Gastric pH and Therapeutic Responses to Exsomeprazole in Patients With Functional Dyspepsia: Potential Clinical Implications

Author’s Accepted Manuscript Gastric pH and Therapeutic Responses to Esomeprazole in Patients with Functional Dyspepsia: Potential Clinical Implications Marek Majewski, Irene Sarosiek, Chad J. Cooper, Grzegorz Wallner, Richard W. McCallum, Stanley A. Edlavitch, Jerzy Sarosiek www.elsevier.com

PII: DOI: Reference:

S0002-9629(16)30506-7 http://dx.doi.org/10.1016/j.amjms.2016.09.010 AMJMS296

To appear in: The American Journal of the Medical Sciences Received date: 24 June 2016 Revised date: 30 August 2016 Accepted date: 21 September 2016 Cite this article as: Marek Majewski, Irene Sarosiek, Chad J. Cooper, Grzegorz Wallner, Richard W. McCallum, Stanley A. Edlavitch and Jerzy Sarosiek, Gastric pH and Therapeutic Responses to Esomeprazole in Patients with Functional Dyspepsia: Potential Clinical Implications, The American Journal of the Medical Sciences, http://dx.doi.org/10.1016/j.amjms.2016.09.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Gastric pH and Therapeutic Responses to Esomeprazole in Patients with Functional Dyspepsia: Potential Clinical Implications 1

Marek Majewski, MD, PhD,* 2Irene Sarosiek, MD*, 2Chad J. Cooper, MD, MHA, 1 Grzegorz Wallner, MD, PhD, 2Richard W. McCallum, MD, 3 Stanley A. Edlavitch, PhD, MA 2Jerzy Sarosiek, MD, PhD 1 Medical University of Lublin, Lublin, Poland 2 Texas Tech University Health Sciences Center of El Paso, Texas 4 University of Missouri School of Medicine, Kansas City, Missouri

*Equal contribution Corresponding Author: Jerzy Sarosiek, MD, PhD Professor of Medicine & Vice Chair for Research; Internal Medicine Department; Internal Medicine Research Committee Chairman; Director, Molecular Medicine Research Laboratory; 4800 Alberta Av. El Paso, TX 79905-2709 Tel: 915-215-5255 Fax: 915-545-6636 [email protected] Acknowledgement: The authors wish to thank Mr. Jim Bramich, MIS from AstraZeneca for his great support and encouragement.

Short Title: Esomeprazole vs. Placebo in Functional Dyspepsia

Disclosures: All authors declare no financial, professional or personal conflicts. Subjects were not charged for participation in this study. Subjects were paid for their participation in this study. Strict patient confidentially was maintained throughout the entire study. Study subjects were allowed to withdrawal from the study at any time. All Authors were involved in manuscript preparation and literature review. Esomeprazole and placebo capsules were provided by AstraZeneca

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Address for Correspondence: Stanley A. Edlavitch PhD, MA () Professor of Epidemiology Department of Psychiatry University of Missouri School of Medicine 1000 E24th Street, Kansas City, Missouri 64108 Tel: (816) 512-7426 Fax: (816) 512-7440 Email: [email protected]

Keywords: Esomeprazole, proton pump inhibitors (PPIs), functional dyspepsia, gastric pH. Abstract Background: Therapy of functional dyspepsia (FD) remains a challenge. Study Aims: Evaluate esomeprazole (E) vs. placebo (P) in regards to:1) Effectiveness in providing relief of abdominal pain/discomfort during 16 weeks of therapy in FD patients with moderate/severe symptoms;2) Impacts on gastric acid suppression; and 3) Relationships between symptom relief and gastric pH. Methods: Randomized double-blind, placebo-controlled trial, with 35 P and 38 E 40 patients. Outcomes measured at four 4-week intervals. Drug dose titrated at each visit, based on relief of abdominal symptoms. 24h Gastric pH monitored at baseline, 4 and 8 weeks. Results: After 4 weeks, 71% of E patients (40mg) reported satisfactory symptom relief vs. 34% P (p<0.001). When the dose for non-responders (NR) was titrated to 40mg BID, the esomeprazole relief rate increased to 82% vs. 56% placebo (p<0.05). During the next 4 weeks, with dose

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decreased by 1/2 in responders, E response rate declined to 69% vs. 48% in P group (p<0.10). When the dose was increased for NR during the last 4 weeks, E rate increased to 83% vs. 57% P (p<0.05). At 4 and 8 weeks for E responders and NR, patients' pH > 4 increased significantly compared to baseline. Conclusions: 1) Though esomeprazole 40mg QD is superior to placebo, some patients benefit from 40mg BID; 2) Esomeprazole, 40mg QD, profoundly inhibits gastric acid secretion; 3) Intragastric pH monitoring before and after therapy may help address the relationship between symptomatic relief and gastric acid secretion; and 4) Some patients respond to monitored titrated placebo therapy.

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Introduction: Dyspepsia is a term used to describe pain or discomfort in the upper abdomen unrelated to defecation or stool frequency. The United States prevalence rate reaches 2.5% [1,2]. The pathophysiology of dyspepsia is unclear. Theories include Helicobacter pylori infection, medications (especially NSAIDs), gastric dysmotility, poor mucosal defense and excessive mucosal acid exposure [3]. Rome II clinical history criteria (Table 1) aids in the diagnosis of functional dyspepsia (FD) [4,5]. The majority of patients with dyspepsia will have a normal physical examination, except for epigastric tenderness on palpation. A FD diagnosis requires that symptoms be present for at least 12 weeks in the preceding 12 months [6]. Approximately 75% of patients have FD with no identifiable underlying cause [7,8]. Uninvestigated dyspepsia refers to patients with either new or recurrent dyspepsia symptoms that have not had any diagnostic investigations. Investigated dyspepsia is divided into organic or FD. Organic dyspepsia has a pathophysiological or anatomic explanation for the dyspepsia [1]. In contrast, FD is diagnosed after various investigations have been performed and found to be normal. FD does not include patients with a dominant compliant of heartburn or regurgitation. When the local prevalence of FD is more than 10%, the initial approach to patients with dyspepsia involves screening for H. pylori [9]. The American Gastroenterological Association suggests that patients with dyspepsia must undergo screening for H. pylori and eradication. Standard therapy is that dyspepsia patients with H. pylori or after eradication should be started on proton pump inhibitors (PPIs). Proton Pump Inhibitors (PPIs) are very effective for the suppression of gastric acid secretion

