Randomised clinical trial: sodium alginate oral suspension is non-inferior to omeprazole in the treatment of patients with non-erosive gastroesophageal disease

Authors

  • C.-T. Chiu,

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
    • Correspondence to:

      Dr C.-T. Chiu, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

      E-mail: ctchiu@adm.cgmh.org.tw

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    • Authors (Cheng-Tang Chiu and Chen-Ming Hsu) share co-first authorship.
  • C.-M. Hsu,

    1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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    • Authors (Cheng-Tang Chiu and Chen-Ming Hsu) share co-first authorship.
  • C.-C. Wang,

    1. Division of Gastroenterology, Buddhist Tzu Chi General Hospital, Taipei Branch and School of Medicine, Tzu Chi University, Hualien, Taiwan
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  • J.-J. Chang,

    1. Division of Gastroenterology and Hepatology, Department of Medicine, Chang Gung Memorial Hospital at Keelung, Taiwan
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    • Co-corresponding author – Equal contribution with the corresponding author.
  • C.-M. Sung,

    1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • C.-J. Lin,

    1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • L.-W. Chen,

    1. Division of Gastroenterology and Hepatology, Department of Medicine, Chang Gung Memorial Hospital at Keelung, Taiwan
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  • M.-Y. Su,

    1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • T.-H. Chen

    1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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Summary

Background

The burden of gastroesophageal reflux disease (GERD) is increasing in the Asia area and the majority of GERD patients have non-erosive reflux disease (NERD).

Aim

To evaluate the efficacy and safety of sodium alginate suspension compared to omeprazole in adult subjects with NERD.

Methods

In this 4-week, double-blind, parallel study, 195 NERD subjects were randomised to one of two treatment groups: sodium alginate suspension 20 mL three times a day and omeprazole 20 mg once daily. The primary efficacy endpoint was the percentage of patients achieving adequate heartburn or regurgitation relief at day 28 assessed by patient diary. The secondary efficacy endpoints included percentage of patients achieving adequate heartburn or regurgitation relief, change from baseline of the Reflux Disease Questionnaire total score at day 14 and 28 from baseline, and patients’ overall satisfaction.

Results

In this study, 183 subjects were included in the intent-to-treat population, and 172 subjects were included in the per-protocol population. Non-inferiority of sodium alginate to omeprazole was demonstrated in the intent-to-treat population [difference, 2.7% (53.3% vs. 50.5%, P = 0.175), 95% lower confidence interval −11.9%, above the preset margin of −19%]. All of the secondary efficacy endpoints were comparable between two groups. The incidence of adverse event was relatively low and there was no difference between the two groups (5.4% vs. 5.5% for sodium alginate vs. omeprazole). No severe adverse event was noted in this study.

Conclusion

The study showed that sodium alginate was as effective as omeprazole for symptomatic relief in patients with non-erosive reflux disease (Clinicaltrials.gov NCT01338077).

Introduction

Gastroesophageal reflux disease (GERD) is a common chronic upper gastrointestinal condition that develops when reflux of gastric contents causes troublesome symptoms and/or complication. GERD has traditionally been classified into two major categories based on endoscopic findings, namely erosive GERD (ERD) and non-erosive reflux disease (NERD). The majority of GERD patients did not have endoscopically recognisable lesions in the oesophageal mucosa and were classified as NERD.[1] The prevalence of GERD is increasing in the Asia with 2.5–7.1% of the population suffering at least weekly heartburn and/or acid regurgitation.[2, 3]

Proton pump inhibitors (PPIs) are effective in the symptom relief of erosive GERD, and are widely accepted as the first-line treatment for this condition. However, the response rate of PPIs in the NERD patients is generally lower than that in the patients with erosive GERD.[4] Sodium alginate is an anti-reflux agent indicated for the relief of symptoms due to gastric acid or bile reflux into oesophagus. Alginate exerts its unique mechanism of action by rapid reaction with gastric acid and forming a raft, which floats on the top of gastric contents as anti-reflux barrier.[5] Alginate has been reported for its anti-reflux efficacies in comparison with antacids or H2-blockers in many clinical trials,[5] however, there is no head-to-head study directly compared sodium alginate with PPI in NERD patients. Therefore, the question is raised about whether sodium alginate is no worse than PPI or not in the treatment of NERD.

