clinical trial: esomeprazole for moderate-to-severe nighttime heartburn and gastro-oesophageal...

Clinical trial: esomeprazole for moderate-to-severe nighttimeheartburn and gastro-oesophageal reflux disease-related sleepdisturbancesD. Johnson*, J. A. Crawley�, C. Hwang� & K. Brown�

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

Correspondence to:Dr D. Johnson, Eastern VirginiaMedical School, GastroenterologyDivision, 885 Kempsville Rd, Suite114, Norfolk, VA 23502, USA.E-mail: [email protected]

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

SUMMARY

BackgroundNighttime heartburn, common among patients with gastro-oesophagealreflux disease (GERD), is associated with substantial clinical effects. GERD-related sleep disturbances are underappreciated and undertreated.

AimTo evaluate the efficacy of esomeprazole on GERD-related nighttime heart-burn and associated sleep disturbances.

MethodsIn this multicentre, randomized, double-blind, placebo-controlled study,patients with moderate-to-severe nighttime heartburn and GERD-related sleepdisturbances (endoscopies not required) received esomeprazole 20 mg or pla-cebo each morning for 4 weeks. Heartburn symptoms and GERD-related sleepdisturbances were evaluated using the validated Pittsburgh Sleep Quality Indexand validated Work Productivity and Activity Impairment Questionnaire.

ResultsThe analysis included 262 patients (esomeprazole, n = 137; placebo, n = 125).Significantly more patients receiving esomeprazole achieved nighttime heart-burn 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 distur-bances (P = 0.006), days without GERD-related sleep disturbances (P =0.0003) and complete resolution of sleep disturbances (P < 0.0001) favouredesomeprazole over placebo. Sleep quality, work productivity and regular dailyactivities also improved significantly with esomeprazole vs. placebo.

ConclusionsEsomeprazole 20 mg is effective for patients with moderate-to-severe night-time heartburn and GERD-related sleep disturbances, improving heartburnsymptoms, sleep quality, work productivity and functionality.

Aliment Pharmacol Ther 2010; 32: 182–190

182 ª 2010 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2010.04339.x

Alimentary Pharmacology and Therapeutics

INTRODUCTIONNighttime heartburn is common among patients withgastro-oesophageal reflux disease (GERD) and has a clin-ically significant impact on patients’ lives. Data suggestthat approximately three-fourths of patients with symp-toms of GERD experience heartburn at night.1, 2 Patientswho experience nocturnal GERD have a significantlygreater impairment of health-related quality of lifecompared with those who do not experience nocturnalsymptoms.1, 3, 4 In a survey of 1000 US patients withheartburn, 75% reported that nighttime heartburn affectstheir sleep, 63% indicated that heartburn negativelyaffects their ability to sleep well and 40% believed thatsleep difficulties caused by nighttime heartburn impairtheir ability to function the next day.2 In another study,European patients (N = 2202) showed that gastro-oesophageal reflux symptoms were associated withincreased risks for difficulties in sleep induction, night-mares and nocturnal and early morning awakenings.5

Furthermore, productivity at work and during regularactivities is reduced in patients with GERD symptomscompared with those without GERD symptoms6, 7 andthe effect is greater in those with nocturnal symptomscompared with those with minimal or no nocturnalsymptoms.3 In addition to negatively affecting work pro-ductivity, daytime sleepiness has been associated with anincreased risk of cardiovascular mortality, especially inwomen.8 Moreover, nocturnal reflux symptoms are asso-ciated with an increased risk of oesophageal adenocarci-noma,9 asthma and respiratory symptoms and symptomsof obstructive sleep apnoea syndrome.10

In most patients with symptomatic GERD, refluxevents occur during daytime and nighttime. While day-time reflux events occur frequently, reflux events thatoccur during sleep are less frequent but last longer thanthose that occur during daytime.11 Reflux events can dis-turb sleep, and sleep also can negatively influence refluxevents. During sleep, a dramatic decline occurs in salivaproduction, the frequency of swallowing and the rate ofgastric emptying, leading to a decreased ability to neu-tralize reflux events and a prolonged acid contact time.11