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through the inhibition of the H+/K+ adenosine tri-phosphatase enzyme in parietal cells [10,11]. Esomeprazole (E), the S-isomer of omeprazole, is rapidly absorbed and gradually metabolized by cytochrome P450 (CYP) isoenzymes, particularly CYP2C19 and CYPC3A4 [12]. This results in a profound and long inhibition of gastric acid secretion during a twenty-four hour period [13]. Esomeprazole is used for the treatment of gastroesophageal reflux disease (GERD), peptic ulcers, and the eradication of Helicobacter pylori infection as an addition to antimicrobial agents [14]. PPIs have been shown to provide symptom relief in some, but not all, patients with dyspepsia or FD [15, 16]. The relationship between FD symptom relief and gastric acidity remains to be explored further. The objectives of the current study were to evaluate the efficacy of E 40 mg QD or BID in achieving symptom relief in FD patients with non-ulcer dyspepsia in a 16 week, placebo-controlled study and to explore the relationship of symptom relief with the degree of acid suppression. The current study was conducted with 3 specific aims: 1. Evaluate the efficacy of esomeprazole vs. placebo in providing satisfactory relief of pain/discomfort symptoms in FD patients during 16 weeks of therapy. 2. Evaluate the impact of esomeprazole vs. placebo on gastric acid during 24h pH monitoring. 3. Assess the relationship between relief of dyspepsia symptoms and changes in gastric pH.

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Methods and Statistical Considerations: Study Population: The study was conducted in 73 H. pylori negative subjects (32 males, 41 females; 18-55 years old) with epigastric pain/discomfort related to non-ulcer dyspepsia and without alarm features. This study was conducted as a randomized, double blind, placebo controlled trial. Rome II diagnostic criteria for FD (Table 1) were used to determine patient eligibility. After Institutional Review Board (IRB) approved the protocol, all patients were presented with informed consent, which had to be signed before subjects entered the clinical trial. An additional informed consent for the esophagogastroduodenoscopy (EGD) was obtained prior to the procedure, if required. Inclusion Criteria: 1. 18-55 years old. 2. Diagnosis of epigastric pain/discomfort currently rated by the patient as moderate to severe in intensity (four point scale), unrelated to exercise and present as least 3 times per week for 12 weeks. 3. Patients may have other symptoms, including: heartburn, regurgitation, bloating (abdominal distention), early satiety (feeling of fullness), belching (burping) or nausea. The dominant symptom must be epigastric pain/discomfort. 4. Must be capable of and willing to give informed consent and comply with all study requirements.

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Exclusion Criteria: 1. H. pylori positive serology or had received eradication treatment within the last 12 months. 2. Regular use of NSAIDs, acetylsalicylic acid, or cyclooxygenase-2 selective inhibitors (COX-2). 3. Chronic treatment with any medications such as antibiotics, codeine. 4. History or presence of endoscopic/radiologic evidence of esophagitis, Barrett’s esophagus, gastric, or duodenal ulcers. 5. History or presence of chronic gastritis, duodenal erosions or ulcers. 6. History of previous GI surgery. 7. Presence of concomitant symptoms of irritable bowel syndrome (IBS) assessed by three or more of the Manning or Rome criteria. 8. History or presence of other known other diseases that might explain dyspepsia symptoms (e.g. biliary colic, hiatal hernia, peptic ulcer disease). 9. Pregnancy or lactation. 10. Regular consumption of greater than 2 fluid ounces of alcoholic beverage per day. 11. History of illicit substance abuse. 12. Unwillingness or expected inability to tolerate the absence of anti-secretory medications (antacids, H2 receptor antagonists, PPIs or other GI pharmacotherapy) for the period of time of the study. 13. Previous history of gastrointestinal (GI) malignancy, peptic ulcer disease, previous upper GI surgery or esophageal motility disorders.

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Screening: A screening evaluation was performed up to 14 days prior to the baseline evaluation. It included: 1. Written informed consent. 2. Complete medical history and physical examination. 3. Pregnancy test (urine). 4. H. pylori serology test. Three or more of the additional following symptoms were required for enrollment: upper abdominal pain or discomfort before meals or when hungry; upper abdominal pain or discomfort at night (wakes from sleep); upper abdominal pain or discomfort relieved by food; upper abdominal pain or discomfort relieved by antacids; periodic upper abdominal pain or discomfort; and well localized upper abdominal pain or discomfort. Stratified Randomization: Eligible patients with moderate or severe epigastric pain/discomfort were enrolled. Prior to the stratified randomization, all patients received P (1 capsule daily) for 4 weeks. Stratified randomization codes were assigned sequentially to enrolled patients. Patient and clinician blinding was maintained using identical appearing P and E tablets (blister packs). Outcome Measures: Patient assessment of dyspepsia symptom severity was determined at the beginning of the study using the validated 7-point Global Overall Symptom (GOS) scale for dyspepsia. This consists of: 1) No problem, 2) Minimal problem (can be easily ignored), 3) Mild problem (can be ignored with effort), 4) Moderate problem (cannot be ignored, does not affect daily activities),

