Gastroesophageal reflux disease (GERD) is a chronic gastrointestinal disorder that is caused by retrograde flow or regurgitation of stomach contents into the esophagus. The global pooled prevalence of GERD, as published in 2020, was 13.98% (range: 2.5% – 45.4%). The prevalence in India ranged between 15.0% – 19.9% [1], an increase from 7.6% as reported by the Indian Society of Gastroenterology Task Force (ISG TF) in 2011 [2].

The most predominant symptoms of GERD are heartburn and regurgitation. The primary goals of GERD treatment are symptom relief, prevention of symptom relapse, healing of erosive esophagitis, and prevention of complications. Treatment options include lifestyle and dietary modifications, pharmacotherapy, and surgery. Pharmacotherapy is directed at neutralization of gastric acid or suppression of its secretion. Proton pump inhibitors (PPIs) are the standard of care and are considered the most potent agents for GERD management. These irreversibly bind to and inhibit the hydrogen/potassium ATPase [H+/K+ ATPase] pump on the parietal cells of the stomach, thus decreasing gastric acid secretion [3]. International guidelines recommend the use of PPIs in addition to other management strategies [4-7]. However, there are several limitations associated with PPI administration. There is evidence that 20% – 40% of GERD patients do not respond or respond partially to PPIs, leading to a view that factors apart from acid are implicated in GERD severity. Impaired mucosal integrity has been proposed as one of these factors, and managing it is thought of as a potential treatment [8]. Although benefits of PPIs outweigh risks in case of short-term use, long-term use is being recognized as a contributing factor to multiple adverse effects. Given the overuse and misuse of PPIs stemming from increase in GERD incidence due to changing lifestyles, it is essential that over-prescription of PPIs is avoided. Instead, PPIs is recommended be used for the shortest required time at the smallest effective dose [9]. We believe this is possible if PPI treatment is supplemented with a cytoprotective agent that would protect the mucosal surface thus reducing damage. We, therefore, endeavored to investigate the effectiveness of concomitant administration of the cytoprotective agent, sucralfate, with PPI.

Sucralfate, a mucosal protective agent, is a salt of sucrose sulfate and aluminium hydroxide [10]. Based on its reported superiority over placebo [11] and its comparable efficiency to histamine-2 receptor antagonists (H2RAs) [12] in providing symptomatic relief, the ISG TF [6] and the Romanian Society of Neurogastroenterology [10] advocate the use of sucralfate.

Gastric acid secretion is not increased in GERD; therefore, an optimum management strategy would be to inhibit acid secretion and prevent the contact of acid with esophageal mucosa. To the best of our knowledge, there are no combination studies of sucralfate and PPI, and therefore, it remains unknown whether sucralfate supplementation to PPI-based therapy is effective. With this rationale, the current study aimed to compare the efficacy and safety of combinatorial treatment of sucralfate and PPI to that of PPI monotherapy.

This prospective, open-label, active controlled study was conducted at three sites in India: SRM Institutes of Medical Sciences (Chennai), KEM Hospital (Mumbai), and Peerless Hospitex Hospital and Research Center Limited (Kolkata). The study was conducted in accordance with the principles of Declaration of Helsinki and guidelines for clinical trials on Pharmaceutical Products in India–Good Clinical Practice (GCP) Guidelines as mentioned in NDCT rules 2019, issued by the Central Drugs Standard Control Organization, Ministry of Health, Government of India, as well as in compliance with the requirements of the clinical study protocol approved by the Ethics Committees of the study sites. Written informed consent was obtained from all subjects prior to enrollment. The trial was registered with the Clinical Trials Registry India (CTRI) on 17 September 2020 (reference number: CTRI/2020/09/027875).

Based on inclusion criteria of the study, a total of 100 adult subjects aged 18-65 years with mild symptoms of GERD occurring on two or more days a week or moderate or severe symptoms occurring on one or more days a week were screened and randomized by 1:1 allocation to be treated with either PPI (pantoprazole) alone or PPI in combination with sucralfate (along with advice on lifestyle modifications and standard of care). PPI was used at a dosage of 20 mg once daily before breakfast while dosage for sucralfate (suspension) was 1 g (10 ml) three times a day prior to a meal; both medications were consumed orally. Written informed consent was obtained prior to enrollment.