Patients with GERD with sleep complaints may havea more severe form of reflux disease. A study demon-strated that patients who have significant nighttimeheartburn and sleep complaints have a greater numberof reflux events lasting longer than 5 min and a greaterduration of time with acidic oesophageal pH (pH <4)than patients without nighttime heartburn.12 Increasedseverity or frequency of GERD symptoms is associated

with more concomitant diseases, lower health-relatedquality of life, reduced work productivity, impairment indaily activities and increased health care utilization.6, 13

Previous studies have suggested that effective acidsuppressive treatment can ameliorate the negative clinicalimpact of nocturnal symptoms.14–19 Although several ofthese studies were uncontrolled and ⁄ or observed only asmall number of patients, one placebo-controlled studythat observed 650 patients with moderate-to-severenighttime heartburn and GERD-associated sleepdisturbances has been published; Johnson et al.14 showedthat significantly more patients receiving esomeprazole40 mg and 20 mg (53.1% and 50.5%, respectively)achieved relief of nighttime heartburn symptoms (pri-mary end point) compared with patients receiving pla-cebo (12.7%; P < 0.0001). Additionally, secondary endpoints, including resolution of GERD-related sleep dis-turbances, improvements in sleep quality and work hourssaved per week per patient compared with baseline, allsignificantly (P < 0.0001) favoured both esomeprazolegroups over placebo.14 The present study was conductedto confirm the findings of Johnson et al.14 for esomep-razole 20 mg once daily, which is the dosage approvedby the US Food and Drug Administration for the healingof erosive oesophagitis and symptomatic GERD.20 Theprimary objective was to assess the difference in effectsbetween esomeprazole 20 mg once daily taken in themorning before breakfast for 4 weeks and placebo on therelief of GERD-related nighttime heartburn. Secondaryobjectives included assessments of the impact of esomep-razole 20 mg on GERD-related sleep disturbances,daytime and 24-h heartburn, work productivity andfunctionality during regular daily activities.

METHODS

Study design and patient protocolsThis multicentre, randomized, double-blind, placebo-controlled, prospective study (D9612L00122; NCT00660660)was conducted between 7 April 2008 and 10 July 2008 inthe United States in accordance with Good Clinical Prac-tice, the Declaration of Helsinki and applicable regula-tory requirements. Approval from appropriateInstitutional Review Boards for the participating centresand written informed consent were obtained beforeinitiation of study procedures.

Men, and nonpregnant, nonlactating women aged 18–85 years with GERD were eligible for study entry if theyhad episodes of heartburn or acid regurgitation for

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‡3 months or history of erosive oesophagitis and night-time GERD symptoms averaging at least two episodes ina 7-day period before enrolment. Patients must havehad a history of GERD-related sleep disturbances (e.g.trouble falling asleep, frequent awakenings, overall poorsleep quality) for ‡1 month before enrolment. In addi-tion, patients must have had GERD-related sleep distur-bances and moderate or severe nighttime heartburn onat least three of the last seven nights of the 1- to 2-week run-in period. Patients were excluded if they hadconditions other than GERD known to affect sleep (e.g.sleep apnoea, obstructed airway, severe depression),were shift workers who worked between the hours of12 AM (midnight) and 6 AM or had active gastrointesti-nal bleeding. The study protocol did not requireendoscopic evaluations, so the study population wasexpected to include patients with and without erosiveoesophagitis.

Sleep medication was allowed if use was stable(‡3 months) and was expected to remain stable through-out the study. Proton pump inhibitor (PPI) use was notallowed within 1 week before screening. Gelusil� antacidtablets (Pfizer Inc., New York, NY, USA) were allowedas rescue medication throughout the study (£6 tabletsduring 24-h period and £21 tablets over any 7-dayperiod).

Assignment. After a 1- to 2-week run-in period, patientswere randomized (from a centralized centre using a com-puterized randomization schedule) to esomeprazole20 mg (Nexium�; AstraZeneca LP, Wilmington, DE,USA) once daily or placebo taken before breakfast for4 weeks.

Masking. Patients who met all study entry criteria andwho provided written informed consent were random-ized in a double-blind fashion and assigned an allocationnumber in sequential order within each study centre. Atthe randomization visit, patients received a bottle ofinvestigational product with the assigned allocation num-ber. A single-dummy design (identical appearance ofstudy drug and placebo capsules) was used to ensurecontinued blinding.