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5) Moderately severe problem (cannot be ignored, occasionally affects daily activities), 6) Severe problem (cannot be ignored, affects daily activities), 7) Very severe problem. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was also utilized at baseline, 4, 8, 12 and 16 weeks after starting treatment. QOLRAD contains 25 itemized questions in 5 relevant domains: emotional distress (6 items), sleep disturbance (5 items), drink/food problems (6 items), social/physical functioning (5 items) and vitality (3 items). Each question has seven options and results are reported as average scores for each domain. A higher score correlates with a better quality of life. Patients were instructed to rate the severity of dyspepsia (epigastric pain/discomfort) using validated seven graded diary cards over the last 7 consecutive days of the 2 week run in period and at the end of each treatment period (4, 8, 12, 16 weeks). The efficacy of therapy was based on the symptom scores recorded on these diary cards. The diary cards ask: “Please state for each day if you have experienced pain or discomfort in the stomach”. The global assessment of overall severity of symptoms was measured as secondary end points using a Likert 4 categorical scale (1= symptom free, 2= improved, 3= unchanged and 4= worse) at the end of each treatment period (4, 8, 12, 16 weeks). A 7 point Likert scale was used to assess how much or often the item described the feeling of patient; degree of distress (none at all, hardly any at all, a little, some, a moderate amount, a lot, a great deal); frequency of the problem (none of the time, hardly any of the time, a little of the time, quite a lot of the time, most of the time, all of the time). A mean item score was calculated for each patient. This report presents information on responders (R) to randomized therapy versus nonresponders (NR). Patients were considered a responder to the acid suppression therapy if they

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reported their symptoms were no more than mild and these symptoms occurred on frequency of less than two days per week. A responder to therapy was defined (mathematically) as a patient whose sum of symptom scores was 0 or 1. Outcome measures included: relief of pain/discomfort symptoms, measured at four consecutive 4 weeks intervals (16 weeks total), a 7-day daily diary preceding each visit, a quality of life questionnaire and a global overall symptoms assessment. At each visit, patients were asked to rate any adverse effect that occurred as mild, moderate or severe. Randomization Patients (mean age of 44.2; 56% F) were randomized to P (N=35) or E regimens (N=38) 40 mg (Table 1). Investigators, study personnel and patients were blinded to therapy assignment until the study’s completion. Esomeprazole and placebo tablets were identical in their appearance. Patients were initially randomized to E 40 mg or P 40 mg, and were instructed to take the study drug at least 1 hour before breakfast. Patients that required twice a day dosing of E 40 mg later in the course of the study were given one tablet in the morning and one in the evening. The study lasted a total of 16 weeks and the patient adjusted the dose of either active drug or P at 4-week intervals, based on self-reported symptom relief. Medication compliance was assessed by tracking the pill count of the returned medication at each 4 visit. At baseline, prior to randomization, gastric acidity was evaluated by 24-hour pH monitoring using 2 electrodes placed at 5 cm and 10 cm below the lower esophageal sphincter. After 4 weeks of therapy, a second symptom score and global assessment of symptoms were measured using diary cards over the 4th weeks on treatment. All patients underwent a 2nd 24hour gastric pH-monitoring test after 4 weeks of therapy. Patients that failed to achieve

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satisfactory symptom relief at 4 weeks were continued on a double dose of P or E (40 mg twice a day), for an additional 4 weeks (8 weeks total). Patients with satisfactory symptom relief at 4 weeks were continued on the single daily dose of medication (E or P, blinded) for an additional 4 weeks (8 weeks). pH monitoring was repeated after 8 weeks of therapy. Patients, who failed to achieve satisfactory symptom relief at 8 weeks, were continued of a double dose of either P or E (40 mg twice daily) respectively, for an additional 4 weeks (12 weeks total). Patients that achieved symptomatic relief at 8 weeks underwent a step down dose adjustment (from 80 mg to 40 mg daily or from 40 mg to 20 mg daily) and continued on this dosage for another 4 weeks of therapy (12 weeks total). At 12 and 16 weeks only outcome measures were reassessed. Patients, who failed to achieve symptomatic relief at 12 weeks, were continued on therapy for another 4 weeks (16 weeks total) with a double dose of either P or E (40 mg twice daily) respectively. Patients that achieved symptomatic relief underwent a step down dose adjustment (from 80 mg to 40 mg daily or from 40 mg to 20 mg daily) and continued on this dosage for another 4 weeks of therapy (16 weeks total). If symptoms increased after step down dose adjustment, the dose was increased to the dose that was effective in symptom relief during the last 4 weeks of therapy. Outcomes measures were repeated after 16 weeks of therapy. Gastric pH was monitored using dual probe catheter and pH Monitoring System (Sandhill Sci.). In the 24-hour pH monitoring recordings, daytime and nighttime diurnal median gastric pH during were calculated. In addition, the percentage of time gastric pH remains >4.0 was evaluated and correlated with the degree of symptom relief and improvement of QOLRAD. Each patient had a binder with diaries, QOLRAD questionnaires and relevant forms for results of

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all conducted tests throughout the study protocol.

Statistical Analysis: The 95% confidence intervals or p values were calculated for all data analyses. A p<0.05 was considered statistically significant on applied statistical tests. A graded 7 Likert scale and the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was utilized at baseline, 4, 8, 12 and 16 weeks of therapy to assess whether the patient was a responder versus non-responder. A responder to therapy was defined as a patient whose sum of symptom scores was 0 or 1 at the end of each treatment interval. Descriptive statistics were used in the analysis of baseline characteristics. Mean, SD and SD from 25-75% values were obtained based on the time (min.) that the gastric pH was >4 within the 24 hour period. The 24-hr pH monitoring was performed at baseline (Visit 2 – V2), week 4 (Visit 3 – V3) and week 8 (Visit 4 – V4). Comparative data analyses were performed using t-test, paired t-test, Mann-Whitney Rank Sum Test and Wilcoxon Signed Rank Test as stated in tables 2-5.

