A Study in Patients With Erosive Esophagitis to Investigate Safety, Tolerability, and Healing Rates After 4 Weeks Treatment of X842 or Lansoprazole and Symptom Pattern During Subsequent 4 Weeks Treatment With Lansoprazole

Study Overview
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Brief Summary
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This study will be conducted in patients with erosive esophagitis due to gastro-esophageal reflux disease (GERD) Los Angeles (LA) grades C or D, and in patients with at least partial symptom response but still endoscopically unhealed (LA grades A or B) after 8 weeks history of standard treatment healing course with PPI, designed to support dose selection for Phase 3 and to investigate safety, tolerability, and healing rates after 4 weeks treatment of X842 or Lansoprazole, and symptom pattern during subsequent 4 weeks treatment with Lansoprazole.

Detailed Description
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This is a randomized, double-blind, active comparator-controlled study with a parallel-group design including four arms with X842 and one arm with Lansoprazole. Randomization to one of the treatments with X842 twice daily (BID) 25 mg, 50 mg, 75 mg, 100 mg, or Lansoprazole 30 mg once daily (QD) will be based on a 1:1:1:1:1 scheme. The duration of each patient's participation in the study, including screening, blind treatment period, and open-label treatment period will be approximately 60 days. The patients will be randomized for 4 weeks of double-blind treatment and will be provided with investigational medicinal product for 35 days. All patients will have an endoscopic evaluation after 4 weeks of treatment. Following the endoscopic evaluation, all patients will receive subsequent 4 weeks of open-label treatment with Lansoprazole. Repeated symptom evaluation to detect symptom patterns will be assessed during this period.

Official Title
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A Randomized Double-blind, Double Dummy, Active Comparator-controlled Dose-finding Study in Patients With Erosive Esophagitis Due to Gastro-esophageal Reflux Disease (GERD) Los Angeles Grade C or D, and Patients With at Least Partial Symptom Response But Endoscopically Still Unhealed After 8 Weeks History of Standard Treatment Healing Course With Proton-pump Inhibitor (PPI), to Investigate Safety, Tolerability, and Healing Rates After 4 Weeks Treatment of X842 or Lansoprazole, and Symptom Pattern During Subsequent 4 Weeks Treatment With Lansoprazole

Conditions
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Erosive Esophagitis