Symptoms. Daytime and nighttime heartburn symptomseverity (none, mild, moderate, severe) was assessed eachmorning using a daily diary card. The primary endpoint, relief of nighttime heartburn, was defined as adaily diary response of ‘none’ on ‡6 of the last 7 days ofthe study, allowing for one ‘mild’ response. Complete

resolution of heartburn was defined as a daily diaryresponse of ‘none’ for 7 consecutive days of the study.

Relief of GERD-related sleep disturbances. Relief ofGERD-related sleep disturbances was assessed by a ‘yes’or ‘no’ response to the question, ‘Did you have troublesleeping last night due to your heartburn or other symp-toms of GERD?’ each morning using a daily diary card.Relief of GERD-related sleep disturbance was defined asa daily diary response of ‘no’ on ‡5 of the last 7 consec-utive days of the study. Complete resolution of GERD-related sleep disturbance was defined as a daily diaryresponse of ‘no’ for 7 consecutive days of the study. Daysto complete resolution of GERD-related sleep distur-bances was defined as the number of days until the firstday of the 7-consecutive-day period during which thedaily diary response was ‘no’.

Sleep quality. The Pittsburgh Sleep Quality Index (PSQI)Questionnaire is a validated, disease-independent instru-ment that assesses seven areas of sleep (sleep quality,sleep latency, sleep duration, habitual sleep efficiency,sleep disturbance, use of sleep medication and daytimedysfunction) retrospectively over 1 month. Patients com-pleted the PSQI Questionnaire at randomization andfinal visit. Scores for each of the seven areas of sleep arebased on a 4-point scale (0 = no difficulty to 3 = severedifficulty). The sum of the seven component scores yieldthe global PSQI score, which ranges from 0 to 21 withhigher scores indicating worse sleep quality. A globalPSQI score above 5 indicates that a patient has sleepdisturbances (i.e. severe difficulties in at least twoareas or moderate difficulties in at least three areas).Meanwhile, good sleep is defined as a global PSQI scoreof £5.21

Work productivity. Patients who were employed at thetime of the study completed the Work Productivity andActivity Impairment Questionnaire: Sleep Disturbance-GERD (WPAI-SLEEP-GERD) at randomization and finalvisits. The WPAI-SLEEP-GERD is a validated six-itemquestionnaire6, 22 that assesses hours missed from workbecause of GERD-related sleep disturbance, hours missedfrom work for other reasons, hours actually worked, thedegree (0–10 scale, with higher scores indicating greaterimpairment) that sleep disturbance secondary to GERDsymptoms affected productivity while working and thedegree that sleep disturbance due to GERD symptomsaffected regular activities. Answers were based on theprevious 7 days. Overall work hours lost because of

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184 Aliment Pharmacol Ther 2010; 32: 182–190


GERD-related sleep disturbance were calculated as thesum of the hours missed because of GERD plus theactual hours worked multiplied by the degree (convertedto a percentage) that GERD affected work productivity.The overall work hours saved were the differencesbetween baseline and the week-4 values.

Compliance. At each study visit, patients were instructedto return all unused study and rescue medication. Treat-ment compliance was assessed by reviewing accountabil-ity records. Patients who consumed 75–125% of studymedications were considered compliant.

Safety. Adverse events were recorded throughout thestudy. Clinical laboratory measurements were completedat baseline and final visits. Vital signs were assessed atbaseline and weeks 2 and 4.

Statistical analysesAnalysis was performed on the modified intention-to-treat(mITT) population to observe a population with prespeci-fied key protocol criteria. The mITT population wasdefined as patients who received at least one dose of studymedication, had post-treatment data beyond day 7,reported a history of heartburn and had moderate or severenighttime heartburn and GERD-related sleep disturbanceson ‡3 of 7 consecutive days of the run-in period.