Results The mean age of the patient population was 44.2 years, 56% of study subjects female. After 4 weeks of therapy, 71% patients receiving esomeprazole (E) 40mg capsule QD reported satisfactory relief of symptoms vs. 34% on P (p<0.001) (Fig. 1, Visit 3). The rate of satisfactory relief of symptoms increased to 82% when visit 3 E non-responders (NR) doubled their dose to 40 twice daily (BID).

The P response rate also increased to 56% (p<0.05) on BID dosing

amongst NR at visit 3 (Fig. 1, Visit 4). During the next 4 weeks of therapy (dose in responders (R)

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at visit 4) reduced to 20 or 40 QD correspondingly), the E response rate declined to 69%, compared to a P response rate of 48% (p<0.10) (Fig. 1, Visit 5). When the dose at visit 5 was increased again for NR during the last 4 weeks of therapy the response rate in patients on E increased to 83% vs. 57% on P (p<0.05) (Fig. 1, Visit 6). In the E patients, there was a statistical significant increase of pH > 4 compared to baseline (V2) at both the proximal and distal channels at 4 weeks (V3- 2nd pH test) and at 8 weeks (V4- 3rd pH test; p <0.001; Table 2a). In the P patients, there was no statistical significance increase of pH > 4 value compared to baseline at either the proximal or distal channel at 4 weeks (V3- 2nd pH test) or 8 weeks (V43rd pH test) (Table 2b). The baseline mean values of gastric pH monitoring (V2) in patients randomized to E or P were similar (Table 3). After 4 weeks of either E or P, our data demonstrates a statistically significant difference in (p<0.001) in pH >4 values between E and P at both the proximal and distal channels at 4 weeks of therapy (V3; 2nd pH test) and 8 weeks of therapy (V4; 3rd pH test) (Table 3). Comparing E versus P patients at the proximal channel at 4 weeks (V3-2nd pH test), the increased difference in time of pH > 4 value was 46% and at 8 weeks it was 36%. Comparing the E versus P patients at the distal channel at 4 weeks of therapy (V3-2nd pH test), the increased difference in time of pH > 4 value was 264% and at 8 weeks of therapy (V4-3rd pH test), it was 186% (Table 3). We also considered whether responders (R) and non-responders (NR) differed in pH>4 changes in response to therapy. There was no statistical significance in the pH >4 value at the proximal or distal channel in subjects who were either an R or NR to E therapy at baseline

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(Table 4, Fig. 2a & 2b). As noted, the time pH>4 was significantly increased in E patients at subsequent visits. This increase did not appear to differ in E responders and non-responders. Subjects that received E and were R at either 4 weeks (V3; 2 nd pH test) or 8 weeks (V4; 3rd pH test) had a statistical significance (p<0.001) in pH > 4 value at the proximal and distal channels in comparison with their baseline. The subjects that were NR also demonstrated an increase in pH > 4 time value, but this was less significant at the proximal channel (P=0.02; Table 4). At the 4th week (V3; 2nd pH test) of E therapy, the R had an increased duration of pH >4 value at the proximal channel by 82% and at the distal channel of 34% compared to the baseline time pH value. On analysis of the 8th week (V4; 3rd pH test) of E therapy, the R had an increased duration of pH >4 value at the proximal channel by 67% and at the distal channel of 361% compared to the baseline time pH value. During the 8 th week of E therapy, the difference in time pH > 4 value between the baseline and V4 3rd pH test of NR was not statistically significant (P=0.22) at proximal channel and also nonsignificant to distal channel (P=0.12). This demonstrates a relationship between the acid suppression by E and symptomatic response to therapy. There was no statistical significance in the pH >4 value at the proximal or distal channel in either R or NR to P therapy (Table 5, Fig. 2b). The only exception occurred in the comparison of R to P at the 4th week (V3; 2nd pH test) at the distal channel with pH >4 values increased by 47% compared to baseline values (P=0.03).

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Discussion: Our subjects were considered to be diagnosed with investigated FD.

Screening

determined that they were H. pylori negative, did not use NSAIDs, and had a negative history of peptic ulcer disease with no anemia or episodes of upper gastrointestinal bleeding. The pathophysiology of FD is not well identified. However, multiple confounding factors are likely involved,

such

as

physiologic,

genetic,

environmental

and

psychological

factors.

Pharmacological management of function dyspepsia is difficult. The effectiveness of PPI’s may vary depending on the pharmacokinetics and pharmacodynamics of the drug and the metabolism of the patient [1]. Current medications are aimed at only one target, however multiple pathophysiological mechanisms may be involved in the effectiveness of acid suppression therapy. Therefore, understanding the pathophysiology, especially the role of gastric acid secretion can help gain a better understanding of how to effectively treat FD. Our findings, based on longer follow-up than most previous studies, confirm the major findings of E effectiveness and the relationship of E to Intragastric pH, when measured at 4 and 8 weeks following initiation of therapy. Johnson et al, conducted a two-way crossover study in 45 patients H. pylori negative patients with GERD randomized to receive either lansoprazole 30mg QD or E 40mg with dose increased to BID for each therapy and pH assessment at and on day 10 of therapy. They found the mean time pH > 4.0 and mean 24-hr pH were highest for E 40mg BID followed by lansoprazole 30mg QD, E 40mg QD and then lansoprazole 30mg QD [17]. They concluded that the response to acid suppression varies by therapeutic regimen but E 40mg BID provided the best control of intragastric pH compared to the other regimens in the study.