This prospective, large-scale, multicentre, randomised, double-blind study was the first one to directly compare the 4-week treatment efficacies of sodium alginate suspension with those of omeprazole in NERD patients.

Methods

Study design

This was a multicentre, randomised, double-blind, parallel-group, two-arm comparative study of 4 weeks duration. The study was conducted in patients with NERD documented by screening endoscopy. The primary purpose was assessed by the percentage of adult patients achieving adequate heartburn or regurgitation relief after treatment with sodium alginate suspension 20 mL t.d.s. (50 mg/ml) or omeprazole 20 mg q.d.s. for 4 weeks. The secondary objectives were to assess percentage of patients achieving adequate heartburn or regurgitation relief after treatment with sodium alginate or omeprazole for 2 weeks, change from baseline in the Reflux Disease Questionnaire (RDQ)[6, 7] and patients’ overall satisfaction. The safety profiles of patients were also evaluated for incidence of adverse events and change from baseline in the laboratory test data.

Subjects were enrolled by 18 investigators to participate in the study for 5 weeks including 1 week of screening period and 4 weeks of treatment period. After a 1-week screening period, subjects who fulfilled the inclusion criteria and none of the exclusion criteria were 1:1 randomised and assigned a pre-generated treatment allocation code by investigators based on their participating sequences into either the alginate group or the omeprazole group for a double-blind 4-week treatment period. Subjects received study drug and rescue medication on day 1 and came back to clinics at weeks 2 and 4 for assessing GERD symptoms by diary cards, RDQ score, concomitant medication use and safety profiles. Unused study drug and rescue medication were collected at weeks 2 and 4 and new study drug and rescue medication dispensed at week 2. All study subjects underwent a complete physical examination and laboratory investigation at screening and at week 4. Female subjects received urine pregnancy test at screening and at week 4 visits.

This study was conducted at five sites: four sites in Chang Gung Memorial Hospital at Linkou, Taoyuan, Taipei and Keelung, and at one site in Tzu Chi General Hospital Taipei branch. The study protocol was approved by the Institutional Review Board at each participating study hospital. The study was registered at ClinicalTrials.gov (efficacy and safety of sodium alginate oral suspension to treat non-erosive gastroesophageal reflux disease; NCT01338077).

Patients

Subjects who met all of the following criteria were eligible to enter this study: age of 20–75 years old (inclusive) of both genders in Taiwan; out-patients who had been diagnosed as non-erosive GERD [Endoscopic appearance of non-erosive GERD is defined as normal (N) and minimal change (M) according to the modified Los Angeles (LA) classification][8]; heartburn or regurgitation (either one) as main symptom at least 2 days a week and had been present for ≥1 month before screening; heartburn or regurgitation (either one) during the 7 days screening period, either with frequency for ≥4 days of mild symptom or ≥2 days of moderate to severe symptom and agreement to sign the informed consent form.

Patients with any one of the following conditions were ineligible to enter the study: erosive GERD, Barrett's oesophagus or oesophageal stricture; active or healing gastroduodenal ulcer (except scars); history of gastric, duodenal or oesophageal surgery; malignant disease of any kind; intrahepatic stone, gallstone, gall-bladder sludge, hepatic or pancreatic carcinoma as evidenced by abdominal ultrasonography; ischaemic heart disease as evidenced by electrocardiogram (EKG); pregnant or nursing mother; history of allergy to any of the study drugs or their related compounds; history of alcohol or drug abuse; clinically significant liver disease (AST/SGOT, ALT/SGPT >2 × upper limits of normal); clinically significant renal disease (serum creatinine >1.5 mg/dL); using a proton pump inhibitor (PPI) within 14 days before screening, or a H2-blocker, prokinetic agent or antacid within 7 days before screening; participating any investigational drug trial within 4 weeks before screening; any other conditions or diseases that an investigator considered not appropriate study.

Treatment allocation

Treatment allocation was based on pre-generated permuted block randomisation with SAS software (ver. 9.2) by statistician. Block size of four was chosen to make sure subjects were enrolled with a 1:1 ratio of the alginate group to the omeprazole group. Randomisation was performed at the investigational sites.

