Efficacy and Safety of DLBS2411 in the Management of GERD

Study Overview
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Brief Summary
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This is a 2-arm, prospective, double-blind double-dummy, randomized-controlled study comparing DLBS2411 at a dose of 250 mg twice daily with omeprazole at a dose of 20 mg twice daily, given before morning and evening meals, for an 8-week course of therapy. Subjects should avoid taking meals 2-3 hours before bedtime. The bioactive fraction of DLBS2411 has been proved at cellular and genetic levels to have an antiulcer effect through both suppressing the gastric acidity and enhancing gastric mucosal protection. The anti-secretory effect of DLBS2411 is exerted through the inhibition of H+/K+ ATPase 'pump' as well as down-regulation of the H+/K+ ATPase gene expression, thus suppressing gastric acid secretion; while its cytoprotective defense mechanism works through the promotion of cyclooxygenase-2 (COX-2) derived prostaglandin (PgE2) synthesis, thus promoting gastrointestinal submucosal blood-flow, stimulating secretion of gastric-epithelial mucous and bicarbonate; anti-oxidative activity; and endothelial-nitric oxide (NO) formation. Recent study of DLBS2411 which was conducted in healthy volunteers, demonstrated the effective role and safety of DLBS2411 in suppressing intragastric acidity. Having such mechanisms of action, DLBS2411 is hypothesized to benefit patients with gastric acid disorders such as in gastroesophageal reflux disease (GERD).

Detailed Description
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There will be 2 groups of treatment; each group will consist of 129 subjects with the treatment regimens for 8 weeks: Treatment I : 1 capsule of Omeprazole 20 mg and 1 placebo caplet of DLBS2411, twice daily Treatment II : 1 caplet of DLBS2411 250 mg and 1 placebo capsule of omeprazole, twice daily Each study medication will be administered twice daily, 30 minutes before morning (the first) and evening (the last) meals. The eligible subjects will be randomly allocated to receive study medication (Treatment 1 or Treatment 2) for 8 weeks of treatment, in a double blind fashion. They will be asked to come to the clinic every 4-week interval throughout the study period. Treatment Group 1 will receive Omeprazole twice daily and Placebo DLBS2411 twice daily. While Treatment Group 2 will receive DLBS2411 twice daily and Placebo Omeprazole twice daily. Subjects will be evaluated for treatment efficacy at baseline and at interval of 4 weeks over the 8-week course of therapy. Throughout the 8-week therapy, subjects should record the frequency (presence and absence) of each of GERD symptoms (heartburn, regurgitation, epigastric pain, nausea) daily in the provided Patient's Diary. The severity of each symptom experienced should also be self-evaluated and recorded. The safety profile of study medication other than vital signs and adverse event will be measured at baseline and end of study. Along the study, subjects should avoid taking meals 2-3 hours before bedtime. All subjects will be under direct supervision of a medical doctor during the study period.

Official Title
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Efficacy and Safety of DLBS2411 Compared to Omeprazole in the Management of Gastroesophageal Reflux Disease (GERD)

Conditions
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Gastroesophageal Reflux Disease (GERD)

Intervention / Treatment
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* Drug: Omeprazole
* Drug: DLBS2411
* Drug: Placebo capsule of Omeprazole
* Drug: Placebo caplet of DLBS2411