Intervention / Treatment
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* Drug: X842
* Drug: X842 Dummy
* Drug: Lansoprazole
* Drug: Lansoprazole Dummy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) ≥ 18 and ≤ 40 kg/m^2 at screening. Gastro-esophageal reflux disease with endoscopically confirmed esophagitis: LA grade C or D ≤7 days before randomization (with or without historical PPI treatment) or LA grade A or B ≤7 days before randomization and history of treatment with the standard healing course of PPI for minimum of 8 weeks prior to screening and ≤7 days of non-treatment during this period and at least partial symptom response during the minimum of 8 weeks of PPI treatment. Willing and able to comply with all aspects of the protocol (including capsule swallowing, diary completion, etc.). Capable of signing informed consent form. Exclusion Criteria: History or presence of any clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disease or disorder. Patients with so-called alarm features in symptomatology, like odynophagia, severe dysphagia, bleeding, weight loss, anemia, and blood in stool pointing to a possible malignant disease of the gastrointestinal (GI) tract. Present clinically significant psychiatric diagnosis. History of malignancy of any organ system. Presence of esophageal ulcer, stricture, Barrett´s esophagus or suspected esophagitis secondary to infection, inflammatory disease, ingestion of erosive chemicals or history of any surgical or medical condition which might significantly alter the Gastro-oesophageal reflux disease (GERD) status or the absorption, distribution, metabolism or excretion of drugs. Known severe atrophic gastritis. Any planned major surgery within the duration of the study. History of a positive result for human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), antibody to Hepatitis B core antigen (anti-HBcAg), or antibody to Hepatitis C virus (anti-HCV) or presence of these findings on screening. History of long QTc syndrome (e.g. QTc ≥450 ms for males and ≥470 ms for females). Cardiac arrhythmias or any clinically significant abnormalities in the resting 12-lead ECG at the time of screening, as judged by the Investigator. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity. Current or history of alcohol, drug abuse and/or use of anabolic steroids within 2 years prior to screening. Women who are pregnant or breastfeeding. Patients who have previously participated (completed or withdrawn) in this study CX842A2201.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: X842 25 mg BID<br>Patients will receive 2 tablets (X842 25mg + X842 dummy) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 25 mg + X842 dummy) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. | Drug: X842<br>* Patients will receive X842 tablets.<br>Drug: X842 Dummy<br>* Patients will receive matching placebo tablets for X842.<br>Drug: Lansoprazole<br>* Patients will receive Lansoprazole capsule.<br>Drug: Lansoprazole Dummy<br>* Patients will receive matching placebo capsules for Lansoprazole.<br>|
| Experimental: X842 50 mg BID<br>Patients will receive 2 tablets (X842 50 mg + X842 dummy) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 50 mg + X842 dummy) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. | Drug: X842<br>* Patients will receive X842 tablets.<br>Drug: X842 Dummy<br>* Patients will receive matching placebo tablets for X842.<br>Drug: Lansoprazole<br>* Patients will receive Lansoprazole capsule.<br>Drug: Lansoprazole Dummy<br>* Patients will receive matching placebo capsules for Lansoprazole.<br>|
| Experimental: X842 75 mg BID<br>Patients will receive 2 tablets (X842 50 mg + X842 25 mg) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 50 mg + X842 25 mg) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. | Drug: X842<br>* Patients will receive X842 tablets.<br>Drug: Lansoprazole<br>* Patients will receive Lansoprazole capsule.<br>Drug: Lansoprazole Dummy<br>* Patients will receive matching placebo capsules for Lansoprazole.<br>|
| Experimental: X842 100 mg BID<br>Patients will receive 2 tablets (X842 50 mg×2) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 50 mg×2) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. | Drug: X842<br>* Patients will receive X842 tablets.<br>Drug: Lansoprazole<br>* Patients will receive Lansoprazole capsule.<br>Drug: Lansoprazole Dummy<br>* Patients will receive matching placebo capsules for Lansoprazole.<br>|