Study medications were administered by subjects themselves. For subjects allocated to the alginate group, 20 mL (50 mg/mL) sodium alginate suspension (Alginos; Center Laboratories, Inc., Hsinchu, Taiwan) three times after meals plus one omeprazole matching placebo capsule (TTY Biopharm Co., Ltd., Chungli, Taiwan) before breakfast were planned to be taken every day during the 4-week treatment period. Each mL of Alginos contains 50 mg sodium alginate, 26.7 mg sodium bicarbonate and 16 mg calcium carbonate. For subjects allocated to the omeprazole group, one omeprazole 20 mg capsule (Omelon; YSP Ind. Co., Ltd., Taichung, Taiwan) before breakfast along with 20 mL placebo suspension three times after meals were assigned to be administered daily during the 4-week treatment period. The placebo suspension (Center Laboratories, Inc., Hsinchu, Taiwan) was composed of talc, carbomer 934P (polymer), sodium hydroxide, propylparaben, methylparaben, sucralose, essence of strawberry, edetate disodium, Food Yellow No.4, Food Red No.40 and purified water. This placebo formula can achieve identical physical appearance and taste as active Alginos. Neither subjects nor investigators were able to differentiate subject's treatment group. Patient selection and endpoint evaluation bias were to be minimised by the double-blind fashion. The blinding was not broken throughout the entire study.

Patients were allowed to receive antacid (Macgel; YSP Ind. Co., Ltd., Taichung, Taiwan) as rescue medication if necessary in an open-label fashion up to a maximum of six tablets per day. Each tablet contains aluminium hydroxide 200 mg, magnesium hydroxide 200 mg and simethicone 25 mg.

Primary efficacy endpoint

The primary efficacy endpoint was the percentage (%) of patients achieving adequate heartburn or regurgitation relief at day 28 as assessed by patient diary. Heartburn was defined as a burning feeling or pain behind the breastbone. Regurgitation was defined as an acid taste in the mouth or unpleasant movement of material upwards from the stomach. Adequate heartburn or regurgitation relief was defined as no more than 1 day of mild heartburn or regurgitation episodes in the last 7 days before day 28.[4] Patients were instructed to record the severity of heartburn and/or regurgitation on patient diary during the 1-week screening period. Whichever was more severe was chosen as the only one reflux symptom to be assessed in the subsequent 4-week treatment period. Patients rated the daily severity of symptom according to the following four-point scale: 0 = none (no symptom), 1 = mild (symptoms were easily tolerated, the discomfort was only minimal and did not affect normal activities), 2 = moderate (symptoms were sufficient to affect normal activities), and 3 = severe (symptoms markedly affected normal activities). The weekly symptom score was calculated by the sum of 1 week period daily symptom score.

Secondary efficacy endpoints

The secondary efficacy endpoints included the following items: (i) percentage (%) of patients achieving adequate heartburn or regurgitation relief at day 14 as assessed by patient diary; (ii) change from baseline of the RDQ total score at day 14 and 28; and (iii) patients’ overall satisfaction at the end of study. Adequate heartburn or regurgitation relief was defined as no more than 1 day of mild heartburn or regurgitation episodes in the last 7 days before visit 3 (day 14). RDQ was a 12-item self-administered questionnaire and there were three subscales that evaluate frequency and severity of heartburn, regurgitation and dyspepsia. Each item was scored on a six-point Likert scale ranging from 0 to 5. The RDQ total scores were determined by the sum of 12-item scores. The overall satisfaction is categorised as a six-point scale, using the following definition: 0 = very poor, 1 = poor, 2 = unsatisfactory, 3 = satisfactory, 4 = good and 5 = very good.

Safety assessment

The safety assessment included incidence of adverse events (AE) and data from the laboratory test results. All adverse events reported during the study, regardless of their relationship with the investigational product, were recorded in detail respect to the date of onset, date stopped (if applicable), seriousness, severity, the required treatment modification, the causal relationship with the study medication, and outcome. Laboratory test results at screening and final visit served as part of the safety evaluations. Clinically meaningful changes from baseline were monitored for laboratory data. The following laboratory assessments were conducted using the standard methods at hospital: white blood cells (WBC) with differential counts, red blood cells (RBC), haematocrit, haemoglobin, platelet count, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), γ-glutamine transferase(γ-GT), serum creatinine, albumin, globulin, alkaline phosphatase (Alk-P), sugar AC, bilirubin, electrolytes (calcium, phosphorus, sodium, potassium) and urinalysis.