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Agree to participate in the study under signed informed consent. Male or female subjects aged 18-65 years old. Subjects with diagnosis of GERD confirmed by endoscopy, with esophagitis grade A-B according to the LA Classification. Able to take oral medication. Subjects or subjects' legally acceptable representatives are able and willing to record adverse events in diary. Subjects or subjects' legally acceptable representatives have the ability to comply with the trial protocol, including instruction for taking trial medication. Exclusion Criteria: For females of childbearing potential: pregnancy and breast-feeding. Patients must accept pregnancy tests during the trial if menstrual cycle is missed Fertile patients must use a reliable and effective contraceptive Subjects with Zollinger Ellison syndrome or peptic ulcer diseases. History or current evidence of Barrett's esophagus, esophageal strictures, odynophagia, pyloric stenosis, esophageal motility disorders (such as achalasia, scleroderma), anatomic esophageal abnormality (such as large hiatal hernia), pill-induced esophagitis. Helicobacter pylori positive as confirmed by urea breath test (UBT). History of esophageal, gastric or intestinal surgery including vagotomy. Presence of comorbid diseases, such as symptomatic coronary artery disease (CAD) or cardiovascular disease, pulmonary disease (including asthma), hemostasis disorder, pancreatitis, malabsorption, or inflammatory bowel disease, and any other chronic diseases (including chronic cough, laryngitis), any serious infection(s), or malignancy(ies). Inadequate liver function defined as ALT or alkaline phosphatase > 2.5 times upper limit of normal. Inadequate renal function defined as estimated Glomerular Filtration Rate (eGFR) < 60 mL/min. Taking any proton pump inhibitors (PPIs) or sucralfate within 14 days prior to screening. Requiring regular and chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, aspirin, anticholinergics, cholinergics, spasmolytics, or opiates, misoprostol or prokinetics. Hypersensitivity to proton pump inhibitors. Subjects with chronic alcoholism (>40 g alcohol/day) or drug abuse. Active heavy smokers (i.e. consuming >10 cigarettes per day). Participation in any other clinical studies within 30 days prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment 1<br>1 Omeprazole capsule 20 mg and 1 placebo caplet of DLBS2411, twice daily | Drug: Omeprazole<br>* 1 Omeprazole 20 mg capsules twice daily<br>Drug: Placebo caplet of DLBS2411<br>* 1 placebo caplet of DLBS2411, twice daily<br>* Other names: Placebo caplet of Redacid;|
| Experimental: Treatment II<br>1 DLBS2411 caplet 250 mg and 1 placebo capsule of Omeprazole, twice daily | Drug: DLBS2411<br>* 1 DLBS2411 caplet 250 mg, twice daily<br>* Other names: Redacid;Drug: Placebo capsule of Omeprazole<br>* 1 placebo capsule of omeprazole, twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Healing rate by endoscopy | Healing rate is defined as proportion of subjects with either complete or achieving lower endoscopic grade of esophagitis (according to the Los Angeles (LA) classification) at Week 8 (end of study). | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in GERD Questionnaire (GERDQ) sum scores | Changes in GERDQ sum scores from baseline to Week 4 and Week 8 of treatment. | 4 and 8 weeks | 
| Composite heartburn and regurgitation response rate | Composite heartburn and regurgitation response rate: defined as proportion of subjects with neither heartburn nor acid regurgitation during the last 7 days (complete resolution of heartburn and acid regurgitation) by Week 4 and Week 8. | 4 and 8 weeks | 
| Heartburn response rate | Heartburn response rate: defined as proportion of subjects with no heartburn during the last 7 days (complete resolution of heartburn) by Week 4 and Week 8 (end of study). | 4 and 8 weeks | 
| Regurgitation response rate | Regurgitation response rate: defined as proportion of subjects with no regurgitation during the last 7 days (complete resolution of regurgitation) by Week 4 and Week 8 (end of study). | 4 and 8 weeks | 
| Overall response rate | Overall response rate: defined as proportion of subjects with controlled GERD symptoms by Week 4 and 8 of treatment, defined as proportion categorized as: complete relief (no GERD symptoms during the last 7-day); partial relief (a decrease in frequency but not complete relief of GERD symptoms during the last 7-day); and no response (increase or no change in frequency of GERD symptoms). | 4 and 8 weeks | 
| Vital sign | Vital sign (blood pressure) from baseline to every follow-up visit including end of study | 4 and 8 weeks | 
| Electrocardiography (ECG) | Electrocardiography (ECG) at baseline and at the end of study | 8 weeks | 
| Liver function | Liver function (serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin)from baseline to every follow-up visit including end of study | 4 and 8 weeks | 
| Renal function | Renal function (serum creatinine and blood urea nitrogen (BUN) level) from baseline to every follow-up visit including end of study | 4 and 8 weeks | 
| Adverse event | Adverse event, will be observed throughout the study conduct | 4 and 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GERD, DLBS2411, omeprazole