Clinical trial NCT04028466: Effectiveness of Vonoprazan vs Omeprazole as Empiric Therapy for Gastroesophageal Reflux Disease (GERD) Patients Without Alarm Features
Official title: Effectiveness of Vonoprazan vs Omeprazole as Empiric Therapy for Gastroesophageal Reflux Disease (GERD) Patients Without Alarm Features in a Primary Care Setting: A Pragmatic, Randomized, Single Blind Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: GERD
Gastro Esophageal Reflux
Keywords: GERD
gastro esophageal reflux
proton pump inhibitor
Potassium-Competitive Acid Blocker
H(+)-K(+)-Exchanging ATPase
Randomized Controlled Trial
Lead sponsor: St. Luke's Medical Center, Philippines
Sponsor class: OTHER
First posted: 2019-07-22
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pragmatic, Randomized, Single Blind Study
Primary purpose: TREATMENT

Brief summary: Gastroesophageal reflux disease is a commonly encountered disorder in daily practice. Proton pump inhibitor therapy has been the cornerstone of treatment for decades. Although it has been proven to be highly effective, there is still room for improvement. A local study showed that only 57.3% of subjects are asymptomatic after 4 weeks treatment with rabeprazole. Recently a new drug was developed with better absorption, higher bioavailability, more sustained increased pH in the stomach and more targeted action to the H-K ATPase pump. Vonoprazan, belongs to a new class of acid suppressant medications, the potassium-competitive acid blocker (P-CAB). Vonoprazan has been studied and used successfully in Japan for H pylori eradication therapy, GERD, gastric and duodenal ulcers with favorable safety profile. However, to the author's knowledge, no study yet exists comparing vonoprazan to a proton pump inhibitor in the treatment of GERD outside Japan. This study aims to determine whether vonoprazan is superior to omeprazole in relieving symptoms in treatment-naïve adult patients with GERD.

Detailed description: Gastroesophageal Reflux Disease (GERD) is globally defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. The Philippine Clinical Practice Guideline on the Diagnosis and Treatment of GERD defined is as a condition resulting from recurrent backflow of gastric contents into the esophagus and adjacent structures causing troublesome symptoms and/or tissue injury. It is a commonly encountered disorder in the clinics and daily practice. A clinical diagnosis of GERD is acceptable with typical symptoms of acid regurgitation and/or heartburn is present. The Philippine guidelines state that empiric therapy can be started in GERD patients without alarm features and don't require further laboratory exam or workup. The guideline recommends standard dose proton pump inhibitor (PPI) therapy once daily for 8 weeks as cornerstone for treatment.

Proton pump inhibitor (PPI) therapy has been used as first line therapy of reflux symptoms for more than a decade. Even though it has been proven to be highly effective for reflux symptoms, there are still unaddressed issues. A local study by Lontok et al in 2013 evaluated response of GERD patients to rabeprazole 20mg once daily using a locally validated Frequency Scale of Symptoms of GERD (FSSG) in a primary care setting. Their study showed that a 4 week rabeprazole therapy resulting in complete resolution of individual symptoms ranging from 81.9-90.3%, with only 57.3% of all subjects being completely asymptomatic at the end of treatment. Proton pump inhibitors also have unmet issues needing improvement. PPIs usually takes 5 days for their maximal effect. Because of their slow onset of action, a significant number of patients are not sufficiently relieved after the first dose of PPI. Approximately half of patients still have symptoms after 3 days of treatment. PPIs are influenced by the cytochrome P450 (CYP) 2C19 polymorphism, with rapid metabolizers having the lowest intragastric pH compared with slow metabolizers. PPIs are also not sufficiently effective in controlling nocturnal heartburn symptoms because overnight recovery of gastric acid is frequently seen, therefore causing loss of sleep and health-related reductions in quality of life.

Recently, a new drug that promises better pharmacokinetic and pharmacodynamics properties was developed. Its use has been mostly in Japan for the past 2 years. Vonoprazan, is a novel, potassium-competitive acid blocker (P-CAB) that binds and inhibits H-K ATPase, the final step in acid secretion from the parietal cells of the stomach. It can inhibit the proton pump in both acidic and neutral environments with high affinity. The drug is retained for a long time inside the parietal cells and can inhibit H-K ATPase that is activated by further stimulation of acid secretion. Vonoprazan offers the advantage of not being required to be taken before meals, compared to conventional PPIs where 30 minutes before a meal is required, and is unaffected by the CYP2C19 polymorphism. Vonoprazan is also effectively absorbed and quickly accumulates in parietal cells, therefore, acid inhibition is more pronounced after the first dose of vonoprazan, compared to conventional PPIs where it usually takes 3-5 days for maximal effect. Vonoprazan is therefore, a stronger acid blocker that has rapid, stable and longer-lasting effects. Of the author's knowledge only 2 large scale randomized controlled trial have been done with vonoprazan, both these studies were done in Japan and focus only on those with erosive esophagitis. Vonoprazan has been showed to be effective and noninferior to lansoprazole for curing erosive esophagitis, as well as PPI resistant erosive esophagitis, with healing rates more pronounced for Grade C and D erosive esophagitis. Other studies on the use of vonoprazan for GERD have been done only in Japan, and comprised of noninferiority and small retrospective open label trials.