A sample size of 120 patients per treatment group wasdetermined to provide ‡90% power to detect a 20% differ-ence in relief rates, assuming a 40% relief rate for theesomeprazole 20 mg group and a 20% relief rate for theplacebo group, with a two-sided test at an alpha level of0.05 using the chi-squared test for proportions. Differencesbetween treatment groups in complete resolution andrelief of GERD-related sleep disturbances and daytime,nighttime and 24-h heartburn symptoms were assessedusing a chi-squared test. The percentage of days withoutGERD-related sleep disturbances was analysed with a one-way analysis of variance. The difference in time to firstcomplete resolution of sleep disturbances between treat-ment groups was assessed using a log-rank test.

Changes from baseline to end of treatment in globalPSQI scores and WPAI-SLEEP-GERD end points wereanalysed using analysis of covariance with baseline scoreas a covariate. Achievement of good sleep at week 4 wasanalysed using a Cochran-Mantel-Haenszel test withbaseline response as a stratifying factor.

Overall work hours saved per patient at week 4 wereconverted to monetary values using the US Bureau ofLabor Statistics labor compensation standard23 from June

2008 of $28.48 per hour, which included the cost of ben-efits and the mean hourly wage, and were analysed usinganalysis of variance to compare treatment differences.

RESULTS

PatientsOf 276 patients randomized to the study, 262 wereincluded in the mITT population. For inclusion in thestudy, patients had to have nighttime heartburn gradedas moderate or severe on 3 of the last 7 days of therun-in period. The reasons for early discontinuationfrom the study were voluntary discontinuation of treat-ment (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 enrol-ment (n = 1) in the placebo group (Figure 1). Thesepatients were excluded from the mITT population. Base-line demographics of the 262 patients in the mITT popu-lation were similar between the esomeprazole 20 mg andplacebo groups (Table 1).

Efficacy outcomesSymptoms. The primary end point was the percentage ofpatients with relief of nighttime heartburn during the last7 days of the study. Significantly more patients in theesomeprazole treatment group achieved this end pointcompared with those receiving placebo (P < 0.0001; Fig-ure 2, Table 2). Esomeprazole treatment also resulted insignificant improvement in several secondary end points,including relief or complete resolution of nighttime, day-time and 24-h heartburn symptoms during the last 7 daysof the study (P < 0.0001 vs. placebo for all; Table 2).

Sleep disturbances. Relief of GERD-related sleep distur-bance was seen significantly (P = 0.006) more in theesomeprazole group compared with the placebo groupduring the last 7 days of the study (Table 3). Similarly,patients receiving esomeprazole had significantly (P =0.0003) more days without GERD-related sleep distur-bances compared with the placebo group (Table 3).Complete resolution of GERD-related sleep disturbancesduring the last 7 days of the study also was seen signifi-cantly more (P < 0.0001) in the esomeprazole group(48.2%) compared with the placebo group (21.6%). Reso-lution of sleep disturbances also was faster in theesomeprazole group, with a median number of days tothe first complete resolution of sleep disturbance of9 days. More than 50% of patients who received placebodid not experience complete resolution during the course




Screened (n = 431)

Failed screening (n = 155)

Voluntary by subject (9)Lost to follow-up (6)Sponsor request (106)Other (34)

Randomized to placebo (n = 133)Received placebo (n = 132)

Included in mITTanalysis (n = 137)

Randomized (n = 276)

Discontinuations (n = 4)Adverse event (1)Voluntary by subject (2)Other (1)

Completed study (n = 138)

Included in mITTanalysis (n = 125)

Analysis exclusionsNo study drug or postbaseline measurement (2)No history of heartburn or no nighttime heartburnon ≥ 3 days of run-in (4) No GERD-related sleep disturbances on ≥ 3 days of run-in (2)

Analysis exclusionsNo study drug or postbaseline measurement (6)No history of heartburn or no nighttime heartburnon ≥ 3 days of run-in (1)No GERD-related sleep disturbances on ≥ 3 days of run-in (1)

Discontinuations (n = 8)Incorrect enrollment (1)Lost to follow-up (5)Lack of therapeutic response (2)

Completed study (n = 124)

Randomized to esomeprazole 20 mg (n = 143)

Received esomeprazole 20 mg (n = 142)

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

Table 1 | Patient demographicand baseline clinical charac-teristics

CharacteristicEsomeprazole20 mg (n = 137) Placebo (n = 125)

Women, n (%) 89 (65) 85 (68)

Mean age (s.d.), years 47.0 (11.7) 46.8 (12.9)

Mean BMI (range), kg ⁄m2 30.3 (17.3–65.6) 30.9 (18.3–63.1)

Race, n (%)

White 105 (77) 104 (83)

Black 25 (18) 13 (10)

Asian 3 (2) 2 (2)

Other 4 (3) 6 (5)

Mean nighttime heartburn severity score (s.d.)during run-in period*

2.0 (0.5) 2.0 (0.5)

Mean number of days (s.d.) without heartburnduring run-in period

0.6 (1.2) 0.7 (1.5)

BMI, body mass index.

