Clinical trial: Comparison of Vonoprazan to Esomeprazole in Participants With Symptomatic GERD Who Responded Partially to a High Dose of Proton Pump Inhibitor (PPI) (NCT02743949)

Eligibility criteria:
Inclusion Criteria:

          1. In the opinion of the investigator, the participant is capable of understanding and
             complying with protocol requirements.

          2. The participant or, when applicable, the participant's legally acceptable
             representative signs and dates a written, informed consent form and any required
             privacy authorization prior to the initiation of any study procedures.

          3. Is a man or a woman and ≥18 years of age, at the time of the Screening visit.

          4. Has a documented history of symptoms of both heartburn (burning pain) and acid
             regurgitation prior to entry into the study.

          5. The subject has a medical history of ≥ 8 weeks of persistent heartburn symptoms in the
             presence of regurgitation symptoms (persistent heartburn symptoms defined as heartburn
             symptoms on ≥ 2 days a week) that are troublesome despite appropriate and correctly
             performed treatment with a PPI at standard doses.

          6. Is ≥85% compliant at taking their Run-in medication and completing their e-Diary.
             Compliance for taking the Run-in medication is defined as the medication provided
             (esomeprazole and placebo) taken for 85% of the 6 weeks Run-in Period (or on 36 of 42
             days of the Run-in Period).Compliance for the e-Diary is defined as the percentage of
             scheduled assessments that are completed based on 2 assessments per day (daytime and
             nighttime). For randomization, 85% compliance is required and is defined as 12 of 14
             assessments completed over the 7-day period (Day -21 to Day-14) prior to the single
             blind Placebo Run-in Period.

          7. Has a partial response to a PPI defined as having heartburn on 2 to 5 days and
             regurgitation on at least one day of the last week (Week 4) of a 4 week PPI Run-In
             Period with esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn
             in the last week of a 2 week Placebo Run-In Period (4 to 7 symptom days) and at least
             one symptom day with regurgitation compared with the last week of the PPI Run-In
             Period.

          8. A female participant of childbearing potential who is sexually active with a
             nonsterilized male partner agrees to use routinely adequate contraception from signing
             of informed consent throughout the duration of the study and for 4 weeks after last
             dose of the study medication.

        Exclusion Criteria:

          1. Has received any investigational compound within 30 days prior to the Screening Visit.

          2. Has received vonoprazan in a previous clinical study.

          3. Is an immediate family member, study site employee, is in a dependent relationship
             with a study site employee who is involved in conduct of this study (eg, spouse,
             parent, child, sibling), or may have consented under duress.

          4. Has, in the judgment of the investigator, clinically significant abnormal
             hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening.

          5. Has a history of erosive esophagitis of Los Angeles (LA) Classification Grade B
             severity or worse prior to screening or at Screening endoscopy.

          6. Has a history of or any coexisting diseases affecting the esophagus (eg, Barrett's
             esophagus, eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal
             infection, or esophageal stricture), history of radiation therapy or cryotherapy to
             the esophagus, caustic trauma, or physiochemical trauma such as sclerotherapy to the
             esophagus.

          7. Has "alarm features" in symptomatology, including odynophagia, severe dysphagia,
             bleeding, weight loss, anemia, and blood in stool, pointing to a possible malignant
             disease of the gastrointestinal (GI) tract. Participants displaying "alarm symptoms"
             in addition to the "typical" gastroesophageal reflux disease (GERD) symptoms may be
             included based on endoscopic exclusion of malignancy.

          8. Has current or historical chest pain due to cardiac diseases (eg, within one year).

          9. Has had surgical treatment for GERD (eg, cardiaplasty), dilation of an esophageal
             stricture (other than Schatzki ring) or gastric or duodenal surgery, except simple
             oversew of an ulcer or endoscopic polypectomy of benign polyps.

         10. Has active gastric or duodenal ulcers which have been confirmed by endoscopy within 30
             days prior to Screening. Gastric or duodenal erosions are not exclusionary, unless
             considered severe and symptomatic by the investigator.