Subjects with alarm symptoms such as unintentional weight loss, progressive difficulty in swallowing (dysphagia), iron deficiency anemia, persistent coughing, laryngitis, pharyngitis, or epigastric mass, and subjects with significant gastrointestinal obstruction, major gastric or esophageal surgery (excluding appendicectomy or cholecystectomy), esophageal stricture or pyloric stenosis, extra-esophageal manifestations of reflux disease, erosive esophagitis, Barrett's esophagus (>3cm), Zollinger-Ellison Syndrome, scleroderma, or malignancy (other than non-melanoma skin cancers) within last 5 years were excluded from the study. Known hypersensitivity to rabeprazole or esomeprazole or any PPI was also considered an exclusion criterion. Apart from these, any other significant condition that, in the opinion of the investigator, could interfere with the patient’s participation or compliance in the study such as past or current history of alcohol or drug abuse, hepatic, renal, pulmonary, respiratory abnormalities, or who had participated in an investigational drug or investigational device study within 30 days prior to the baseline visit or who were expected to do so during the 4-week study period were also excluded. Female patients who were pregnant or breast feeding at screening, or who, in the opinion of the investigator, might become pregnant during the study were excluded. Use of H2RAs (within 7 days of randomization), anticholinergics, cholinergics, spasmolytics, opiates, sucralfate, prokinetics, antibiotics in relation to H. pylori treatment, or bismuth compounds (within 14 days of randomization) were also considered as exclusion criteria. Subjects known to be infected with Human Immunodeficiency Virus (HIV), or detected with Hepatitis B or C were also excluded.

Subjects underwent treatment and monitoring for 28 days. For efficacy analysis, we used selected parameters on the Patient Assessment of Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM) [13], which is a questionnaire designed to assess the severity of the disease based on patient response to questions related to symptom severity. The parameters used in the current study included heartburn, regurgitation, heartburn when lying down, regurgitation when lying down, feeling of discomfort inside chest, bitter/acid/sour taste in mouth, and retching. The primary endpoints of the study were proportion of responders assessed by mean change in scores of the selected PAGI-SYM parameters and proportion of subjects requiring dose escalation of PPI. Proportion of adverse events was evaluated as the secondary endpoint of the study. All statistical methods were based on the International Conference on Harmonization (ICH) E9 document “Statistical Principles for Clinical Trials” and all statistical analyses were done using IBM SPSS 28.0.1.1. All hypothesis testing was carried out at the 5% (2-sided) significance level. Categorical data were analyzed using Z-test.

A total of 100 subjects [male, 58/100 (58%); female, 42/100 (42%)] were enrolled in the study, the proportion of male subjects was 60% in PPI group and 56% in PPI + Sucralfate group. Subjects in the PPI group were of 37.7 years and those in the PPI + Sucralfate group were of 43.3 years, on average. The mean height and weight of subjects in PPI group was 162.4 cm and 66.5 kg, respectively; the mean height and weight of subjects in PPI + Sucralfate group was 159.3 cm and 66.9 kg, respectively. The mean duration of GERD in subjects of PPI and PPI + Sucralfate groups was 22.3 and 14.9 months, respectively.

A total of 12 subjects (PPI, 4; PPI + Sucralfate, 8) were lost to follow-up; thus, 88 subjects (PPI, 46; PPI + Sucralfate, 42) completed the study (Figure 1).

Figure 1: Subject disposition.

A total of 100 subjects were screened and randomized 1:1 into two treatment arms, PPI and PPI + Sucralfate. A total of 88 subjects completed the study.

The diary of 1 subject from the PPI + Sucralfate group could not be retrieved; therefore, the total number of subjects considered for efficacy analysis was 87 (PPI, 46; PPI + Sucralfate, 41).

