Eosinophilic Esophagitis, Milk Allergy
Conditions
Keywords
Milk Allergy, Viaskin Milk, Epicutaneous ImmunoTherapy (EPIT), Eosinophilic Esophagitis, Milk-Induced Eosinophilic Esophagitis
Brief summary
This is a single-site, double-blind, placebo-controlled, randomized trial to study efficacy and safety of the Viaskin® Milk Patch for children with milk induced Eosinophilic Esophagitis (EoE). 20 subjects will be randomized 3:1 to Viaskin® Milk or placebo patch.
Detailed description
This is a double-blind, placebo-controlled, randomized trial to study the efficacy and safety of Viaskin® Milk, an allergen extract of milk administered epicutaneously using the Viaskin® epicutaneous delivery system (EPIT) in subjects from 4 to 17 years old with a milk induced Eosinophilic Esophagitis. Subjects will be randomized in a 3:1 ratio into two different treatment groups, to receive EPIT with Viaskin® Milk (500 µg of milk proteins) or placebo. Subjects who complete the double-blind treatment period (approximately 11 months), will automatically rollover into an open label treatment period (additional 11 months). All subjects will receive the 500 µg (micrograms) Viaskin Milk patch.
Interventions
Biological: Viaskin Milk 500 mcg Subjects epicutaneously administered daily (up to 24 hours application per day) with a patch containing 500 mcg cow's milk proteins.
DRUGViaskin Placebo
Biological: Viaskin Placebo Subjects epicutaneously administered daily (up to 24 hours application per day) with a patch containing a matching placebo formulation.
Sponsors
DBV Technologies
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Well-documented medical history of Eosinophilic Esophagitis after ingestion of milk and currently following a strict milk-free diet. * Upper endoscopy and biopsy at initial clinical evaluation during Visit 2 showing greater than 15 eosinophils/high power field (HPF) isolated to the esophagus meeting the consensus diagnosis of Eosinophilic Esophagitis, after milk was re-introduced into the subject's diet (30 ml/day for 1 week to 2 months), while the subject was on proton pump inhibitor. * Upper endoscopy and biopsy at second clinical evaluation during Visit 3 showing less than 5 eosinophils per HPF isolated to the esophagus after a minimum of 6 weeks under milk-free diet, and while the subject is on proton pump inhibitor. * Negative pregnancy test for female subjects of childbearing potential. Females of childbearing potential must use effective method of contraception to prevent pregnancy and agree to continue to practice an acceptable method of contraception for the duration of participation in the study. Sexual abstinence will be accepted as an effective method of contraception for girls below 18 years of age. * Subjects and/or parents/guardians willing to comply with all study requirements during their participation in the study. * Signed informed consent from parent(s)/guardian(s) of children \< 18 years + children's assent. * Subjects agree to maintain a constant diet during the trial, with the exception of milk. * Subjects will maintain constant medications for asthma and allergic rhinitis during the trial.
Exclusion criteria
* Subjects with a history of severe anaphylaxis to milk with the following symptoms: hypotension, hypoxia, neurological compromise (collapse, loss of consciousness or incontinence), Quincke Edema or requiring intubation. * Active IgE- mediated milk allergy. * Pregnancy or lactation. * Subjects with other eosinophilic gastrointestinal disorders. * Subjects on swallowed corticosteroids or anti-leukotrienes for Eosinophilic Esophagitis. * Subjects with symptomatic allergy to pollens whose symptoms during the corresponding pollen season might interfere with the recording of symptoms during the upper endoscopy/biopsy, if the upper endoscopy/biopsy is conducted during the pollen season. The Investigator will have to ensure that the period for conducting the upper endoscopy for such a subject will be outside of the pollen season. * Subjects treated with systemic long-acting corticosteroids (depot corticosteroids) within 12 weeks prior to Visit 1 and/or systemic short-acting corticosteroid within 4 weeks prior to Visit 1 or any systemic corticosteroid at screening. * Subjects with asthma conditions defined as follows: 1. Uncontrolled persistent asthma by National Asthma Education and Prevention Program Asthma guidelines (2007). 2. at least two systemic corticosteroid courses for asthma in the past year or one oral corticosteroid course for asthma in the past three months; 3. prior intubation for asthma in the past two years. * Subjects on β-blocking agents, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers or tricyclic antidepressant therapy. * Subjects undergoing any type of immunotherapy to any food within one year prior to Visit 1. * Subjects presently on aeroallergen immunotherapy and unwilling or unable to discontinue. * Subjects currently treated with anti-tumor necrosis factor drugs or anti-Immunoglobulin E (IgE) drugs or any biologic immunomodulatory therapy within one year prior to Visit 1. * Allergy or known hypersensitivity to placebo excipients either of the Viaskin® or Tegaderm®. * Subjects suffering from generalized dermatologic diseases with no intact skin zones to apply the Viaskin®, or urticarial and mast cell disorders such as chronic idiopathic urticaria. * Subjects (or parents of subjects) with obvious excessive anxiety and unlikely to cope with the conditions of an upper endoscopy and biopsy. * Past or current disease(s), which in the opinion the sponsor-investigator, may affect the subject's participation in this study including but not limited to active autoimmune disorders, immunodeficiency, malignancy, uncontrolled diseases (hypertension, psychiatric (especially anxiety), cardiac), or other disorders (e.g., liver, gastrointestinal, kidney, cardiovascular, pulmonary disease, or blood disorders). * Any history of drug or alcohol abuse in the past five years. * Subjects unable to follow the protocol