Eosinophilic Esophagitis
Conditions
Brief summary
The purpose of this study is to test the safety and effectiveness of Losartan potassium in subjects with eosinophilic esophagitis (EoE) including those with a connective tissue disorder (CTD) and those without a CTD.
Detailed description
The purpose of this research study is to test the safety and effects (good and bad) of Losartan potassium on participants with eosinophilic esophagitis (EoE). If a participant has a connective tissue disorder (CTD) the researchers want to see what effects (good or bad) Losartan has on EoE. EoE is an inflammatory disease of the esophagus that is typically triggered by exposure to food. Connective tissue disorders (CTDs) are disorders that affect the connective tissues in the body such as tendons and ligaments. A protein called transforming growth factor (TGF)-beta is associated with both EoE and CTD. Losartan may decrease the amount of TGF-beta and therefore help EoE and CTD. Losartan is a drug that is approved by the United States Food and Drug Administration (FDA) for use in adults and children over 6 years of age who have high blood pressure. This medication has not been studied in people with EoE.
Interventions
DRUGLosartan Potassium
Losartan potassium
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Allergy and Infectious Diseases (NIAID)
Office of Rare Diseases (ORD)
National Center for Advancing Translational Sciences (NCATS)
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study is an open-label study which means that all participants receive the study medicine.
Eligibility
Sex/Gender
ALL
Age
5 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent/assent * Confirmed, active EoE (at Screening or within 12 weeks prior to enrollment) * Does or does not have diagnosis of a connective tissue disorder (CTD) * Has been on a high dose of proton pump inhibitor (PPI) for at least 8 weeks prior to a diagnostic endoscopy of EoE without histologic resolution (i.e., ≥ 15 eosinophils/HPF). * Maintain the same diet, swallowed steroid and PPI therapies throughout the duration of the study * Female participants must be either: 1. Of non-childbearing potential (pre-menarchal or surgically sterile with documentation). OR 2. Have a negative urine pregnancy test at screening and at each monthly study visit.
Exclusion criteria
* Any past or planned cardiac surgery. * An aortic root Z-score ≥ 3.0 on a previous echocardiogram. * Intolerance to Losartan * A mean blood pressure measurement (both systolic and diastolic) at screening that is below the 2nd percentile for his/her age * Renal dysfunction * Another disorder that causes esophageal eosinophilia (e.g., hypereosinophilic syndrome, Churg Strauss vasculitis, eosinophilic granuloma, or a parasitic infection). * A diagnosis of hepatic insufficiency (e.g., liver failure, history of liver transplantation or persistent liver transaminase elevation). * A history of abnormal gastric or duodenal biopsy or documented gastrointestinal disorders (e.g., Celiac Disease, Crohn's disease or Helicobacter pylori infection), not including chronic gastritis, chronic duodenitis, mucosal eosinophilia or other eosinophilic gastrointestinal disorders (EGIDs). * Use of anti-immunoglobulin (Ig)E monoclonal antibody (mAb), anti-tumor necrosis factor (TNF) mAb, anti-IL-5 agents, or anti-IL-13 within 6 months prior to study entry * Use of methotrexate, cyclosporine, interferon α, or other systemic immunosuppressive or immunomodulating agents within 3 months prior to the screening visit. * A stricture during endoscopy procedure that prevents passage of the endoscope * Taking or is planning to take an angiotensin receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), beta blocker (BB), or calcium-channel blocker therapy at the screening visit or at any time during the study or has been taking any of these medications for 3 months prior to the screening visit. * Taking or planning to take hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, rifampin, or fluconazole. * Taking or planning to take potassium supplements or salt substitutes containing potassium. * A female participant who is pregnant or nursing or, if of childbearing potential, is not using a medically accepted, effective method of birth control (e.g., condom, oral/injectable/subcutaneous contraceptive, intrauterine device, or sexual abstinence). * Participated/participating in any investigative drug or device study within 30 days prior to study entry. * Participated/participating in any investigative biologics study within 3 months prior to study entry. * Unable to be confirmed, active EoE (at Screening or within 12 weeks prior to enrollment)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Eosinophil Count | Baseline, 16 weeks | Peak esophageal eosinophil counts were obtained at baseline and 16 weeks. Change in peak eosinophil count is defined as peak count at 16 weeks minus peak count at baseline. A reduction (negative change) in peak count indicates improvement. Peak count is defined as the highest count between the distal and proximal esophageal eosinophil counts. |
