Multi-Center Study of Panosyl-Isomaltooligosaccharides Adjunctive to PPI Therapy to Treat GERD

A Multi-Center Study of Panosyl-Isomaltooligosaccharides (PIMO) Adjunctive to Proton Pump Inhibitor (PPI) Therapy to Treat Gastroesophageal Reflux Disease (GERD) in Subjects Who Are PPI-Responders or PPI-Partial Responders

This study will be conducted as a multi-center, randomized, double-blind, placebo-controlled trial to evaluate the effect of MHS-1031 on heartburn-free days in subjects with GERD-related heartburn symptoms.

MHS-1031 is a specific proprietary digestion-resistant oligosaccharide carbohydrate that serves as a prebiotic. The active ingredient in MHS- 1031 is a well-defined and well-characterized distribution of panosyl-isomaltooligosaccharides (PIMOs) ranging in degree of polymerization (DP) from DP3 to DP8. This study will be conducted as a multi-center, randomized, double-blind, placebo-controlled trial to evaluate the effect of MHS-1031 adjunctive to PPI therapy on heartburn-free days in subjects with GERD-related heartburn symptoms who self-report improvement while on sustained daily PPI therapy. Heartburn-free days will be determined by subject report specific to any of the three questions ("burning feeling behind the breastbone" and/or "pain behind your breastbone" and/or "heartburn"; Questions 1, 2 & 3 of the RESQ-eD). For purposes of this trial, heartburn-free days are defined as subject report of 'Did Not Have', or 'Very Mild' on each of the three RESQ-eD questions listed above. All candidate subjects must self-report at least partial response to sustained daily PPI acid suppressive therapy (i.e. 'daily' defined as taking PPIs 5-7 days/week on average). Candidate subjects will be screened for medical history of chronic heartburn that may be associated with other medical conditions, and these subjects will be excluded. The entire study consists of three phases: Remote Screening Phase 2-Week Assessment (SP1), on-site Screening Phase Part 2 (SP2) and Treatment Phase (TP). Efficacy will be assessed using patient reported outcome (PRO) questionnaires, concomitant medication assessments, and assessment of adverse events, from baseline (determined during Remote Screening Phase 2-Week Assessment) to Treatment Phase Weeks 1-4 and Weeks 5-8. The primary analyses will be conducted to assess the efficacy of MHS-1031 adjunctive to PPI therapy, and separately as monotherapy subsequent to combined PPI and MHS-1031 therapy, in randomized subjects with GERD-related heartburn as determined by the RESQ-eD validated questionnaire, validated for use online.

Study medication will be supplied as a syrup in individual sachets containing 1g (1.5 mL) of MHS-1031. Subjects will be randomized in 2:1 fashion to either study drug (2) or placebo (1)

Matching placebo is an oral solution formulated to have a degree of sweetness and acidity similar to the study medication and will be provided in equivalent sachets containing 1.5g (1.5 mL) of the oral placebo solution.

The difference between baseline weekly average heartburn-free days and weekly average heartburn-free days during Treatment Phase Weeks 1-4 and Weeks 5-8 (as measured using questions 1, 2 and 3 of the Reflux Symptom Questionnaire Electronic Diary) (RESQ-eD).

The difference between baseline daily average heartburn symptom severity score and daily average heartburn symptom severity score during Treatment Phase Weeks 1-4 and Treatment Phase Weeks 5-8 (as measured using questions 1, 2 and 3 of the Reflux Symptom Questionnaire Electronic Diary) (RESQ-eD).

Any increase between baseline weekly average heartburn-free days and heartburn-free days during Treatment Phase Weeks 1-4 and Weeks 5-8 where Patient Global Assessment Question 1 is ≥ baseline.

Any increase between baseline daily average heartburn severity and heartburn severity during Treatment Phase Weeks 1-4 and Weeks 5-8 where Patient Global Assessment Question 1 is ≥ baseline.

