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ACKNOWLEDGEMENTS Declaration of personal interests: D. Johnson: development of the scientic protocol design and data analysis of the study; clinical investigator; development and revision of the manuscript. K. Brown, C. Hwang, J. A. Crawley: development of the scientic protocol design; data analysis of the study; development and revision of the manuscript. Guarantor of the article: D. Johnson, MD, FACG. D. Johnson is a consultant for AstraZeneca LP, Takeda, Novartis, Xenoport and Esai. He is a clinical investigator for AstraZeneca LP, Takeda, and Novartis, and has received grant research support from AstraZeneca LP and Takeda. J. A. Crawley, C. Hwang, and K. Brown are employees of AstraZeneca LP. Declaration of funding interests: This study was funded by AstraZeneca LP, Wilmington, DE, USA. The authors thank Bret Fulton (freelance medical writer), Stella Y. Chow, PhD, Lisa M. Klumpp, PhD, and Judy E. Fallon,
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PharmD, from Scientic Connexions, Newtown, PA, USA, for medical writing services (funded by AstraZeneca LP); the patients; and the study-site physician investigators and their staff.

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