| Number of Serious and Grade 3 or Higher Adverse Events | 20 weeks after the start of treatment (16 weeks treatment and 4 weeks follow-up) | The occurrence of serious adverse events and Grade 3 and higher adverse events from Week 0 to Week 20 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Endoscopic Reference Score | Baseline, 16 weeks | The endoscopic reference score (EREFS) utilizes standardized criteria for the presence and degree of 5 major endoscopic features (edema, fixed rings, exudates, furrows, strictures). Total score is the sum of the five feature scores from the distal and proximal esophagus. Total scores range from 0 - 18 with higher scores indicating worse features. Endoscopic features were assessed at baseline and 16 weeks. Change in total endoscopic reference score is defined as total score at 16 weeks minus total score at baseline. A reduction (negative change) in score indicates improvement. |
| Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks | 16 weeks | Percent of participants in complete and partial histologic remission. Complete remission is defined as esophageal peak eosinophil count ≤ 1 eosinophils per high powered field (eos/hpf). Partial remission is defined as esophageal peak eosinophil count of 2 - 14 eos/hpf. |
| Change From Baseline in PedsQL EoE | Baseline, 16 weeks | The Pediatric Eosinophilic Esophagitis Quality of Life Inventory (PedsQL EoE) measures symptoms and problems related to treatment, worry, communication, food/eating, and feelings. The range for PedsQL 3.0 EoE scores is 0 to 100, with a higher score indicating better quality of life. Scores were obtained at baseline and 16 weeks. Change in score is defined as the PedsQL EoE total score at 16 weeks minus total score at baseline as reported by parent proxy. |
| Change From Baseline in PEESS V2.0 | Baseline,16 weeks | The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) V2.0 questionnaire captures EoE-specific symptoms (dysphagia, gastroesophageal reflux, nausea/vomiting, and pain) as reported by their parents (for children 2-18 years of age). The range for PEESS v2.0 scores is 0 to 100, with a higher score being indicative of more frequent and/or severe symptoms. Scores were obtained at baseline and 16 weeks. Change in score is defined as total score at 16 weeks minus total score at baseline as completed by parent proxy. |
| Change From Baseline in Total Histology Scoring System | Baseline, 16 weeks | The histology scoring system (HSS) measures the severity (grade) and extent (stage) of eight histologic abnormalities in the esophagus including eosinophilic inflammation, eosinophilic abscess, eosinophilic surface layering, surface epithelial alteration, dilated intercellular spaces, basal zone hyperplasia, dyskeratotic epithelial cells, and lamina propria fibrosis. Total score is the sum of grade and stage scores from the esophageal biopsy (distal, mid, or proximal) with the highest score (worst abnormalities) divided by the maximum possible score for the biopsy. Total scores range from 0 - 2 with higher scores indicating worse abnormalities. Histology scores were obtained at baseline and 16 weeks. Change in total histology scoring system (HSS) is defined as total HSS score at 16 weeks minus total HSS score at baseline. A reduction (negative change) in score indicates improvement. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from eosinophilic esophagitis specialty clinics (3 sites) in the USA between May 2017 and April 2019.
Pre-assignment details
17 participants screened, 2 excluded (2 met exclusion criteria), and 15 initiated the intervention
Participants by arm
| Arm | Count |
|---|---|
| EoE + CTD Participants with eosinophilic esophagitis (EoE) with connective tissue disorder (CTD) receive Losartan | 8 |
| EoE - CTD Participants with eosinophilic esophagitis (EoE) without connective tissue disorder (CTD) receive Losartan | 7 |
| Total | 15 |
Baseline characteristics
| Characteristic | EoE + CTD | Total | EoE - CTD |
|---|---|---|---|
| Age, Continuous | 10.4 years STANDARD_DEVIATION 3.7 | 12.0 years STANDARD_DEVIATION 4.5 | 13.8 years STANDARD_DEVIATION 5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 15 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 13 Participants | 6 Participants |
| Region of Enrollment United States | 8 participants | 15 participants | 7 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 10 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 8 | 0 / 7 |
| other Total, other adverse events | 12 / 15 | 7 / 8 | 5 / 7 |
| serious Total, serious adverse events | 0 / 15 | 0 / 8 | 0 / 7 |
Outcome results
Primary
Change From Baseline in Peak Eosinophil Count
Peak esophageal eosinophil counts were obtained at baseline and 16 weeks. Change in peak eosinophil count is defined as peak count at 16 weeks minus peak count at baseline. A reduction (negative change) in peak count indicates improvement. Peak count is defined as the highest count between the distal and proximal esophageal eosinophil counts.