Statistical analysis

The sample size of this study was determined to be total 158 evaluable subjects. It was based on a one-sided 95% significance level and a non-inferior margin value of 19% with the assumption that adequate heartburn relief rate of omeprazole was 64%[9-12] to provide 80% power to demonstrate the non-inferiority of sodium alginate suspension to omeprazole in-patients with NERD. The dropout rate was assumed to be 10%. Therefore, it was determined that approximately 180 subjects should be enrolled to ensure the completion of total 158 evaluable subjects.

The Intent-To-Treat (ITT) population consisted of all randomised subjects who administered at least one dose of study medication. It was important to decide whether a subject was to be excluded from the ITT population because at least 158 evaluable subjects were required to achieve in this study. Subjects with minor protocol deviations were considered as evaluable.

The per-protocol (PP) population was a subset of ITT population and further satisfied the following criteria: dosed with four full weeks of prescribed medications, complete documentation of heartburn or regurgitation severity on patient diary in the last 7 days before day 28, and not taking any prohibited medications.

Efficacy analysis was performed on ITT and PP population. The conclusion of efficacy was made according to the results of ITT analysis. The safety conclusion was made only on ITT population.

Demographics and baseline characteristics were summarised by treatment groups. Quantitative data were reported as means and standard deviation (s.d.), whereas categorical data were expressed as proportions. They were analysed between treatments to ensure comparability using statistical methods of either two-sample t-test or Wilcoxon rank sum tests for continuous variables, and using Fisher's exact test or chi-squared test for categorical variables. Percentage of patients achieving adequate symptom relief at day 14 and 28 were analysed by Fisher's exact test. Change in the RDQ total score and number of antacid used were analysed by two-sample t-test. Patients’ overall satisfaction was analysed by Cochran-Mantel-Haenzel test. All statistical tests were carried out two-tailed at the 5% significance level.

Results

Disposition of subjects

This trial was conducted from November 2010 to January 2012. A total of 224 subjects were screened for the study, 29 subjects were screen failure and the remaining 195 subjects were judged as eligible and were randomised into the 4-week, double-blind study. Among them, 97 subjects were assigned to the alginate group, and 98 subjects were randomised to the omeprazole group. Twelve subjects who did not have any record of investigational product administration due to loss of follow-up or missing diary were excluded from the ITT population. Subsequently, additional 11 subjects who did not have record of reflux symptom score at day 28 due to withdrawal or drug discontinuation because of adverse event were excluded from the PP population. As a result, 183 subjects (92 in the sodium alginate group and 91 in the omeprazole group) were included in the ITT population, and 172 subjects (84 in the alginate group and 88 in the omeprazole group) who completed the study were considered to be evaluable as in the PP population (Figure 1).

Figure 1.

Disposition of study subjects.

Demographics and clinical characteristics

Demographic characteristics for all randomised subjects are summarised in Table 1. The mean age of the subjects was comparable between treatment groups. Female subjects accounted for about 76–80% in both groups. The mean body weight, height, body mass index (BMI), waist circumference, smoking status, intake of alcohol, coffee & tea and sleep disturbance were all similar between treatments. As a consequence, subjects of the two treatment groups were fairly comparable in the aspect of demographic characteristics and life styles.

Table 1. Summary of demographic characteristics of the study subjects
DemographicsSodium alginate (n = 92)Omeprazole (n = 91)P-value
  1. BMI, body mass index; s.d., standard deviation.

  2. a

     Two-sample t-test.

  3. b

     Chi-squared test.