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




of the study (P = 0.0001 for comparison of the time tocomplete resolution curves), and the median number ofdays to the first complete resolution of sleep disturbancewas >21 days for these patients.

Sleep quality. Patients receiving esomeprazole 20 mg hadsignificantly (P = 0.003) greater least squares mean(LSM) changes from baseline to end of treatment inPSQI global score compared with the placebo group(Table 3). The mean changes from baseline to end oftreatment (week 4) in each of the PSQI domains exceptsleep disturbance (i.e. global score, sleep quality, sleeplatency, sleep duration, habitual sleep efficiency, use ofsleep medication, daytime dysfunction) were consistentlygreater with esomeprazole 20 mg once daily than withplacebo. Improvements in sleep quality seen in theesomeprazole group occurred regardless of baseline sleepquality. More patients treated with esomeprazole 20 mgwho had good sleep (PSQI £5) or sleep disturbances(PSQI >5) at baseline experienced good sleep after4 weeks compared with patients who received placebo,although the difference did not reach statistical signifi-cance (P = 0.07; Table 3).

Work productivity. Employed patients who receivedesomeprazole (n = 83) reported a significantly largerchange in the overall work hours lost from baseline toend of study attributed to GERD-related sleep distur-bances ()9.5 vs. )4.9 h) compared with those whoreceived placebo (n = 78) [LSM difference, )4.64; 95%confidence interval (CI): )7.2 to )2.1; P = 0.0005]. Theimpact of GERD-related sleep disturbances on work pro-ductivity also was significantly lower in the esomeprazole

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 out-side of work (e.g. work around the house, shopping,childcare, exercising, studying) were significantly lessimpaired by GERD-related sleep disturbances in patientswho received esomeprazole (n = 87) compared withthose 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 perpatient was significantly greater in the esomeprazolegroup (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 betweenesomeprazole treatment and placebo ($123.60) was statis-tically significant (95% CI: $41.41)205.78; P = 0.0035).

Compliance. Treatment compliance was determined withdrug accountability records. Three patients in theesomeprazole group and two patients in the placebogroup were noncompliant with treatment.

SafetyEsomeprazole treatment was well tolerated. The overallincidence of adverse events was 21% (30 of 143) in theesomeprazole group and 18.2% (24 of 133) in the pla-cebo group. Nine events (6.3%) in 143 patients in the

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Figure 2 | Percentage of patients with relief of nighttimeheartburn. Daily diary response of ‘none’ on ‡6 of last7 days of the study, allowing for one night with ‘mild’heartburn. *P < 0.0001 vs. placebo.

Table 2 | Percentages of patients with complete resolu-tion and relief of heartburn

SymptomEsomeprazole20 mg (n = 137)

Placebo(n = 125)

Daytime heartburn

Relief* 40.1� 11.2

Complete resolution� 32.8� 7.2

Nighttime heartburn

Relief* 34.3� 10.4


24-H heartburn

Relief* 32.8� 7.2


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

� P < 0.0001 vs. placebo.

� Daily diary response of ‘none’ for the last 7 consecutive daysof the study.




esomeprazole group and four events (3.0%) in 133patients in the placebo group were considered treatment-related by the investigator. The most common adverseevents 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 pla-cebo group were abdominal pain (n = 2), flatulence(n = 2), nasopharyngitis (n = 2) and pneumonia (n = 2).No serious adverse events were reported with esomepra-zole treatment during the study.