Inclusion Criteria: Ability to participate in the study, undergo all protocol activities, communicate in English, and provide signed informed consents. Ability, during Remote Screening Phase 2-Week Assessment, to complete required online nightly RESQ-eD questionnaires, medication questionnaires, 4-item Patient Health Questionnaire for Depression and Anxiety (PHQ-4) questionnaire and Participant Global Assessment questionnaire. Access to a computer/tablet/phone with internet access and active email account in order to complete online questionnaires nightly throughout study participation. Males or females ≥ 18 and ≤ 75 years of age, with a BMI ≥ 19 and < 35 kg/m2. Female subjects must be postmenopausal or surgically sterile or, if of childbearing potential, must agree to use a medically acceptable form of contraception from the time of signing the informed consent forms through completion of study. If only the barrier method is used, a single barrier or better is adequate. Postmenopausal women must have had ≥ 12 months of spontaneous amenorrhea. Surgically sterile women are defined as those who have had a hysterectomy, bilateral ovariectomy, or bilateral tubal ligation. All women of childbearing potential must have a negative pregnancy test result before administration of study drug. Must be on stable doses of medications, if any, prescribed for chronic conditions other than GERD. Subject must be taking PPI, daily (defined as 5-7 days/week on average) at no more than the dosing listed in the table below, for at least four (4) consecutive weeks with self-reported symptom improvement (frequency and/or severity) prior to the Screening Call selected from the following list of medications: omeprazole (40 mg) esomeprazole (40 mg) lansoprazole (30 mg) dexlansoprazole (30 mg) pantoprazole (40 mg) rabeprazole (20 mg) Onset of GERD-related heartburn for a minimum of 3 months prior to Screening Call (i.e., "burning feeling behind the breastbone" and/or "pain behind your breastbone" and/or "heartburn" per questions 1, 2 or 3 of RESQ-eD). Subject has maintained a stable diet and exercise regimen for ≥ 30 days prior to the Screening Call and is willing to maintain that diet and exercise regimen for the duration of the study (ie, if subject is currently following diets including, but not limited to, Keto, FODMAP, Vegan, Vegetarian, s/he must be willing to continue this dietary lifestyle through end-of-study visit). Exclusion Criteria: Any daily PPI dosing greater than that listed above. For this study PPI daily dosing is defined at 5-7 days/week on average. Currently taking more than one type of PPI. Current use of any mouthwash (e.g., Listerine, Scope, others) or unwilling to discontinue use for the duration of the study (requires 3-day washout prior to starting the Remote Screening Phase 2-Week Assessment). Teeth whitening within 7 days of Screening Call or current use of teeth whitening substances (not including teeth whitening toothpaste) or unwilling to discontinue use for the duration of the Remote Screening Phase 2-Week Assessment). Current use of histamine 2 receptor antagonists (H2RAs) and unwilling to discontinue use for the duration of the Remote Screening Phase 2-Week Assessment (requires 7-day washout prior to starting the Remote Screening Phase 2-Week Assessment). Surgical procedure requiring general anesthesia within 60 days of the Screening Call. Colonoscopy, high colonic, colonic cleanse, or barium enema in the past 30 days, or scheduled for colonoscopy or barium enema at any time for the duration of the study, and unwilling to postpone until after study completion. History of cancer diagnosis and/or treatment (other than basal cell carcinoma of the skin) within the preceding (5) five years. Concomitant illness with potential to confound outcome assessments for this study, including, but not limited to: History of untreated peptic or gastric ulcer, Zollinger-Ellison syndrome, or Helicobacter pylori (H. pylori) positivity without a history of successful treatment. History of ulcerative colitis, Crohn's disease, colon cancer, current stomach ulcers, pancreaticobiliary disorders (e.g., symptomatic gallstones within the past 6 months, bile duct stones, pancreatic stones, pancreatitis), diverticulitis. Acute or chronic hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection. Significant morbidity of the heart, kidney, liver or lung. History of Long QT Syndrome History of Torsades de pointes (TdP) Current neurological or psychiatric disorder (e.g., Parkinson's, Huntington's chorea, schizophrenia, seizures, bi-polar disorder, major depressive disorder). Known or suspected alcoholism, drug addiction, or significant drug abuse within 1 year of the Screening Call based on subject reporting and PI assessment. Active history of tobacco or nicotine use (of any type) in the last 6 months. Alcohol abuse (for alcohol defined as: > 14 drinks/week or 4 drinks/day for men, >7 drinks/week or 3 drinks/day for women). Intake of acetylsalicylic acid (i.e., aspirin) at doses > 162 mg/day. Non-steroidal anti-inflammatory pain relievers (NSAIDs) such as ibuprofen (Advil, Motrin IB, others) > 2 days/week. Acetaminophen > 2 days/week or > 2,000 mg/day. Inhalation