| Active Comparator: Lansoprazole<br>Patients will receive 2 tablets (X842 dummy×2) and 1 capsule (Lansoprazole 30 mg) in the morning, and 2 tablets (X842 dummy×2) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. | Drug: X842 Dummy<br>* Patients will receive matching placebo tablets for X842.<br>Drug: Lansoprazole<br>* Patients will receive Lansoprazole capsule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Esophageal Mucosa Healing | The healing of erosive esophagitis due to gastro-esophageal reflux disease (GERD) was assessed. It supported the dose selection X842,through the assessment of healing of erosive esophagitis due to GERD based on endoscopic assessment after 4 weeks of treatment. The dose that would lead to having 85% of the patients have esophageal mucosa healing after 4 weeks of treatment. Following the endoscopic evaluation, all patients received subsequent 4 weeks of open-label treatment with lansoprazole. Repeated symptom evaluation was assessed during this period to detect the symptom pattern. Endoscopy evaluation at 4 weeks was based on the level and duration of acid control achieved with X842. Symptom evaluation was assessed using the validated patient-reported outcome (PRO) QOLRAD (Heartburn version) and patient diaries (RESQ-eDiary). | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events (AEs) | The safety and tolerability of the four dose levels of X842 and Lansoprazole were evaluated, where Lansoprazole served as the active comparator. Here TEAE- Treatment-emergent adverse event, ADR- Adverse drug reaction, SAE- Serious adverse event, and AESI- Adverse events of special interest. | From Screening (Day -7 to Day 0) until Week 8 | 
| Percentage of Heartburn-Free 24-hour Days | Heartburn-free in a 24-hour day was a day where patient reported having no burning feeling or pain behind breast or in center of upper stomach for both morning and evening. Percentage of heartburn-free 24-hour days based on eDiary(Reflux Symptom Questionnaire electronic Diary: RESQ-eDiary) was evaluated. Reflux-related symptom pattern was evaluated during initial 4 weeks of treatment with four dose levels of X842 and with Lansoprazole, and symptom pattern during subsequent additional 4 weeks Lansoprazole treatment in open-label. Modified RESQ-eDiary was validated self-reported questionnaire electronic symptom diary. mRESQ-eD has 3 domains [i.e. Heartburn (min-max: 0-10), Other GERD signs/symptoms (min-max:0-15) and Regurgitations/Reflux (min-max: 0-8)]. Endoscopy followed by lansoprazole administration and symptom evaluation using PRO QOLRAD (Heartburn version) and patient diaries assessed acid control achieved with X842 at 4 weeks. | Weeks 1 and 8 | 
| Percentage at Most-mild Heartburn 24-hour Days | Heartburn with at most mild symptoms in a 24-hour day was defined as a day where the patient reported having either no symptoms, very mild symptoms, or mild burning feeling or pain behind the breast or in the center of the upper stomach (score between 0-2) for both morning and evening. Heartburn assessed the severity as per the following scores (0=Did not have, 1=Very mild, 2=Mild, 3=Moderate, 4=Moderately severe, 5=Severe). Here higher scores represent the worst outcome, whereas lower scores represent the better outcome. After endoscopic evaluation, patients received lansoprazole, and symptom evaluation was conducted to detect patterns. Endoscopy evaluation at 4 weeks was based on the level and duration of acid control achieved with X842. Symptom evaluation involved the use of validated PRO QOLRAD (Heartburn version) and patient diaries. | Weeks 1 and 8 | 
| Investigator Assessment of Symptoms by Frequency and Severity | Investigator assessed severity and frequency of patients' heartburn, regurgitation, and dysphagia in 7 days. Assessment included both severity grade (for severity, items were coded: none, mild, moderate, severe where none represented no complaints, severe represented incapacitating symptoms) and frequency (for frequency, a 7-graded Likert scale was used, ranging from none to all of time) of symptoms. Symptoms were scored as follows: none (no complaints), mild (aware of symptom, but easily tolerated), moderate (discomforting symptom, sufficient to cause interference with normal daily activities and/or sleep), severe (incapacitating symptom, with inability to perform normal daily activities and/or sleep). Following endoscopic evaluation, patients received lansoprazole and underwent symptom evaluation using validated PRO QOLRAD (Heartburn version) and patient diaries.Here, for frequency- All of the time and None of the time, and for symptoms- none and severe data has been presented. | Weeks 1 and 8 | 
| Change From Baseline in Quality of Life in Reflux and Dyspepsia (QOLRAD) Score | Reflux-related symptom pattern was evaluated during initial 4 weeks of treatment with 4 dose levels of X842 and with Lansoprazole, and symptom pattern during subsequent additional 4 weeks of open-label treatment with Lansoprazole. Heartburn version of QOLRAD is a disease-specific instrument containing 25 questions addressing concerns associated with gastrointestinal symptoms. Questions were rated on a seven-grade (1-7) Likert scale, where a score of 1 represented low quality of life, and as score increased, the patient's condition was considered better. Questions were categorized into 5 domains: emotional distress, sleep disturbance, vitality, food/drink problems, and physical/social functioning. The score in each domain was calculated as the mean of all items in that domain. The score ranges from 1 to 175, higher scores mean a better outcome. After endoscopic evaluation, patients received lansoprazole and underwent symptom evaluation using validated PRO QOLRAD and patient diaries. | Baseline, Weeks 1, and 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lansoprazole, Los Angeles Grade, Double-blind, Active comparator-controlled, Proton-pump inhibitor, Dose selection