DISCUSSIONIn the present study, treatment with esomeprazole 20 mgonce daily for 4 weeks relieved moderate-to-severe night-time heartburn and GERD-related sleep disturbances.Resolution of sleep disturbances (i.e. 7 consecutive daysof no sleep disturbance) occurred significantly earlierand in more patients with esomeprazole treatment. Theeconomic benefits of increased work productivity associ-ated with esomeprazole ($123.60 per patient at week 4)are likely to substantially offset the costs of therapy tothe employer who is providing prescription benefits aspart of health insurance coverage to the employees.Although the savings attributed to improved work pro-ductivity from a 1-week analysis should extrapolate toother weeks of therapy, further study is warranted toconfirm whether this type of intervention would provideexpanded benefit.

The inclusion and exclusion criteria in the presentstudy were designed to enrol patients experiencing sleepdisturbances associated with GERD and not other medi-cal conditions, work schedules or excessive caffeine

intake. As previously noted, esomeprazole 20 mg wasused because it is the dose approved for the healing oferosive oesophagitis and symptomatic GERD.20 Addi-tionally, a 4-week study period was selected because it isthe approved treatment period for patients with symp-tomatic GERD20 and because a majority of patients witherosive oesophagitis are healed with PPI treatment within4–8 weeks.20, 24

Because of the association of nighttime heartburn withpoor sleep quality and next-day functionality in GERDpatients, one can reasonably assume that treatment ofnighttime heartburn may improve sleep and daytimefunctioning. However, the efficacy of acid suppressivetherapy in patients with nighttime GERD is not wellestablished. A randomized, placebo-controlled study,14 astudy of self-treating subjects25 and several other smallor uncontrolled studies15–19 have suggested that acid sup-pression can provide benefits in patients with nighttimeheartburn or GERD-related sleep disturbances. A pla-cebo-controlled study of 864 subjects with nighttimeheartburn found that lansoprazole 15 mg or 30 mg oncedaily reduced nights with heartburn; however, no out-come measures or assessments of sleep were evaluated.25

In a large prospective, uncontrolled study in 6215patients with GERD who were receiving routine care,esomeprazole 40 mg or 20 mg daily was associated withimprovements from baseline in the sleep subscale of theQuality of Life in Reflux and Dyspepsia questionnaire at2 weeks.18 The previously described randomized, double-blind, placebo-controlled trial by Johnson et al.14 specifi-cally was conducted to focus on GERD-associatedsleep disturbances and moderate-to-severe nighttime

Table 3 | Relief of GERD-related sleep disturbances andimprovement in sleep quality

Esomeprazole20 mg (n = 137)

Placebo(n = 125) P value

GERD-related sleep disturbances

Patients with relief, %* 71.5 55.2 0.0060

Days without disturbances, mean %* 73.0 59.3 0.0003

PSQI

Global score, LSM change from baseline� )2.93� )1.80§ 0.0034

Patients with score £5, % 90.5� 82.8§ NS

Patients with score >5, % 44.2� 33.0§ NS

GERD, gastro-oesophageal reflux disease; LSM, least squares mean; NS, not significant;PSQI, Pittsburgh Sleep Quality Index.

* Last 7 consecutive days of the study.

� Baseline (randomization) to week 4.

� n = 134.

§ n = 123.




heartburn. In that study, treatment with esomeprazole40 mg or 20 mg once daily reduced nighttime heartburn,reduced GERD-related sleep disturbances, improvedwork productivity, improved productivity in regularactivities and decreased work hours lost compared withplacebo.14 The inclusion criteria and end points of thepresent confirmatory study for the esomeprazole 20 mgonce daily dosage were the same as those in the Johnsonet al. study, with the exception of an additional analysison time to relief of symptoms in the present study.

Results of the current study confirm the findings ofJohnson et al.14 and other previous studies.

Strengths of this study include the relatively largestudy population; the multicentre, randomized, double-blind, placebo-controlled design; and the consistent effi-cacy observed in a wide range of variables (i.e. heartburnsymptoms, sleep disturbances, sleep quality, work pro-ductivity). A limitation of the study is that the protocolrestricted entry to patients with moderate-to-severeheartburn. Thus, as in the study by Johnson et al.,14 theeffect on sleep disturbances in patients with less severeand less frequent heartburn remains to be establishedand the observed magnitude of benefits in the presentstudy should not be presumed to extend to patients withless severe symptoms. In addition, the study populationwas expected to include patients with and without ero-sive oesophagitis. However, endoscopies were notrequired for inclusion in the study, so the proportion (ifany) of patients who had erosive oesophagitis remainsunknown. Therefore, it also remains unclear whetheresomeprazole is beneficial in improving nighttime heart-burn and sleep disturbances in patients with erosiveoesophagitis, without erosive oesophagitis or both.