Age (years), Mean ± s.d.46.1 ± 13.048.6 ± 13.20.190a
Female74 (80.4%)70 (76.9%)0.562b
Weight (kg), Mean ± s.d.60.4 ± 10.560.3 ± 1.20.872a
Height (cm), Mean ± s.d.159.0 ± 7.4159.8 ± 7.60.497a
BMI, Mean ± s.d.23.9 ± 4.023.5 ± 2.90.453a
Waist circumference (cm), Mean ± s.d.84.1 ± 10.383.0 ± 8.30.432a
Cigarette smoking, n (%)7 (7.6%)6 (6.6%)0.789b
Alcohol intake, n (%)14 (15.2%)9 (9.9%)0.277b
Coffee intake, n (%)47 (51.1%)50 (55.0%)0.601b
Tea intake, n (%)46 (50.0%)56 (61.5%)0.116b
Sleep disturbance (time/week), Mean ± s.d.1.1 ± 1.90.8 ± 1.60.366a

Disease status at baseline for ITT subjects is summarised in Table 2. The duration of reflux symptoms had been present for approximately 36 months in subjects before they entered this study. About 72–74% of the subjects used to receive medical intervention for treatment, and 54–58% of them had received PPI treatment. Reflux symptom predominately occurred in day-time (65%).The average baseline weekly heartburn or regurgitation symptom scores were 8–9 in both groups. Abnormal urea breath test (UBT) was reported in around 18–23% of the subjects, it suggested that the H. pylori infection rate was relatively low in both groups. There were no clinically important differences in terms of duration of disease, medical intervention, the time symptom predominately occurred, baseline symptom score or UBT results between the two groups.

Table 2. Summary of diseases status at baseline
Disease statusSodium alginate (n = 92)Omeprazole (n = 91)P-value
  1. UBT, urea breath test.

  2. a

     Two-sample t-test.

  3. b

     Chi-squared test.

Duration of disease (months), Mean ± s.d.36.6 ± 57.537.7 ± 51.70.900a
Medical intervention previously
Yes67 (72.8%)68 (74.7%)0.770b
No25 (27.2%)23 (25.3%)
Treatment of medical intervention
PPI39 (58.2%)37 (54.4%)0.658b
Antacids17 (25.4%)20 (29.4%)
Others18 (26.9%)24 (35.3%)
Symptom predominately occurs during
Day-time60 (65.2%)59 (65.6%)0.983b
Night-time21 (22.8%)21 (23.3%)
All time11 (12.0%)10 (11.1%)
Baseline weekly symptom score at diary
Mean ± s.d.8.7 ± 4.19.0 ± 4.30.600a
UBT
Normal74 (76.3%)76 (81.7%)0.359b
Abnormal23 (23.7%)17 (18.3%)

Primary efficacy analysis

The percentage of patients achieving adequate heartburn or regurgitation relief at day 28 in the alginate group was 53.3% (95% CI, 42.9–63.7%), which was comparable with that in the omeprazole group (50.5%, 95% CI, 40.1–61.0%) in ITT populations (P = 0.175) (Figure 2). In PP populations, the percentage of patients achieving adequate heartburn or regurgitation relief at day 28 in the alginate group was comparable with that in the omeprazole group (58.3% vs. 52.3%, P = 0.427). Non-inferiority of alginate to omeprazole for adequate heartburn or regurgitation relief was also proven (lower limit of one-sided 95% confidence interval of percentage difference −11.9%, above the preset margin of −19%). Symptom improvement defined as decrease of symptom score at day 28 compared with baseline was found in 98.8% (83/84) in the alginate group and 96.6% (85/88) in the omeprazole group.

Figure 2.

Percentage of patients with adequate reflux symptom relief at day 28 [Intent-To-Treat (ITT) population].

Secondary efficacy analysis

All of the secondary efficacy endpoints were without statistically significant treatment difference. An average of 32% achieving rate after 14 days treatment was observed in sodium alginate medications, and a mean value of 39% achieving rate was found in the omeprazole group (Table 3).

Table 3. Percentage of subjects achieving adequate relief at day 14
 Sodium alginateOmeprazoleP-value
  1. a

     Fishers Exact test.