When vonoprazan is used for short term acid suppression, there are no problematic side effects. Treatment emergent adverse events irrespective of causal relationship to study medication are nasopharyngitis, diarrhea, constipation, upper respiratory infection, fall, gastroenteritis and eczema. Most of these treatment emergent adverse events were classified as mild in intensity. Studies are ongoing in Japan to assess the long term safety and efficacy of vonoprazan

. The Philippine Clinical Practice Guideline for GERD recommends locally-validated standardized questionnaire to assess treatment response to GERD. Commonly used questionnaires in the Philippines are the Frequency Scale for Severity of GERD (FSSG) and the Gastroesophageal Reflux Disease Questionnaire (GERDQ); both have undergone local validation studies. FSSG has been shown to correlate with endoscopic severity of GERD and assess response to proton pump inhibitor therapy.2 The FSSG comprises 12 questions where patients would rate individual symptoms as never (0% of the time), occasionally (around 30% of the time), sometimes (50%), often (70%) or always (100%). GERD is diagnosed if the score is more than 8, with sensitivity of 62%, specificity of 59% and accuracy of 60% for endoscopic diagnosis of esophagitis.

Vonoprazan was just recently introduced to the Philippine market recently. Whether or not this drug may replace conventional PPIs as first line therapy remains to be determined. This study aims to determine whether vonoprazan is superior to omeprazole in treating treatment-naïve adult patients with GERD. Data from this study will help formulate policies and recommendations on the treatment of GERD, as well as formulate new treatment strategies for patients with GERD.

Eligibility criteria: Inclusion Criteria:

* All Adult patients with clinically diagnosed with Gastroesophageal Reflux Disease (GERD) without alarm features (heartburn and acid regurgitation)
* Age more than 18 years at the time of written consent
* Those who provide written consent with their own free will
* Both treatment naïve and treatment experienced patients will be included. Treatment experienced patients should not be taking any proton pump inhibitors for 2 weeks to allow for washout period.

Exclusion Criteria:

* Patients that have alarm features as defined by the Philippines Guidelines for GERD (dysphagia, odynophagia, weight loss, anemia, hematemesis, family history of esophageal adenocarcinoma, nocturnal choking, abdominal mass, recurrent/frequent vomiting, chest pain)
* Patients with atypical GERD symptoms (cough, laryngitis, chest pain, etc.)
* Patients already taking proton pump inhibitors for the past 2 weeks
* Patients who scored less than 8 on the FSSG questionnaire
* Patients who have undergone gastroesophageal surgery
* Patients who are poorly compliant to medications
* allergy to PPI or vonoprazan
* With serious comorbidities, such as but not limited to: heart failure, renal failure, malignancy or hepatic failure
* Pregnant, breastfeeding or possibly pregnant
* Patients that would not provide consent
* Patients who are unable to complete the FSSG Questionnaire independently
* Patients who are unable to follow up at designated periods
* Patients taking rilpivirine or atazanavir.
* Patients with elevated baseline liver function tests (more than twice the upper limit of normal)

Primary outcomes:
measure: Proportion of asymptomatic patients at Day 3
timeFrame: day 3 of therapy
measure: Proportion of asymptomatic patients at Day 7
timeFrame: day 7 of therapy
measure: Proportion of asymptomatic patients at Day 14
timeFrame: day 14 of therapy
Secondary outcomes:
measure: Proportion of partial responders at Day 3
timeFrame: day 3 of therapy
measure: Proportion of partial responders at Day 7
timeFrame: day 7 of therapy
measure: Proportion of partial responders at Day 14
timeFrame: day 14 of therapy
measure: Proportion of nonresponders at Day 14
timeFrame: day 14 of therapy
measure: Percent change in the symptom score from baseline (Vonoprazan Group) - Day 3
timeFrame: day 3 of therapy
measure: Percent change in the symptom score from baseline (Vonoprazan Group) - Day 7
timeFrame: day 7 of therapy
measure: Percent change in the symptom score from baseline (Vonoprazan Group) - Day 14
timeFrame: day 14 of therapy
measure: Difference in percent change in the symptom score (between groups)
timeFrame: day 3, 7, and 14 of therapy
measure: Number of Patients with Adverse Effects
timeFrame: Day 14 of therapy
Other outcomes:
Locations:
city: Quezon City
country: Philippines
facility: St. Luke's Medical Center
state: National Capital Region
Study officials:
affiliation: Institute of Digestive and Liver Diseases, St. Luke's Medical Center, Quezon City
name: Nicodemus L Ong, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Digestive and Liver Diseases, St. Luke's Medical Center, Quezon City
name: Sherrie Isabel Q De Ocampo, MD
role: PRINCIPAL_INVESTIGATOR
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