In summary, sleep disturbance is a common complica-tion in patients with GERD. Recent evidence on theprevalence and negative impact of sleep disorders arguefor the inclusion of improved sleep quality as an impor-tant treatment goal for patients with GERD. Results ofthis study demonstrate that esomeprazole is an effectivetreatment for patients with moderate-to-severe nighttimeheartburn and GERD-related sleep disturbances.

ACKNOWLEDGEMENTSDeclaration of personal interests: D. Johnson: develop-ment of the scientific protocol design and data analysisof the study; clinical investigator; development and revi-sion of the manuscript. K. Brown, C. Hwang, J. A.Crawley: development of the scientific protocol design;data analysis of the study; development and revision ofthe manuscript. Guarantor of the article: D. Johnson,MD, FACG. D. Johnson is a consultant for AstraZenecaLP, Takeda, Novartis, Xenoport and Esai. He is aclinical investigator for AstraZeneca LP, Takeda, andNovartis, and has received grant ⁄ research support fromAstraZeneca LP and Takeda. J. A. Crawley, C. Hwang,and K. Brown are employees of AstraZeneca LP.Declaration of funding interests: This study was fundedby AstraZeneca LP, Wilmington, DE, USA. The authorsthank Bret Fulton (freelance medical writer), Stella Y.Chow, PhD, Lisa M. Klumpp, PhD, and Judy E. Fallon,

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Figure 3 | Mean size of effect of gastro-oesophagealreflux disease (GERD)-related sleep disturbances on(a) work productivity (P = 0.0002) and (b) regularactivities (P = 0.003). P values are for change frombaseline in esomeprazole vs. placebo. For (a), patientsanswered the question, ‘During the past 7 days, howmuch did your sleep disturbance due to GERD symp-toms affect your productivity while you were working?’on a scale of 0–10, with 0 indicating that GERD-relatedsleep disturbance had no effect on work and 10 indicat-ing that GERD-related sleep disturbance completelyprevented working. For (b), patients answered the ques-tion, ‘During the past 7 days, how much did your sleepdisturbance due to GERD symptoms affect your abilityto do your regular daily activities, other than work at ajob?’ on a scale of 0–10, with 0 indicating that GERD-related sleep disturbance had no effect on dailyactivities and 10 indicating that GERD-related sleepdisturbance completely prevented daily activities.




PharmD, from Scientific Connexions, Newtown, PA,USA, for medical writing services (funded by AstraZen-

eca LP); the patients; and the study-site physician inves-tigators and their staff.

REFERENCES1. Farup C, Kleinman L, Sloan S, et al. The

impact of nocturnal symptoms associ-ated with gastroesophageal reflux diseaseon health-related quality of life. ArchIntern Med 2001; 161: 45–52.

2. Shaker R, Castell DO, Schoenfeld PS,et al. Nighttime heartburn is an under-appreciated clinical problem that impactssleep and daytime function: the resultsof a Gallup Survey conducted on behalfof the American GastroenterologicalAssociation. Am J Gastroenterol 2003;98: 1487–93.

3. Dubois RW, Aguilar D, Fass R, et al.Consequences of frequent nocturnalgastro-oesophageal reflux disease amongemployed adults: symptom severity,quality of life and work productivity.Aliment Pharmacol Ther 2007; 25:487–500.

4. Mody R, Bolge SC, Kannan H, et al.Effects of gastroesophageal reflux diseaseon sleep and outcomes. Clin Gastro-enterol Hepatol 2009; 7: 953–9.

5. Janson C, Gislason T, De Backer W,et al. Prevalence of sleep disturbancesamong young adults in threeEuropean countries. Sleep 1995;18: 589–97.