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Meineche-Schmidt et al. studied 805 patients with uninvestigated dyspepsia that were considered to be acid-related , and who were randomized to either 2 weeks of E 40 mg or P daily therapy. A response to therapy was observed in 68% of the E group and 44% in the P group (p < 0.00001) [18]. The multinational Supportive Test for Acid-Related Symptoms (STARS) II study demonstrated esomeprazole to be moderately effective for symptomatic improvement in patients with dyspepsia. In this study van Zanten et al. studied 1,250 patients with uninvestigated dyspepsia that underwent 1 week of E therapy and was then randomized to either E or P group for 7 weeks. Following 1 week of E therapy, the proportion of patients that responded was similar between those that received E 40mg QD (39%) or BID (43%) (P=0.16) [19]. After being treated for 7 weeks, there was a significant increase in the percentage of responders to E than P (47% vs. 34%; P < 0.001). Van Zanten and Armstrong et al. performed a randomized placebo controlled trial in 224 adult patients with FD with moderate severity symptoms. Patients were excluded that had predominant symptoms of heartburn or regurgitation. A baseline endoscopy was performed. Patients were randomized to either E 40mg once daily or P for 8 weeks [7]. The 4 week symptom relief of E was 50.5% versus P 32.2%, p = 0.009, 8 wk. E 55.1% versus P 46.1%, p = 0.16. This study concluded that E was more effective than P for symptom relief at 4 weeks. They were uncertain as to why there was a difference in therapeutic gain at 8 weeks in the P group. In another study, van Zanten and Flook et al. aimed to evaluate whether 1 week of acid suppression would help predict the response of these patients at 8 weeks of therapy [20]. In a

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randomized placebo controlled trial of H. pylori negative patients with uninvestigated epigastric pain or burning, patients were either started on E 40mg QD or BID for 1 week followed by E 40mg QD or P for 7 weeks. The patients rated the severity of their symptoms on a daily basis. The response rate at the end of 1 week was 39% and 43% with E 40 mg QD and BID respectively. At 4 weeks the response rate was 38% for E and 25% for P. At 8 weeks the response rate was 47% for E and 34% for P [20]. They concluded that the predictive value of therapy response based on 1 week of acid suppression is of limited clinical value. Esomeprazole provided better symptomatic control compared to P at 4 and 8 weeks of therapy. Talley et al. also evaluated whether 1 week of acid suppression was useful in identifying true responders to E therapy [21]. Patients were randomized to either receive E 40mg QD or BID for 1 week followed by E 40 mg QD or P for 7 weeks. Dyspepsia symptoms such as epigastric burning sensation/pain were recorded using a 4-point Likert scale (O = none to 3 = severe). A favorable symptom response to therapy was considered to be a symptom sum score of 1 or less on last 3 days of therapy during the first week and same score but the last 7 days at the end of 8 weeks of therapy. At the end of 1 week of therapy, the response rates were 33% for E QD, 29% for E BID and 23% for P (P = 0.002 for E groups vs. P). The overall response rates at week 4 were 27% with E and 26% with P (p = 0.86). The overall response rates at week 8 were 39 % for E and 33% for P. However, they concluded that response to 1-week acid suppression trial is of limited use for predicting symptom response at 8 weeks in patients with uninvestigated dyspepsia [21]. One of the potential downfalls of conducting clinical trials in patients with FD is the overlap that could exist with GERD [22, 23]. In our study we included patients that met criteria

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for investigated dyspepsia further classified as functional or non-ulcer dyspepsia. Many of the studies mentioned above note that PPI’s are effective at acid suppression of pH >4 and in symptomatic relief of dyspepsia. None of these studies comprehensively investigate simultaneous measurement of intragastric pH and symptomatic improvement of dyspepsia with PPI therapy. Our study demonstrates that the majority of patients that achieved a longer duration of time of pH >4.0 also had better symptom improvement of dyspepsia with E compared to P. The administration of E resulted in a statistical significant increase of time pH > 4 value as compared to baseline at either the proximal or distal channel at 4 weeks (2nd pH test) and at 8 weeks (3rd pH test). The P group did not have a significant increase of time pH > 4. This is an expected finding that E does in fact cause acid suppression compared to P, specifically more at the distal gastric portion. However, the observation was that the greater the time pH > 4 correlated with symptomatic improvement of dyspepsia.

This was not observed for every

patient. Non-responders (based on self-reports of symptoms) had adequate gastric acid suppression with E, but the time pH > 4 was not as long as those that responded to therapy. Therefore the time pH > 4 did not always correlate with improvement in dyspepsia. We speculate that other factors are involved in addition to increased gastric acidity resulting in dyspepsia. The only exception in our data occurred in the comparison of responders to P at the 4 th week (2nd pH test) at the distal channel with pH >4 values being increased by 47% compared to baseline value. It is known that a placebo effect can be substantial in trials of GI disorders especially dyspepsia. However, we are uncertain of the reason for such a significant increase

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time pH > 4 in the placebo group after 4 weeks of therapy and none after 8 weeks. One possible explanation is that this is due to a natural variation in the severity of the symptoms and is independent of treatment. Another may be that these patients might benefit by receiving increased attention, i.e. by participating in the study they feel they are being treated appropriately. However, this modifier effect may apply to either group not just the placebo arm. This study was not designed to evaluate this possibility. It is unknown if there are maximum placebo effects in patients with FD, or if this response will plateau over time. The current treatment options for FD are still suboptimal. Unfortunately, no other treatment approach has convincingly been shown to be more efficacious. A trial of a PPI for at least 4 to 8 weeks is a reasonable therapy option [24]. PPIs are well tolerated and adverse events are minimal. Our findings support the use of PPIs for empiric therapy for patients with uninvestigated dyspepsia, as recommended by the current guidelines. An 8-week trial of acid suppression with once daily dosing of a PPI is a reasonable course of action in patients with FD who have predominant symptoms of pain or burning in the upper abdomen [23]. The huge difference in the benefit of PPI therapy over placebo was much unexpected. This study highlights that in patients with uninvestigated dyspepsia who present with epigastric pain or burning, the burden of illness is substantial. Symptom resolution with acid-suppressive therapy is accompanied by significant improvements in quality of life and improvement in productivity compared with the placebo group [25]. This study supports our hypothesis that evaluating gastric acid secretion can help gain a better understanding of how to effectively treat FD In dyspepsia patients E, 40mg QD, provides profound inhibition of gastric acid secretion as reflected in the time pH >4.0 in patients