The mean scores of selected PAGI-SYM parameters (heartburn, regurgitation, heartburn when lying, regurgitation when lying, feeling of discomfort inside chest, bitter/acid/sour taste in mouth, and retching) were recorded at baseline and thereafter 14- and 28-days post treatment initiation. Statistically significant improvement in score from baseline to study end (day 28) was observed for all parameters in the PPI group and for all parameters except ‘retching’ in the PPI + Sucralfate group. Between baseline and day 14 or day 28, significant changes were observed for all parameters in the PPI group. In the PPI + Sucralfate group, all parameters except ‘regurgitation when lying down’ and ‘retching’ changed significantly from baseline to day 14 while for the change from baseline to day 28, only the change in ‘retching’ did not attain statistical significance. Considering improvement between day 14 and day 28, the percentage of change in all analyzed PAGI-SYM parameters, except ‘bitter/acid/sour taste in mouth’, was higher in the PPI + Sucralfate group than the PPI group; the differences between the treatment groups were statistically significant in case of ‘regurgitation’, ‘regurgitation when lying’, and ‘feeling of discomfort inside chest’. Percentage change in ‘bitter/acid/sour taste in mouth’ was significantly higher in the PPI group compared to the PPI + Sucralfate group (Table 1).

Table 1: Percentage of change in estimated marginal means of selected PAGI-SYM parameters between day 14 and day 28 of treatment.

Abbreviation: PPI = Proton Pump Inhibitor

**: p<0.01; ***: p<0.001

#For the difference between treatment groups in percentage change from day 14 to day 28.

We also analyzed the proportion of responders, that is, subjects who showed symptomatic improvement. Upon treatment with PPI + Sucralfate, the proportion of responders increased significantly between day 14 and day 28 in case of ‘regurgitation’, ‘heartburn when lying’, ‘regurgitation when lying’, and ‘feeling of discomfort inside chest’. The proportion of responders in case of other symptoms also increased from day 14 to day 28, although statistical significance was not attained. Same was true for all symptoms among subjects in the PPI group (data not shown). Furthermore, between day 14 and day 28, there were more responders in the PPI + Sucralfate group as compared to that in the PPI group, with respect to symptoms of ‘regurgitation’, ‘heartburn when lying’, ‘regurgitation when lying’, ‘feeling of discomfort inside chest’, ‘heartburn’, and ‘retching’. Except for the symptoms of ‘heartburn’ and ‘retching’, the differences were statistically significant. In case of ‘bitter/acid/sour taste in mouth’ more subjects in the PPI group had symptom relief between day 14 and day 28 as compared to those in the PPI + Sucralfate group (Table 2 and Figure 2). At the end of 28 days of treatment, the proportion of responders was higher in the PPI + Sucralfate group as compared to the PPI group for symptoms of ‘regurgitation’, ‘heartburn when lying’, ‘feeling of discomfort inside chest’, and ‘bitter/acid/sour taste in mouth’ (Table 2).

Table 2: Proportion of responders between day 14 and day 28.

Abbreviation: PPI = Proton Pump Inhibitor

*: p<0.05; **: p<0.01; ***: p<0.001

#For the difference between treatment groups in the change in proportion of responders between day 14 and day 28. 

Figure 2: Proportion of responders between day 14 and day 28 from treatment initiation.

symptoms of gastroesophageal reflux disease or GERD (x-axis) between day 14 and day 28 after treatment initiation have been graphically represented for the two treatment groups.

Dose escalation of PPI was required in a total of 4 subjects, 2 subjects from each treatment group. There were no serious adverse events (SAEs) reported in the study. Only 5/50 (10%) subjects in the PPI + Sucralfate group reported mild/moderate AEs, all of which resolved completely with or without administration of prescribed medications. Of these five subjects, three subjects (with complaints of vomiting, fatigue, and insomnia) were withdrawn from the study while the other two subjects (with complaints of mild headache and throat pain, and oral ulcers) continued in the study.