6. Wahlqvist P, Carlsson J, StålhammarN-O, et al. Validity of a workproductivity and activity impairmentquestionnaire for patients with symp-toms of gastro-esophageal reflux disease(WPAI-GERD)—results from across-sectional study. Value Health2002; 5: 106–13.

7. Dean BB, Crawley JA, Reeves JD, et al.The cost of gastroesophageal reflux dis-ease: it’s what you don’t see that counts.J Manag Care Med 2003; 7: 6–13.

8. Newman AB, Spiekerman CF, Enright P,et al. Daytime sleepiness predicts mor-tality and cardiovascular disease in olderadults. The Cardiovascular Health Study

Research Group. J Am Geriatr Soc 2000;48: 115–23.

9. Lagergren J, Bergstrom R, Lindgren A,et al. Symptomatic gastroesophagealreflux as a risk factor for esophagealadenocarcinoma. N Engl J Med 1999;340: 825–31.

10. Jaspersen D. Extra-esophageal disordersin gastroesophageal reflux disease. DigDis 2004; 22: 115–9.

11. Orr WC, Heading R, Johnson LF, et al.Review article: sleep and its relationshipto gastro-oesophageal reflux. AlimentPharmacol Ther 2004; 20(Suppl 9):39–46.

12. Chen C-L, Robert JJT, Orr WC. Sleepsymptoms and gastroesophageal reflux.J Clin Gastroenterol 2008; 42: 13–7.

13. Wahlqvist P, Karlsson M, Johnson D,et al. Relationship between symptomload of gastro-oesophageal reflux diseaseand health-related quality of life, workproductivity, resource utilization andconcomitant diseases: survey of a UScohort. Aliment Pharmacol Ther 2008;27: 960–70.

14. Johnson DA, Orr WC, Crawley JA, et al.Effect of esomeprazole on nighttimeheartburn and sleep quality in patientswith GERD: a randomized, placebo-con-trolled trial. Am J Gastroenterol 2005;100: 1914–22.

15. Orr WC, Goodrich S, Robert J. Theeffect of acid suppression on sleep pat-terns and sleep-related gastro-oesopha-geal reflux. Aliment Pharmacol Ther2005; 21: 103–8.

16. Chand N, Johnson DA, Tabangin M,et al. Sleep dysfunction in patients withgastro-oesophageal reflux disease: preva-lence and response to GERD therapy, apilot study. Aliment Pharmacol Ther2004; 20: 969–74.

17. DiMarino AJ Jr, Banwait KS, EschingerE, et al. The effect of gastro-oesophageal

reflux and omeprazole on key sleepparameters. Aliment Pharmacol Ther2005; 22: 325–9.

18. Kulig M, Leodolter A, Vieth M, et al.Quality of life in relation to symptomsin patients with gastro-oesophagealreflux disease—an analysis based on theProGERD initiative. Aliment PharmacolTher 2003; 18: 767–76.

19. Yi CH, Chen CL, Kuo TB, et al. Theeffect of acid suppression on sleep andcardiac autonomic regulation in GERD.Hepatogastroenterology 2008; 55:1649–52.

20. AstraZeneca LP. Nexium [prescribinginformation]. Wilmington, DE: Astra-Zeneca LP, 2008.

21. Buysse DJ, Reynolds CF III, Monk TH,et al. The Pittsburgh Sleep Quality Index:a new instrument for psychiatric practiceand research. Psychiatry Res 1989; 28:193–213.

22. Reilly MC, Zbrozek AS, Dukes EM. Thevalidity and reproducibility of a workproductivity and activity impairmentinstrument. Pharmacoeconomics 1993;4: 353–65.

23. Bureau of Labor Statistics. Employercosts for employee compensation newsrelease. Available at: http://www.bls.gov/news.release/ecec.htm. Accessed June2008.

24. Chiba N, De Gara CJ, Wilkinson JM,et al. Speed of healing and symptomrelief in grade II to IV gastroesophagealreflux disease: a meta-analysis. Gastro-enterology 1997; 112: 1798–810.

25. Peura DA, Riff DS, Snoddy AM, et al.Clinical trial: lansoprazole 15 or 30 mgonce daily vs. placebo for treatment offrequent nighttime heartburn in self-treating subjects. Aliment PharmacolTher 2009; 30: 459–68.




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