ITT(n = 92)(n = 91) 
Achieving, n (%)29 (31.5%)35 (38.5%)0.328a
Not achieving, n (%)63 (68.5%)56 (61.5%) 
95% CI for relief rate[21.8%; 41.2%][28.3%; 48.6%] 
PP(n = 84)(n = 88) 
Achieving, n (%)27 (32.1%)35 (39.8%)0.300a
Not achieving, n (%)57 (67.9%)53 (60.2%) 
95% CI for relief rate[21.9%; 42.3%][29.3%; 50.2%] 

The mean RDQ total score before treatment (at baseline) was about 19 in both arms, while it significantly decreased to 11 after 2 weeks treatment, and further significantly declined to about 6–8 after 28 days treatment with investigational products. There was no significant difference between treatment groups regarding the mean change from baseline of the RDQ total score either at day 14 or at day 28 (Table 4). Patients were encouraged to voluntarily return to hospital once 4 weeks after the end of study for RDQ rebound assessment. Patients in both groups (n = 50 in alginate group and n = 57 in omeprazole group) showed significant rebound of RDQ total score to about 11–12, and the rebound (vs. day 28) was comparable between two groups (data not shown).

Table 4. Change from baseline of the RDQ score
PopulationTimeSodium alginateOmeprazoleP-value
  1. The values are expressed as mean ± s.d.

  2. a

     Two Sample t-test.

  3. b

     RDQ at day 14 minus RDQ at baseline.

  4. c

     RDQ at day 28 minus RDQ at baseline.

ITTBaseline(n = 92)(n = 91) 
RDQ at baseline19.4 ± 9.719.5 ± 11.1 
Day 14(n = 87)(n = 91) 
RDQ at day 1411.6 ± 9.111.7 ± 10.4 
P-value (vs. baseline)<0.0001<0.0001 
Change from baselineb−7.8 ± 9.4−7.8 ± 8.90.996a
Day 28(n = 83)(n = 89) 
RDQ at day 286.8 ± 7.87.9 ± 9.0 
P-value (vs. day 14)<0.0001<0.0001 
Change from baselinec−12.4 ± 8.4−11.4 ± 9.80.487a
PPBaseline(n = 84)(n = 88) 
RDQ at baseline19.5 ± 9.819.4 ± 11.2 
Day 14(n = 84)(n = 88) 
RDQ at day 1411.4 ± 9.111.2 ± 10.2 
P-value (vs. baseline)<0.0001<0.0001 
Change from baselineb−8.1 ± 9.3−8.2 ± 8.80.964a
Day 28(n = 83)(n = 88) 
RDQ at day 286.8 ± 7.88.0 ± 9.0 
P-value (vs. day 14)<0.0001<0.0001 
Change from baselinec−12.4 ± 8.4−11.3 ± 9.80.441a

At the end of 28-day treatment, subjects were asked to categorise his/her overall satisfaction. The sum of the subjects who graded as ‘good’ plus ‘very good’ accounted for more than 86% of the total subjects in both groups (Table 5). The overall satisfaction of sodium alginate was very similar to that of omeprazole and no significant difference could be found.

Table 5. Patients’ overall satisfaction
PopulationCategorySodium alginateOmeprazoleP-value
  1. a

     Mantel-Haenszel chi-squared test.

ITT (n = 84)(n = 89) 
Poor0 (0.0%)1 (1.1%)0.778a
Unsatisfactory3 (3.6%)4 (4.5%) 
Satisfactory8 (9.5%)7 (7.7%) 
Good41 (48.8%)43 (48.3%) 
Very good32 (38.1%)34 (38.2%) 
PP (n = 84)(n = 87) 
Poor0 (0.0%)1 (1.1%)0.876a
Unsatisfactory3 (3.6%)3 (3.4%) 
Satisfactory8 (9.5%)7 (8.0%) 
Good41 (48.8%)43 (49.4%) 
Very good32 (38.1%)33 (37.9%) 

The number of antacid (Macgel) used by subjects was utilised as an indicator to evaluate the efficacy of study medications. Subjects in the sodium alginate group consumed a mean of 5 tablets of Macgel during the 4-week treatment period while patients in the omeprazole group took an average of 9 tablets antacid. The mean number of antacid used was comparable between sodium alginate and omeprazole groups in both ITT and PP populations.

Safety analysis

Low incidence of adverse events was observed between 2 treatment arms (5.4% in the alginate group vs. 5.5% in the omeprazole group). The severity of all adverse events was mild or moderate, no severe adverse events were reported during the study period. None of the assessed laboratory test items was significant different between two treatment groups (data not shown).