Time frame: Baseline, 16 weeks
Population: Per protocol population (protocol violation excluded from data analysis)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| EoE +/- CTD | Change From Baseline in Peak Eosinophil Count | Baseline | 63.3 eosinophils per high power field |
| EoE +/- CTD | Change From Baseline in Peak Eosinophil Count | Change | -11.2 eosinophils per high power field |
| EoE + CTD | Change From Baseline in Peak Eosinophil Count | Baseline | 67.7 eosinophils per high power field |
| EoE + CTD | Change From Baseline in Peak Eosinophil Count | Change | -1.9 eosinophils per high power field |
| EoE - CTD | Change From Baseline in Peak Eosinophil Count | Baseline | 58.9 eosinophils per high power field |
| EoE - CTD | Change From Baseline in Peak Eosinophil Count | Change | -20.6 eosinophils per high power field |
Primary
Number of Serious and Grade 3 or Higher Adverse Events
The occurrence of serious adverse events and Grade 3 and higher adverse events from Week 0 to Week 20
Time frame: 20 weeks after the start of treatment (16 weeks treatment and 4 weeks follow-up)
Population: Intent to treat analysis including participants enrolled in the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EoE +/- CTD | Number of Serious and Grade 3 or Higher Adverse Events | Serious Adverse Events | 0 events |
| EoE +/- CTD | Number of Serious and Grade 3 or Higher Adverse Events | Grade 3 or higher adverse events | 1 events |
| EoE + CTD | Number of Serious and Grade 3 or Higher Adverse Events | Grade 3 or higher adverse events | 0 events |
| EoE + CTD | Number of Serious and Grade 3 or Higher Adverse Events | Serious Adverse Events | 0 events |
| EoE - CTD | Number of Serious and Grade 3 or Higher Adverse Events | Serious Adverse Events | 0 events |
| EoE - CTD | Number of Serious and Grade 3 or Higher Adverse Events | Grade 3 or higher adverse events | 1 events |
Secondary
Change From Baseline in PedsQL EoE
The Pediatric Eosinophilic Esophagitis Quality of Life Inventory (PedsQL EoE) measures symptoms and problems related to treatment, worry, communication, food/eating, and feelings. The range for PedsQL 3.0 EoE scores is 0 to 100, with a higher score indicating better quality of life. Scores were obtained at baseline and 16 weeks. Change in score is defined as the PedsQL EoE total score at 16 weeks minus total score at baseline as reported by parent proxy.
Time frame: Baseline, 16 weeks
Population: Per protocol population (protocol violation excluded from data analysis)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| EoE +/- CTD | Change From Baseline in PedsQL EoE | Baseline - PedsQL Total Score | 74.4 score on a scale |
| EoE +/- CTD | Change From Baseline in PedsQL EoE | Change - PedsQL Total Score | 6.7 score on a scale |
| EoE + CTD | Change From Baseline in PedsQL EoE | Baseline - PedsQL Total Score | 73.3 score on a scale |
| EoE + CTD | Change From Baseline in PedsQL EoE | Change - PedsQL Total Score | 4.8 score on a scale |
| EoE - CTD | Change From Baseline in PedsQL EoE | Baseline - PedsQL Total Score | 75.6 score on a scale |
| EoE - CTD | Change From Baseline in PedsQL EoE | Change - PedsQL Total Score | 9.0 score on a scale |
Secondary
Change From Baseline in PEESS V2.0
The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) V2.0 questionnaire captures EoE-specific symptoms (dysphagia, gastroesophageal reflux, nausea/vomiting, and pain) as reported by their parents (for children 2-18 years of age). The range for PEESS v2.0 scores is 0 to 100, with a higher score being indicative of more frequent and/or severe symptoms. Scores were obtained at baseline and 16 weeks. Change in score is defined as total score at 16 weeks minus total score at baseline as completed by parent proxy.