         11. Has had an acute upper gastrointestinal hemorrhage within 30 days prior to Screening.

         12. Has current or historical evidence of Zollinger-Ellison syndrome or other
             hypersecretory condition.

         13. Has current or historical evidence of eosinophilic esophagitis (evidence may be based
             on the following: missing response to acid suppressive therapy, the presence of
             eosinophilia in histological probes of the esophageal mucosa, a normal pH profile of
             the distal esophagus, symptoms of dysphagia and food impaction). The exclusion of
             participants based on a predominance of the "typical" eosinophilic esophagitis
             symptoms only (as above) is considered acceptable. However, in participants with a
             predominance of "typical" symptoms and co-existing significant dysphagia and food
             impaction, the syndrome should be excluded by endoscopy with biopsy.

         14. Has a documented history (within 6 months prior to screening) of functional dyspepsia
             (suggested by the presence of one or more of the following symptoms: epigastric pain,
             postprandial fullness or early satiety), or irritable bowel syndrome or other
             gastrointestinal diseases which are not acid-related, and therefore, are nonresponsive
             to gastric acid-blocking treatment.

         15. Has a documented history of familial adenomatous polyposis.

         16. Has known intolerance, hypersensitivity or allergies to any PPI or their components
             (including lansoprazole, dexlansoprazole, omeprazole, rabeprazole, pantoprazole, or
             esomeprazole), any component of vonoprazan, or antacid(s) selected as rescue
             medication for this study.

         17. Has a history of alcohol abuse, illegal drug use, or drug addiction within the 12
             months prior to Screening, or regularly consumes >21 units of alcohol (1 unit = 12
             oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) per week.
             Participants must have a negative drug screen at Screening.

         18. Has evidence of a serious uncontrolled concomitant disease including: clinically
             significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic,
             gastrointestinal, systemic, or endocrine disease or other abnormality (other than the
             disease being studied), which may impact the ability of the participant to participate
             or potentially confound the study results.

         19. Has planned, or is likely to require, in-patient surgery during the course of the
             study.

         20. Has a history of cancer (except basal cell carcinoma of the skin) within 3 years prior
             to Screening.

         21. Is known to have acquired immunodeficiency syndrome or chronic hepatitis due to any
             etiology.

         22. Has abnormal laboratory values at Screening that suggest a clinically significant
             underlying disease or condition that may prevent the participant from completing the
             study.

         23. Has an alanine aminotransferase (ALT), aspartate aminotransferase (AST) or T-bilirubin
             level which exceeds upper limit of normal (ULN) set by the testing laboratory at the
             Screening.

         24. If female, the participant is pregnant or lactating or intending to become pregnant
             before, during, or within 1 month after participating in this study; or intending to
             donate ova during such time period.

         25. Is required to take excluded medications or it is anticipated that the participant
             will require treatment with at least 1 of the disallowed concomitant medications
             during the study.

         26. In the opinion of the investigator, is unable to comply with the requirements of the
             study or is unsuitable for any reason.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 48-year-old man comes to the office complaining of heartburn and acid reflux.  He has taken over-the-counter antacids but sees no relief.  Other medical history is unremarkable.  The patient does not use tobacco, alcohol, or illicit drugs.  Vital signs are within normal limits.  BMI is 31 kg/m2.  Physical examination is  positive for mild tenderness in upper stomach. Chest x-ray shows an air-fluid opacity behind the heart.  A barium swallow study reveals approximately 1/3 of the stomach herniating through the esophageal hiatus.

Patient description (patient's own words): I went to my doctor's office because of a non-stop heartburn and some acid reflux. I took over-the-counter medications, but it keeps going strong! I don't smoke, take drugs or drink alcohol, I'm healthy! The doctor took my vitals, which turned out normal. My BMI is 31, which might be a bit too much for a 48-year-old guy like me. They examined my stomach and found a mild tenderness in the upper part. I also did some X-rays, and they found out that I have an air-fluid opacity behind my heart. I did another X-ray, and it turns out that a part of my stomach went up my chest through a hole in my diaphragm!

Does the patient match the trial criteria? 1