Discussion

This study showed that treatment with sodium aligniate suspension 20 mL three times daily for 4 weeks can provide non-inferior efficacy compared to omeprazole 20 mg once daily in adult patients with NERD. In ITT population, the proportion of NERD patients achieving adequate symptom relief was 53% for the alginate group, which was statistically not significantly different from the omeprazole group (50%, P = 0.175). The adequate symptom relief at day 14 was also not different between the alginate and omeprazole groups. Furthermore, reduction from baseline RDQ score at day 14 and day 28 were equally comparable between alginate and omeprazole treatments.

Although alginate-based formulations are used for the treatment of heartburn and esophagitis for over 30 years, the clinical evidence of these agents utilised in NERD patients was limited. To date, only two studies were found about the therapeutic effect of alginate on NERD patients.[13, 14] The first study reported alginic acid was superior to hydrotalcite (an antacid agent) after 6-week treatment.[13] The second study reported sodium alginate plus omeprazole had significantly better efficacy than omeprazole alone over a period of 4 weeks.[14] However, direct comparison of sodium alginate with PPI in NERD patients was not found in literature. Thus, this study was the first study to directly compare sodium alginate with omeprazole in a prospective, double-blinded, and randomised fashion in NERD patients.

The rate of adequate symptom relief in the study was higher than that of complete symptom relief with either alginate or omeprazole treatment. 41.7% subjects in the sodium alginate group vs. 39.8% subjects in the omeprazole group achieved complete relief after 4 weeks treatment (P = 0.802). It suggested that sodium alginate was as effective as omeprazole in achieving either adequate or complete symptom relief. The rate of complete symptom relief using omeprazole in our study was higher than that reported in a Japanese randomised study in NERD patients (25.7%) recently,[14] but was quite consistent with the pooled rate of previously reported PPI symptomatic response pooled rate (36.7%) in a systematic review of 1854 patients from seven randomised trials.[4] Many GERD patients could accept a therapy that offer substantial symptom relief rather than complete symptom control.[15] Therefore, sufficient symptom control may be an adequate clinical end point for NERD patients due to the low risk of developing erosive esophagitis.[4]

The rate of symptom relief significantly increased from baseline to 2-week assessment and from 2-week to 4-week evaluation in both groups in this study. This finding is concordant with previous pooled analysis of PPI therapy in NERD patients.[4] Furthermore the increase of response to alginate over time was higher than that to omeprazole in this study. Thus, longer treatment period should be considered in future study design of NERD population.[16]

Goves et al. compared the therapeutic effect of antacid/alginate liquid 10 mL q.d.s. with 10 mg omeprazole once daily for dyspeptic symptoms relief including heartburn complaint.[17] This multicentre open-label parallel study reported omeprazole was significantly better than alginate for complete heartburn relief (64% vs. 30%, P < 0.001). Pouchain et al. also compared omeprazole (20 mg/day) with Gaviscon (4 × 10 mL/day) to treat GERD patients in a 14-day randomised double-blind double-dummy study.[18] Secondary outcomes including the proportion of patients without heartburn by day 7, pain relief by day 7, and reduction in pain intensity by day 7 and day 14 were all in favour of omeprazole, although Gaviscon achieved non-inferiority to omeprazole in terms of the mean time to onset of the first 24-h heartburn-free period. This inconsistent finding might be due to no upper endoscopy was conducted in their trials to stratify ERD and NERD patients, therefore inclusion of patients with ERD which could be more responsive to PPI treatment in their trials.

Patient satisfaction is an alternative end point for the assessment of therapeutic response in NERD population.[15, 19, 20] In this study, the overall satisfaction of omeprazole was 87%. It was similar to the findings of a meta-analysis including twelve trials which showed 93% (95% CI 87–99%) GERD patients satisfied with 4 weeks PPIs.[20] Our results showed that overall satisfaction of sodium alginate was slightly higher than that of omeprazole, but without significant difference. It suggested that sodium alginate was not inferior to omeprazole for the treatment of NERD in-patient's satisfaction. Factors that affect patient satisfaction include treatment regimen, general level of well-being, the bedside manner of the physician and the quality of patient–physician communication.[19] Improvement of symptom, thorough investigation study design and interactive consultation process in our trial may contribute to the high proportion of patient satisfaction.