Time frame: Baseline,16 weeks
Population: Per protocol population (protocol violation excluded from data analysis)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| EoE +/- CTD | Change From Baseline in PEESS V2.0 | Baseline - PEESS Total Score | 29.9 score on a scale |
| EoE +/- CTD | Change From Baseline in PEESS V2.0 | Change - PEESS Total Score | -9.7 score on a scale |
| EoE + CTD | Change From Baseline in PEESS V2.0 | Baseline - PEESS Total Score | 32.7 score on a scale |
| EoE + CTD | Change From Baseline in PEESS V2.0 | Change - PEESS Total Score | -12.5 score on a scale |
| EoE - CTD | Change From Baseline in PEESS V2.0 | Baseline - PEESS Total Score | 26.7 score on a scale |
| EoE - CTD | Change From Baseline in PEESS V2.0 | Change - PEESS Total Score | -6.89 score on a scale |
Secondary
Change From Baseline in Total Endoscopic Reference Score
The endoscopic reference score (EREFS) utilizes standardized criteria for the presence and degree of 5 major endoscopic features (edema, fixed rings, exudates, furrows, strictures). Total score is the sum of the five feature scores from the distal and proximal esophagus. Total scores range from 0 - 18 with higher scores indicating worse features. Endoscopic features were assessed at baseline and 16 weeks. Change in total endoscopic reference score is defined as total score at 16 weeks minus total score at baseline. A reduction (negative change) in score indicates improvement.
Time frame: Baseline, 16 weeks
Population: Per protocol population (protocol violation excluded from data analysis).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| EoE +/- CTD | Change From Baseline in Total Endoscopic Reference Score | Baseline - EREFS Total Score | 5.1 score on a scale |
| EoE +/- CTD | Change From Baseline in Total Endoscopic Reference Score | Change - EREFS Total Score | -1.3 score on a scale |
| EoE + CTD | Change From Baseline in Total Endoscopic Reference Score | Baseline - EREFS Total Score | 5.4 score on a scale |
| EoE + CTD | Change From Baseline in Total Endoscopic Reference Score | Change - EREFS Total Score | -1.7 score on a scale |
| EoE - CTD | Change From Baseline in Total Endoscopic Reference Score | Baseline - EREFS Total Score | 4.9 score on a scale |
| EoE - CTD | Change From Baseline in Total Endoscopic Reference Score | Change - EREFS Total Score | -0.9 score on a scale |
Secondary
Change From Baseline in Total Histology Scoring System
The histology scoring system (HSS) measures the severity (grade) and extent (stage) of eight histologic abnormalities in the esophagus including eosinophilic inflammation, eosinophilic abscess, eosinophilic surface layering, surface epithelial alteration, dilated intercellular spaces, basal zone hyperplasia, dyskeratotic epithelial cells, and lamina propria fibrosis. Total score is the sum of grade and stage scores from the esophageal biopsy (distal, mid, or proximal) with the highest score (worst abnormalities) divided by the maximum possible score for the biopsy. Total scores range from 0 - 2 with higher scores indicating worse abnormalities. Histology scores were obtained at baseline and 16 weeks. Change in total histology scoring system (HSS) is defined as total HSS score at 16 weeks minus total HSS score at baseline. A reduction (negative change) in score indicates improvement.
Time frame: Baseline, 16 weeks
Population: Per protocol population (protocol violation excluded from data analysis).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| EoE +/- CTD | Change From Baseline in Total Histology Scoring System | Baseline - Total HSS | 0.79 score on a scale |
| EoE +/- CTD | Change From Baseline in Total Histology Scoring System | Change - Total HSS | -0.09 score on a scale |
| EoE + CTD | Change From Baseline in Total Histology Scoring System | Baseline - Total HSS | 0.89 score on a scale |
| EoE + CTD | Change From Baseline in Total Histology Scoring System | Change - Total HSS | -0.15 score on a scale |
| EoE - CTD | Change From Baseline in Total Histology Scoring System | Baseline - Total HSS | 0.70 score on a scale |
| EoE - CTD | Change From Baseline in Total Histology Scoring System | Change - Total HSS | -0.03 score on a scale |
Secondary
Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks
Percent of participants in complete and partial histologic remission. Complete remission is defined as esophageal peak eosinophil count ≤ 1 eosinophils per high powered field (eos/hpf). Partial remission is defined as esophageal peak eosinophil count of 2 - 14 eos/hpf.
Time frame: 16 weeks
Population: Per protocol population (protocol violation excluded from data analysis)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EoE +/- CTD | Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks | Complete remission (≤ 1 eos/hpf) | 7 percentage of subjects |
| EoE +/- CTD | Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks | Partial remission (2 - 14 eos/hpf) | 21 percentage of subjects |
| EoE + CTD | Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks | Complete remission (≤ 1 eos/hpf) | 14 percentage of subjects |
| EoE + CTD | Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks | Partial remission (2 - 14 eos/hpf) | 14 percentage of subjects |
| EoE - CTD | Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks | Complete remission (≤ 1 eos/hpf) | 0 percentage of subjects |
| EoE - CTD | Percent of Participants in Complete and Partial Histologic Remission at 16 Weeks | Partial remission (2 - 14 eos/hpf) | 29 percentage of subjects |