GERD, a chronic gastrointestinal disorder caused by retrograde flow of stomach contents into the esophagus, is a global concern that necessitates effective management strategies [1, 2]. Although PPIs are widely prescribed, their effectiveness is often limited in some patients. In order to overcome this limitation and to investigate whether the concomitant administration of a mucosal protective agent might be beneficial, this trial was designed to study the effect of sucralfate supplementation with PPI. The effects were compared with PPI monotherapy in this open label, multicentric study. Both groups received standard of care with advice on lifestyle modifications. Of the 100 enrolled adult subjects, most [88/100 (88%)] were compliant with the use of the treatment drugs and completed the study.

Considering improvement between day 14 and day 28, the percentage of change in ‘regurgitation’, ‘regurgitation when lying’, and ‘feeling of discomfort inside chest’ were significantly higher in the PPI + Sucralfate group than the PPI group; the percentage of change in ‘heartburn’, ‘heartburn when lying’, and ‘retching’ were also higher in the PPI + Sucralfate group.  Only the percentage of change in case of ‘bitter/acid/sour taste in mouth’ was significantly higher in the PPI group compared to the PPI + Sucralfate group.

As measured after 28 days of treatment, the proportion of responders was higher in the PPI + Sucralfate group than the PPI group in case of the symptoms of ‘regurgitation’, ‘heartburn when lying’, ‘feeling of discomfort inside chest’, and ‘bitter/acid/sour taste in mouth’. Considering symptom improvement between day 14 and day 28, there were significantly more responders in the PPI + Sucralfate group, as compared to the PPI group, with respect to symptoms of ‘regurgitation’, ‘heartburn when lying’, ‘regurgitation when lying’, and ‘feeling of discomfort inside chest’. Relief from symptoms of heartburn/pain after using sucralfate for 3 weeks was earlier reported by Carling et al. This study further showed that after 6 and 12 weeks of treatment, esophageal lesions were completely healed in 42% and 54% patients using sucralfate, respectively, versus 35% and 41% using placebo, respectively [14]. Similar findings were reported by Herrera et al. wherein a combinatorial treatment of cimetidine and sucralfate for 12 weeks was found to be superior to cimetidine alone in improving symptoms of heartburn during daytime [15].

Previous studies have firmly established the efficacy of sucralfate over placebo. In a study by Simon et al., the rate of responders was significantly higher for patients treated with sucralfate (71% versus 29%); a 'good' or 'excellent' overall response was received from 45% of patients treated with sucralfate versus 22% treated with placebo [11]. Greater healing or improvement was also reported with sucralfate as compared to placebo (81% versus 59%) in a study wherein complete healing was observed in 36% patients and improvement was observed in an additional 45%; the corresponding proportions in case of placebo were 35% and 24%, respectively [16]. In a comparative study, endoscopic improvement was observed in 53% patients and healing of esophagitis in 31% after sucralfate treatment [17].

The test drug combination showed a good safety profile in our study with only 10% subjects reporting mild/moderate AEs, all of which resolved completely with or without administration of prescribed medications. This is similar to a previous study wherein the percentage of adverse events was reported as 10% with the use of sucralfate [11].

Overall, our study showed that PPI in combination with sucralfate is an effective treatment strategy for most of the common symptoms presented by GERD patients. Compared to the control group treated with PPI alone, a greater proportion of subjects undergoing combinatorial treatment with PPI and sucralfate showed relief in symptoms of ‘heartburn’, ‘regurgitation’, ‘heartburn when lying’, ‘regurgitation when lying’, ‘feeling of discomfort inside chest’, and ‘retching’ between the treatment duration of 14 and 28 days. Overall, the proportion of responders in the PPI + Sucralfate group was higher than that in the PPI group. Furthermore, the current study proves the safety of using PPI + Sucralfate; very few subjects faced mild/moderate AEs and most subjects were compliant with the treatment. Thus, this study gives convincing evidence to support the use of PPI + Sucralfate in GERD management. This treatment modality might enable clinicians to reduce the time of treatment with PPIs and their dose escalation. However, follow-up studies are required to ascertain this with confidence. Also, studies of longer duration are required to investigate the long-term effect of the combinatorial treatment.

Funding for this study was provided by Fourrts (India) Laboratories Pvt. Ltd. 

The authors would like to acknowledge support of Medclin Research in the conduct of the study and statistical analysis for manuscript development.

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