This study showed that 4 weeks of treatment with both alginate and omeprazole were well tolerated. No serious adverse events or clinically significant abnormalities of laboratory tests were found in this short period trial. However, for most patients, GERD is a chronic condition that demand long term either unceasing or intermittent treatment. Alginate is a safe product (pregnancy category A) without systemic complications,[5] therefore it can be considered as an alternative choice for the treatment of NERD.

NERD is an umbrella term which includes true NERD and functional heartburn (FH).[21, 22] NERD patients can be categorised into three subgroups, namely true NERD, hypersensitive oesophagus and FH, by using oesophageal pH-impedance studies.[23] The subgroup of FH accounted for 26% of NERD patients.[23] In this study, there was no oesophageal pH-impedance test prior to randomisation for better characterising subgroups of NERD patients. Therefore, the percentage of patients who were FH was not clear in our patient population. However, oesophageal pH-impedance examination, which is not routinely performed in clinical practice, in these patients in this study makes the results more applicable for clinicians.[16]

There is concern about the placebo, which might have some therapeutic effects on the NERD symptoms improvement. Based on previous studies, the complete heartburn resolution rate after 4-week placebo administration in NERD patients ranged from 5% to 21%, and the sufficient heartburn resolution rate was about 24%.[12, 24-28] The adequate relief rates in our trial were more than 50% in both arms. It is clear that the therapeutic gain of both sodium alginate and omeprazole over placebo ranged from 25% to 30%, which is quite consistent with previous data.[4] However, we did not design a pure placebo group in this trial to evaluate placebo effect. The double-dummy technique was designed to minimise the placebo effect, if any. Furthermore, there have been standard medications such as PPIs for the treatment of NERD patients. So a pure placebo group is deemed inappropriate to be introduced in this trial from an ethical point of view.

Recent researches suggest that acid pocket is an important mechanism for post-prandial acid reflux events in GERD patients.[29-31] Sweis et al. recently reported direct evidence of MRI images to show alginate can form a mass at the oesophago-gastric junction 15 min after administration.[32] Alginate-antacid formulation was also displayed to neutralise the acid pocket and shift it downwards away from the lower oesophageal sphincter in GERD patients.[33] Therefore, alginates can rapidly and effectively relieve symptom of reflux through its unique fast raft-forming property.[34]

In conclusion, sodium alginate was confirmed to be not inferior to omeprazole for the treatment of NERD in this study. The clinical efficacy and safety profiles of sodium alginate were comparable to omeprazole after 4-week treatment in NERD subjects. With its unique raft-forming ability, alginate can be considered as a relevant and effective alternative medication for NERD patients in general practice.

Authorship

Guarantor of the article: C.T. Chiu, MD.

Author contributions: All authors performed the research. C.T. Chiu, J.J. Chang and C.M. Hsu collected and analysed the data. C.T. Chiu and C.M. Hsu designed the research and wrote the paper. J.J. Chang and C.C. Wang contributed to the design of the study. All authors approved the final version of the article, including the authorship list.

Acknowledgements

Declaration of personal interests: Cheng-Tang Chiu, MD, has served as an Asia Pacific advisory board member for Takeda Pharmaceuticals.

The following physicians also participated in this study: H.C. Yeh, Chang Gung Memorial Hospital at Linkou, Taiwan; P.C. Wang, Taipei Tzu Chi General Hospital, Taiwan; C.J. Kuo, Chang Gung Memorial Hospital at Linkou, Taiwan; T.H. Hsiao, Taipei Tzu Chi General Hospital, Taiwan; W.R. Lin, Chang Gung Memorial Hospital at Linkou, Taiwan; Y.P. Ho, Chang Gung Memorial Hospital at Linkou, Taiwan; S.W. Chen, Chang Gung Memorial Hospital at Keelung, Taiwan; C.J. Liu, Chang Gung Memorial Hospital at Keelung, Taiwan; W.P. Lin, Chang Gung Memorial Hospital at Linkou, Taiwan. Initial data analyses were undertaken by F. Hsu.

Declaration of funding interests: This study was found by TTY Biopharm Co., Ltd. Taipei Branch.

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