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accompanied by a significant relief of symptoms. Though the positive differences between E treated patients and placebo patients persisted throughout the study, significant improvements in symptoms and pH values were observed in the placebo patients. A significantly higher degree of gastric acid inhibition in R than NR after prolonged (8 weeks) therapy with 40 mg of E may imply that gastric acid pH monitoring could be helpful in the prediction of therapeutic response and tailoring individualized therapy. Our findings suggest that a trial P followed by E arm might be considered in a future trial. Additionally, it was clear that though esomeprazole administered 40mg QD is superior to placebo, in controlling symptoms and gastric acid, some FD patients may benefit from a dose of E 40 BID. These results also suggest that it would be valuable to further explore whether profound inhibition of gastric acid secretion with a more potent PPI will provide SRP/DS in almost all FD patients. Study Strengths and Limitations: This is the first study that we are aware of that has used a double blind protocol design employing drug titration in dyspepsia patients in active and placebo arms. The therapeutic phase of 16 weeks exceeds follow-up from most trials in the literature, which have typically measured outcomes at 1 to 8 weeks.

Protocol adherence was excellent. The trial only

included FD patients without possible a number of complicating co-morbidities, not requiring chronic treatment with other medications.

Also, patients were permitted to use over the

counter (OTC) medications if their symptoms were severe. Therefore, we are unable to assess the effect that any OTC medications could have on the placebo or treatment groups, nor the

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impact of co-morbid conditions.

In an effort to develop broad treatment guidelines, further

trials should address OTC use and may be designed to include FD patients with co-morbid conditions and should follow patients for a longer duration of therapy. Conclusions: 1. Although esomeprazole administered 40mg QD is superior to placebo, some FD patients benefit from a dose of 40 BID. 2. Esomeprazole, 40mg QD, provides profound inhibition of gastric acid secretion as reflected in time pH>4.0 with dyspepsia accompanied by a significant relief of symptoms. 3. Intragastric pH monitoring before and after therapy may help address the interrelationship between symptomatic relief of dyspepsia symptoms and gastric acid secretion inhibition and could potentially help to tailor individual therapy. 4. Though titrated esomeprazole dosing appears significantly more effective with regards to symptoms and gastric action production, there appears to be a positive response in some FD patients to monitored titrated placebo therapy.

Acknowledgement The authors wish to thank Mr. Jim Bramich, MIS from AstraZeneca for his great support and encouragement.

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References: 1. Brun R, Kuo B. Functional Dyspepsia. Therap Adv Gastroenterol. 2010; 3(3): 145-64. 2. Lacy BE, Talley NJ, Locke GR 3rd, et al. Review article: current treatment options and management of functional dyspepsia. Aliment Pharmacol Ther. 2012; 36(1): 3-15. 3. Robinson M. Dyspepsia: challenges in diagnosis and selection of treatment. Clin Ther. 2001; 23(8): 1130-44. 4. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology. 2006; 130(5): 1466-79. 5. Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology. 2005; 129(5): 1756-80. 6. Lacy BE. Functional dyspepsia and gastroparesis: one disease or two? Am J Gastroenterol. 2012; 107(11): 1615-20. 7. van Zanten SV, Armstrong D, Chiba N et al. Esomeprazole 40mg once a day in patients with functional dyspepsia: the randomized, placebo-controlled “ENTER” trial. Am J of Gastroenterol. 2006; 101(9): 2096-106. 8. Thumshirn M. Pathophysiology of functional dyspepsia. Gut. 2002; 51 Suppl 1:i63-i66. 9. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database System Review. 2005; 1:CD002096. 10. Vachhani R, Olds G, Velanovich V. Esomeprazole: a proton pump inhibitor. Expert Rev Gastroenterol Hepatol. 2009; 3(1): 15-27. 11. Niu XP, Yu BP, Wang YD, et al. Risk factors for proton pump inhibitor refractoriness in Chinese patients with non-erosive reflux disease. World J Gastroenterol. 2013; 19(20): 3124-9.

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12. McKeage K, Blick SK, Croxtall JD, et al. Esomeprazole: a review of its use in the management of gastric acid-related diseases in adults. Drugs. 2008; 68(11): 1571-1607. 13. Yang H, Li J, Zhao Q, et al. Pharmacokinetics, pharmacodynamics, and safety of esomeprazole injection/infusion in healthy Chinese volunteers: A five-way crossover study. J Gastroenterol Hepatol. 2013; 28(12): 1823-8. 14. Rotman SR, Bishop TF. Proton pump inhibitor use in the U.S. ambulatory setting, 2002-2009. PLOS One. 2013; 8(2): e56060. 15. Reimer C, Søndergaard B, Hilsted L, et al. Proton-pump inhibitor therapy induces acidrelated symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009; 137(1): 80-7. 16. Bytzer P, van Zanten SV, Mattsson H, et al. Partial symptom-response to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis - a post hoc analysis of 5796 patients. Aliment Pharmacol Ther. 2012; 36(7): 635-43. 17. Johnson DA, Stacy T, Ryan M, et al. A comparison of esomeprazole and lansoprazole for control of intragastric pH in patients with symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2005; 22(2): 129-34. 18. Meineche-Schmidt V, Christensen E, et al. Randomized clinical trial: identification of responders to short-term treatment with esomeprazole for dyspepsia in primary care - a randomized, placebo-controlled study. Aliment Pharmacol Ther. 2011; 33(1): 41-9. 19. van Zanten SV, Wahlqvist P, Talley NJ, et al. Randomised clinical trial: the burden of illness of uninvestigated dyspepsia before and after treatment with esomeprazole--results from the STARS II study. Aliment Pharmacol Ther. 2011; 34(7): 714-23.

