ERADICATE Hp2 - Treating Helicobacter Pylori With RHB-105 Compared to Active Comparator

A Randomized Double Blind Active Comparator Controlled Phase III Study to Assess the Safety and Efficacy of RHB-105 in the Treatment of Confirmed Helicobacter Pylori (H. Pylori) Infection

The "test and treat" strategy for treating dyspeptic patients who are H. pylori positive is rapidly becoming the standard of care. This study will test the effectiveness of RHB-105, a new triple therapy to treat H. pylori infection in dyspeptic patients against an active comparator.

This is a, randomized, double blind, active comparator-controlled study of RHB-105 in adult subjects complaining of epigastric discomfort that have been screened and found to be positive for H. pylori infection via 13C UBT and gastric biopsy.

The biopsy samples will also be used to conduct H. pylori antibiotic susceptibility/resistance assessment.

The study will be conducted at up to 65 sites in the USA. Eligible subjects will be randomized in a ratio of 1:1 between the RHB-105 arm (n=222) and the active comparator arm (n=222). Subjects will receive RHB-105 or active comparator for 14 consecutive days. Eradication of H. pylori infection will be determined at Visit 5 based on 13C UBT testing conducted between 43 and 71 days after initiation of study drug therapy.

All subjects who meet inclusion and exclusion criteria and have positive13C UBT will undergo upper endoscopy with sampling for culture and sensitivity testing (to rifabutin, amoxicillin, clarithromycin, and metronidazole) prior to randomization. After test of cure at Visit 5, all H. pylori eradication failures will receive susceptibility directed Standard of Care therapy based on initial culture results for subjects, and undergo repeat upper endoscopy for post treatment antibiotic susceptibility/resistance assessment.

Inclusion Criteria:

1. Be ages 18 - 70, inclusive; non-Asian males and females (This population has been demonstrated to have significantly elevated omeprazole levels as per the prescriber information for other omeprazole products). A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam should be considered Asian, and forr this study Asian is defined as having at least one Asian grandparent (Shektar et al, 2014, FDA Guidance for Industry 2016);

2. Positive for H. pylori by 13C Urea Breath Test (UBT) and confirmed positive via gastric biopsy for campylobacter-like organism (CLO) Rapid Urease Test, or H. pylori culture or histology;

3. Symptoms consistent with dyspepsia of at least two weeks duration (defined as recurrent pain or discomfort centered in the upper abdomen, often with a relation to meals);

4. Females must not be pregnant or lactating and:

   1. at no risk of pregnancy for one of the following reasons: postmenopausal for at least one year from the date of informed consent, status post hysterectomy or tubal ligation, OR
   2. are prepared to and agree to use of an intrauterine device (IUD) or practice double method birth control (barrier plus spermicide) from screening through to 30 days post-end of-treatment (EOT); Acceptable double contraceptive methods include barrier (condoms or diaphragms) plus spermicide
   3. Hormonal contraceptives (birth control pills and hormone implants) are not acceptable contraception methods under this protocol;

5. Males must be surgically sterilized or are prepared to and agree to practice double method (barrier plus spermicide) birth control from screening through to 30 days post-EOT;

6. Agree to refrain from consuming alcohol from 1 week prior to screening to Test of Cure/Visit 5;

7. Agree to refrain from taking antacids from screening through day 15 and for at least 24 hours prior to Test of Cure/Visit 5 and if applicable at least 24 hours prior to Visit 8/Test of Cure;

8. Agree to refrain from taking H2 blockers at least 24 hours prior to screening 13C UBT and at least 24 hours prior to Test of Cure/Visit 5 and if applicable at least 24 hours prior to Visit 8/Test of Cure;

9. Agree to refrain from taking sucralfate from one week prior to screening through Test of Cure/Visit5;

10. Agree to refrain from taking bismuth containing medications such as Pepto-BismolTM or other proton pump inhibitors (PPIs) from two weeks prior to screening through Test of Cure/Visit 5;

11. Agrees to refrain from consuming grapefruit, or any other food or supplement known to significantly affect CYP3A4 or CYP2C19 activity from screening to day 15;

12. Provide written informed consent to participate as shown by a signature of subject on the consent form.

Exclusion Criteria:

1. Have alarm symptoms/signs (including unexplained anemia [iron deficiency], melena / hematemesis, anorexia, dysphagia, jaundice, weight loss);
2. Have received prior H. pylori eradication therapy;
3. Use of antibiotics in the 4 weeks immediately prior to screening 13C UBT;
4. Use of any proton pump inhibitors (PPIs) or bismuth-containing medications (such as Pepto-BismolTM) within the 2 weeks immediately prior to screening 13C UBT;
5. Use of any of the following medications within seven days prior screening: alfentanil, allopurinol, amlodipine, anti-herpes agents, anti-retroviral agents, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, boceprevir, buspirone, carbamazepine, cisapride, citalopram dosed greater than 20 mg /d, clomipramine, clopidogrel and other oral anticoagulants, colchicine, dapsone, dihydroergotamine, digoxin, diltiazem, ergotamine, felodipine, fluconazole, gleevec, hormonal contraceptives that are not exclusively norethindrone or norgestrel, imipramine, itraconazole, ketoconazole, latuda, lovastatin, mycophenolate mofetil, nifedipine, nisoldipine, nitrendipine, phenytoin, pimozide, probenecid, proguanil, quinine, roflumilast, terfenadine and voriconazole;
6. Use of amiodarone;
7. Presence of more than two active gastric and/or duodenal ulcers;
8. History of gastric outlet obstruction; or hypersecretory state (e.g., Zollinger Ellison Syndrome);
9. History of esophageal or gastric surgery, except for simple closure of perforated ulcer;
10. History of gastric cancer;
11. History of malignancy within the past five years except for basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been treated with no evidence of recurrence;
12. Positive screening laboratory results for human immunodeficiency virus (HIV) antibody (HIV1 or HIV2), or hepatitis B surface antigen (HBs Ag), or hepatitis C antibody (HCV Ab), unless patient has documented sustained viral response evidenced by prior and/or current absence of viral RNA at least 24 weeks after completing antiviral therapy;
13. Current drug or alcohol abuse or history of drug or alcohol abuse in the past 5 years from screening;
14. Known hypersensitivity or suspected history of hypersensitivity reactions to any of the study drugs or related drugs, including cephalosporins and penicillin;
15. Clinical evidence of any disease that in the opinion of the investigator might interfere with the subject's ability to participate in the trial;
16. History of QT prolongation (QTc greater than 450ms in males and 460ms in females), or ventricular arrhythmia, including torsades de pointes;
17. Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) >3x Upper Limit of Normal (ULN), or Alkaline Phosphatase (APO4) >2x ULN, or Total Bilirubin >2x ULN. Subjects with confirmed diagnosis of Gilbert's Syndrome are excluded if Total Bilirubin > 2.5x ULN;
18. Unable to communicate well with the Investigators and to comply with the study requirements;
19. Involved in any other experimental drug or device protocol (outside of this RHB-105-02 study) within the 4 weeks immediately prior to screening visit through end of study;
20. Subjects with creatinine clearance less than 30 ml/min at screening via estimated Cockcroft-Gault (eCGF) formula: eCGF or estimated creatinine clearance = [140 - age in years] * weight (kg) / 72 * Serum Creatinine (mg/dl) [multiply estimated rate by 0.85 for women], using actual body weight at screening.