or ingestion of products containing delta-9-tetrahydrocannabinol (THC) > 2 days/week on average. Any known medical condition, clinical signs and symptoms, vital signs, abnormal laboratory, or other testing, considered clinically significant by the Principal Investigator (PI), that could interfere with the subject's participation in and completion of the study including, but not limited to: Uncontrolled hypertension Diabetes uncontrolled by diet (i.e., requiring oral medication or insulin) History of adrenal disease, diabetic nephropathy, or gastroparesis Uncontrolled hypothyroidism Untreated mental disorder Spinal cord injury Cerebrovascular event (stroke) or myocardial infarction (MI) within the last 6 months. Structural abnormality of the gastrointestinal (GI) tract, or disease or condition that can affect GI motility, or defecation. Planned travel outside the USA during the study period. History or presence of pseudo-obstruction, malignant polyps, colitis, ischemic colitis, abdominal adhesions, intestinal ischemia, esophageal atresia, laxative or enema abuse, or pelvic floor dysfunction. Current COVID19 infection, or a history of a prior COVID19 infection with ongoing symptoms suggestive of "Long COVID". Endoscopic evidence of any of the following diseases/disorders: Eosinophilic esophagitis, scleroderma, Barrett's esophagus, esophageal cancer, or Candida esophagitis confirmed by histopathology. LA grade B, C or D erosive esophagitis, esophageal stricture or scarring. Hiatal hernia > 2 cm or reported as greater than small. History of surgery or endoscopic treatment including fundoplication and/or dilation for esophageal stricture. History of fecal impaction that required hospitalization or emergency room treatment within 3 months of the Screening Call. History of eating disorder within the last 5 years. History of substantiated (documented by computed tomography (CT) scan or hospitalization) diverticulitis, or any ongoing chronic condition (e.g., polycystic kidney disease, endometriosis, ovarian cysts, or other) that may be associated with chronic abdominal pain or discomfort and might confound the assessments in this study during the 12 months prior to the Screening Call. Surgical history meeting any of the following criteria: Gastric bypass surgery or invasive procedure for the treatment of obesity or surgery to remove a segment of the GI tract at any time prior to the Screening Call. Gastric band present within the past 60 days. Open surgery of the abdomen, pelvis, or retroperitoneal structures within 6 months prior to the Screening Call. Laparoscopic appendectomy or cholecystectomy or other instrumentation of the bowel < 60 days prior to the Screening Call. NOTE: endoscopic removal of benign polyps is not considered exclusionary. Prior use of the study medication MHS-1031. Prior Use of ISOThrive Prebiotic Nectar. Use of fructo-oligosaccharides (FOS) or inulin. History of diseases that have symptoms that may be confused with GERD (i.e., "burning feeling behind the breastbone" and/or "pain behind your breastbone" and/or "heartburn" per RESQ-eD questions 1, 2, or 3): angina, esophageal spasm, achalasia, rumination, or other conditions involving the mouth and/or throat, dysphagia, or dyspnea. Taking any of the following medications at time of Screening Call: Anticholinergics, such as oxybutynin (e.g., Ditropan XL®) Theophylline (e.g., Elixophyllin®, Theochron) Calcium Channel Blockers and Nitrates Progesterone More than one medication for depression and/or anxiety/sleep (e.g., benzodiazepines such as diazepam (Valium) and temazepam (Restoril)), or single depression/anxiety/sleep medication that is not on stable dosing for at least 90 days Tricyclic anti-depressants (e.g., amitriptyline, doxepin, others) Bisphosphonates taken orally, such as alendronate (Fosamax), ibandronate (Boniva) and risedronate (Actonel, Atelvia) Quinidine Metformin Anticoagulants (e.g., Coumadin, Heparin) Iron supplement (other than contained in multi-vitamin) Potassium supplements Asthma medications (other than Albuterol ≤ 1 day/week) Prescription medication to control Irritable Bowel Syndrome or Chronic Idiopathic Constipation Antibiotic use within 60 days of the Screening Call. Narcotic (e.g., opiate) or illicit drug (i.e., illegal at both the Federal and State levels; e.g., Cocaine, Heroin, Methamphetamine) use within 60 days of the Screening Call. Use of any investigational product within 90 days prior to the Screening Call. Use of prescription medication for weight loss within 30 days of Screening Call. Pregnancy, lactation, planned pregnancy or planned ova donation during the study period. Participation in another investigation (clinical trial) during the course of this study. Any major lifestyle change, such as getting married, change in residence, change in job, or other highly stressful event planned during the study period. Sustained daily use of PPIs without self-reported improvement of heartburn symptoms. Self or relative employed directly or indirectly by the Sponsor or relative or employee of investigator or investigator's staff. Other conditions or situations that, in the Principal Investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study.