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20. van Zanten SV, Flook N, Talley NJ, et al. One-week acid suppression trial in uninvestigated dyspepsia patients with epigastric pain or burning to predict response to 8 weeks’ treatment with esomeprazole: a randomized, placebo-controlled study. Aliment Pharmacol Ther. 2007; 26 (5): 665-72. 21. Talley NJ, Vakil N, Lauritsen K, et al. Randomized-controlled trial of esomeprazole in functional dyspepsia patients with epigastric pain or burning: does a 1-week trial of acid suppression predict symptom response? Aliment Pharmacol Ther. 2007; 26 (5): 673-82. 22. Roman S, Serraj I, Damon H, et al. Correlation between gastric pH and gastro-oesophageal reflux contents: ambulatory pH-impedance monitoring results. Neurogastroenterol Motil. 2007; 19(7): 562-8. 23. Weijenborg PW, Cremonini F, Smout AJ, et al. PPI therapy is equally effective in well-defined non-erosive reflux disease and in reflux esophagitis: a meta-analysis. Neurogastroenterol Motil. 2012; 24(8): 747-57, e350. 24. Gwee KA, Hwang JE, Ho KY, et al. In-practice predictors of response to proton pump inhibitor therapy in primary care patients with dyspepsia in an Asian population. J Clin Gastroenterol. 2008; 42(2): 134-8. 25. Sarnelli G, De Giorgi F, Efficie E, et al. Correlation between oesophageal acid exposure and dyspeptic symptoms in patients with nonerosive reflux disease. Eur J Gastroenterol Hepatol. 2008; 20(4): 264-8.

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Figure Legends Figure 1: Satisfactory relief of symptoms over the last 4 weeks Figure 2a: Results of pH >4 Values at the Proximal Channel in Subjects that were Either Responders (R) or Nonresponders (NR) on Esomeprazole or Placebo Therapy Figure 2b: Results of pH >4 Values at the Distal Channel in Subjects that were Either Responders (R) or Nonresponders (NR) on Esomeprazole or Placebo Therapy

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Table 1: Rome 2 Criteria for Functional Dyspepsia At least 12 weeks that does not have to be consecutive within the previous 12 months of: 1. Persistent or recurrent symptoms of upper abdomen pain or discomfort. 2. No evidence of organic disease that could possibly explain the symptoms. 3. No evidence that the dyspepsia is relieved by defection or associated with a change in stool frequency or stool shape (rule out irritable bowel syndrome).

Table 2a. Results of pH >4 values based on 24-hr gastric pH monitoring before (V2) and after 4 week (V3) and 8 week (V4) of therapy with esomeprazole in patients with non-ulcer dyspepsia (NUD).

pH>4

Esomeprazole

Channel Proximal

V2 (Baseline) – 1st pH test (N=38)

V3 – 2nd pH test (N=38) V4 – 3rd pH test (N=38) #

Distal

Mean (SEM) 95% CI

637 (69.1)

194 (32.1)

(497, 777)

(129, 259)

Mean (SEM) 95% CI P

1155 (45.3)

884 (59.9)

(1063, 1247) P≤0.001## vs. Esomeprazole Baseline (1st pH test) 1036 (67.3)

(763, 1005) P≤0.001## vs. Esomeprazole Baseline (1st pH test) 796 (69.6)

(900, 1172) **P≤0.001# vs. Esomeprazole Baseline (1st pH test) P=0.03## vs. Esomeprazole V3 (2nd pH test)

(655, 937) **P≤0.001## vs. Esomeprazole Baseline (1st pH test) P=0.004## vs. Esomeprazole V3 (2nd pH test)

Mean (SEM) 95% CI P

##

Paired t-test Wilcoxon Signed Rank Test *P≤0.05 **P≤0.001 Visit 2 (V2), Visit 3 (V3), Visit 4 (V4)

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Table 2b. Results of pH >4 values based on 24-hr gastric pH monitoring before (V2) and after 4 weeks (V3) and 8 weeks (V4) of therapy with placebo in patients with non-ulcer dyspepsia (NUD).

PH>4

Placebo

Channel Proximal

V2 (Baseline) – 1st pH test (N=35) nd

V3 – 2 pH test (N=35)

V4 – 3rd pH test (N=35)

#

Distal

Mean (SEM) 95% CI

820 (72.3)

252 (49.2)

(673, 967)

(152, 352)

Mean (SEM) 95% CI

794 (70.5)

243 (39.4)

(651, 937)

(163, 323)

P Mean (SEM) 95% CI P

##

P=0.99## vs. Placebo Baseline (1st pH test) 278 (61.4)

P=0.44 vs. Placebo Baseline (1st pH test) 764 (73.9) (614, 914) #

P=0.50 vs. Placebo Baseline (1 pH test) P=0.66# vs. Placebo V3 (2nd pH test)

(153, 403) st

P=0.81## vs. Placebo Baseline (1st pH test) P=0.31## vs. Placebo V3 (2nd pH test)

##

Paired t-test Wilcoxon Signed Rank Test *P≤0.05 **P≤0.001 Visit 2 (V2), Visit 3 (V3), Visit 4 (V4)

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Table 3. Results of pH >4 values based on 24-hr gastric pH monitoring before (V2) and after 4 weeks (V3) and 8 weeks (V4) of therapy with esomeprazole vs. placebo in patients with non-ulcer dyspepsia (NUD).

pH>4 Channel V2 (Baseline) pH test

Proximal Placebo (N=35) Esomeprazole (N=38)

V3 pH test

Placebo (N=35)

Esomeprazole (N=38)

V4 pH test

Placebo (N=35)

Esomeprazole (N=38)

Distal

Mean (SEM) 95% CI Mean (SEM) 95% CI P

820 (72.3)

252 (49.2)

(673, 967) 637 (69.1)

(152, 352) 194 (32.1)

(497, 777) + P=0.054 vs. Placebo Baseline

(129, 259) + P=0.44 vs. Placebo Baseline

Mean (SEM) 95% CI P Mean (SEM) 95% CI P

794 (70.5)

243 (39.4)

(651, 937) ## P=0.44 vs. Placebo Baseline 1155 (45.3)

(163, 323) ## P=0.99 vs. Placebo Baseline 884 (59.9)

(1063, 1237) + **P≤0.001 vs. Placebo V3 ## **P≤0.001 vs. Esomeprazole Baseline 764 (73.9)

(763, 1005) + **P≤0.001 vs. Placebo V3 ## **P≤0.001 vs. Esomeprazole Baseline 279 (61.4)

(614, 904) # P=0.50 vs. Placebo Baseline # P=0.66 vs. Placebo V3 1036 (67.3)

(154, 404) ## P=0.81 vs. Placebo Baseline ## P=0.31 vs. Placebo V3 796 (69.6)

Mean (SEM) 95% CI P Mean (SEM) 95% CI P

(900, 1172) (655, 937) + + P=0.01 vs. Placebo V4 **P≤0.001 vs. Placebo V4 # ## **P≤0.001 vs. Esomeprazole **P≤0.001 vs. Esomeprazole Baseline Baseline ++ ## + t-test #Paired t-test Wilcoxon Signed Rank Test Mann-Whitney Rank Sum Test *P≤0.05 **P≤0.001 Visit 2 (V2), Visit 3 (V3), Visit 4 (V4)

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Table 4. Results of pH >4 values based on 24-hr gastric pH monitoring before (V2) and after 4 weeks (V3) and 8 weeks (V4) of therapy with esomeprazole in non-responders vs. responders in patients with non-ulcer dyspepsia (NUD).

pH>4 Channel

Baseline pH test

Esomeprazole Non-responders (N=11)

Proximal Mean (SEM) 95% CI

628 (155) (282, 974)

Distal 177 (37.7) (93, 261)

641 (76.2) 201 (42.7) (484, 798) (114, 289) Responders (N=27) + + P=0.52 vs. V3-Baseline NonP=0.85 vs. V3-Baseline NonResponders Responders Mean (SEM) 1121 (95) 850 (141) Non-responders 95% CI (929, 1333) (537, 1163) (N=11) ## # P P=0.02 vs. V3-Baseline Non**P=0.001 vs. V3-Baseline (QD – All Patients) Responders Non-Responders Mean (SEM) 1170 (51.6) 898 (63.5) 95% CI (1064, 1276) (767, 1029) Responders (N=27) + + P P=0.65 vs. V3 pH test NonP=0.88 vs. V3 pH test Non(QD – All Patients) Responders Responders # # **P≤0.001 vs. V3-Baseline **P≤0.001 vs. V3-Baseline Responders Responders Mean (SEM) 663 (176) 239 (121) 95% CI (246, 1080) (10, 526) Non-responders + + P P=0.97 vs. V3-Baseline NonP=0.77 vs. V3-Baseline Non(N=8) Responders Responders Mean (SEM) 630 (75.6) 182 (45.3) 95% CI (475, 785) (89, 275) Responders (N=30) + + P P=0.86 vs. V3-Baseline P=0.84 vs. V3-Baseline Responders Responders + ++ P=0.73 vs. V4-Baseline NonP=0.71 vs. V4-Baseline NonResponders Responders Mean (SEM) 976 (168.6) 614 (168.3) 95% CI (577, 1374) (216, 1012) Non-responders ## # P P=0.22 vs. V4-Baseline NonP=0.12 vs. V4-Baseline Non(N=8) Responders Responders (BID – All Patients) + + P=0.65 vs. V3 pH test NonP=0.24 vs. V3 pH test NonResponders Responders Mean (SEM) 1050 (74.3) 839 (75.8) 95% CI (898, 1202) (684, 994) Responders (N=30) + ++ P P=0.66 vs. V4 pH test NonP=0.22 vs. V4 pH test Non(QD – All Patients) Responders Responders # ## **P≤0.001 vs. V4-Baseline **P≤0.001 vs. V4-Baseline Responders Responders + + P=0.5 vs. V3 pH test P=0.70 vs. V3 pH test Responders Responders ++ ## + t-test #Paired t-test Wilcoxon Signed Rank Test Mann-Whitney Rank Sum Test *P≤0.05 **P≤0.001 Visit 2 (V2), Visit 3 (V3), Visit 4 (V4) Once daily (QD), Twice daily (BID)

V4 pH test

Baseline pH test

V3 pH test

Mean (SEM) 95% CI P

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Figure 1 Satisfactory relief of symptoms over the last 4 weeks 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% Visit 3

Visit 4 Esomeprazole

Visit 5

Visit 6

Placebo

Time (min.) pH > 4 at Proximal Channel

Figure 2a: Results of pH >4 Values at the Proximal Channel in Subjects that were Either Responders (R) or Nonresponders (NR) on Esomeprazole or Placebo Therapy 1400 1200 1000 Esomperazole (R)

800

Esomeprazole (NR)

600

Placebo (R) 400

Placebo (NR)

200 0 Visit 2 (V2): Baseline (1st pH test)

Visit 3 (V3): 4 weeks (2nd pH test)

Visit 4 (V4): 8 weeks (3rd pH test)

30

Figure 2b: Results of pH >4 Values at the Distal Channel in Subjects that were Either Responders (R) or Nonresponders (NR) on Esomeprazole or Placebo Therapy Time (min.) pH > 4 at Distal Channel

1000 900 800 700 600

Esomperazole (R)

500

Esomeprazole (NR)

400

Placebo (R)

300

Placebo (NR)

200 100 0 Visit 2 (V2): Baseline (1st pH test)

Visit 3 (V3): 4 weeks (2nd pH test)

Visit 4 (V4): 8 weeks (3rd pH test)

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