and the protocol requirements. * Participation in another clinical intervention study in the three months prior to Study Visit 1. * Subjects on any experimental drugs or treatments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Maximum Esophageal Eosinophil Count From Baseline to End of Double-blind Treatment. (Intent to Treat Population) | From baseline to month 11 (end of double blind phase) | Esophageal biopsy samples will be obtained prior to randomization and after completion of treatment. Intraepithelial eosinophils will be counted in all high powered fields (HPFs) using light microscopy. A HPF will be counted only if at least half of the field is occupied by tissue. The maximum eosinophil count per HPF will be reported for each esophageal biopsy site (at each of 2 levels). The maximum eosinophil count for each patient will be calculated from either level. For the final outcome, mean from each individual patients maximum eosinophil count/hpf along with standard deviation will be calculated. |
| Change in Eosinophils/High Power Field at End of Double-blind (DB) (Per Protocol Patients) | Month 11(end of double blind phase) | Esophageal biopsy samples will be obtained prior to randomization and after completion of treatment. Intraepithelial eosinophils will be counted in all high powered fields (HPFs) using light microscopy. A HPF will be counted only if at least half of the field is occupied by tissue. The maximum eosinophil count per HPF will be reported for each esophageal biopsy site (at each of 2 levels). The maximum eosinophil count for each patient will be calculated from either level. For the final outcome, mean from each individual patients maximum eosinophil count/hpf along with standard deviation will be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Eosinophils Per HPF at End of Double Bind Protocol (Per Protocol) Patients | End of DB Phase, at 11 months | Maximum Eosinophils/HPF after milk reintroduction at the end of double bind phase |
| Pediatric Eosinophilic Esophagitis Symptom Score (ITT) | Month 11, end of Double Blind Phase | Measure of Pediatric Eosinophilic Esophagitis symptom Score (PEESS) at the end of DB phase for the Intent to Treat Population The PEESS® is a 20 question survey asking patient symptom intensity and frequency on a 5 point scale (0 to 4) for each question for the preceding month. Therefore, the total score can range from 0 to 80. The total score is reported and lower score is better |
| Eosinophilic Esophagitis Symptom Score (Intent to Treat Population) | Total Symptom Score at End of DB Phase, Month 11 | Symptoms of Eosinophilic Esophagitis range from abdominal pain, gastroesophageal reflux, vomiting, and difficult swallowing. Investigator assessment of the subject's symptoms was completed on a 4-point Likert scale for 3 separate symptoms (vomiting, abdominal pain and dysphagia). Investigator assessment of the subject's symptoms was completed on a 4-point Likert scale for 3 separate symptoms (vomiting, abdominal pain and dysphagia). (0-none, 1-mild, 2-moderate, 3-severe, ). Total score is reported with a range of 0 to 9. A lower score is better. |
| Pediatric Eosinophil Esophagitis Symptom Score (PP Population) | Month 11, End of Double Blind Placebo Control | Pediatric Eosinophilic Esophagitis Symptom Score at end of DB phase using the validated Pediatric Eosinophilic Esophagitis Symptom Score (PEESS).The PEESS® is a 20 question survey asking patient symptom intensity and frequency on a 5 point scale (0 to 4) for each question for the preceding month. Therefore, the total score can range from 0 to 80. The total score is reported and lower score is better. |
| Endoscopy Score (Per Protocol Patients) | Month 11 (end of double blind phase) | Upper endoscopies with biopsies (2 each of proximal and distal, plus any inflamed areas) will be completed before and after each treatment period. Each endoscopy will be scored using a validated standardized measure which examines 4 major esophageal features (rings, furrows, exudates and edema) and the presence of minor features of narrow caliber esophagus, feline esophagus, stricture and crepe paper esophagus. Each feature is graded: 0-none, 1 mild, 2-moderate, 3-severe. The scores including both major and minor criteria are summed. Total score is presented and lower score is better. The range is from 0-12 |
| Esophageal Endoscopy Score (ITT) | At end of DB phase, at 11 months | Upper endoscopies with biopsies (2 each of proximal and distal, plus any inflamed areas) will be completed before and after each treatment period. Each endoscopy will be scored using a validated standardized measure which examines 4 major esophageal features (rings, furrows, exudates and edema) and the presence of minor features of narrow caliber esophagus, feline esophagus, stricture and crepe paper esophagus. Each feature is graded: 0-none, 1 mild, 2-moderate, 3-severe. The scores are summed including both minor and major criteria. Total score is presented and lower score is better. The range is from 0-12 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Viaskin Milk 500 mcg Viaskin patch containing milk protein. The patch is applied to the skin
Viaskin Milk 500 mcg: Biological: Viaskin Milk 500 mcg Subjects epicutaneously administered daily (up to 24 hours application per day) with a patch containing 500 mcg cow's milk proteins. | 15 |
| Viaskin Placebo Viaksin patch without any milk protein.
Viaskin Placebo: Biological: Viaskin Placebo Subjects epicutaneously administered daily (up to 24 hours application per day) with a patch containing a matching placebo formulation. | 5 |
| Total | 20 |
Baseline characteristics
| Characteristic | Viaskin Milk 500 mcg | Viaskin Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 5 Participants | 20 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 10.46 years STANDARD_DEVIATION 2.99 | 12.71 years STANDARD_DEVIATION 2.03 | 10.69 years STANDARD_DEVIATION 3.64 |
| Eosinophils (Eos) per high power field (HPF) on Milk | 72.4 Eos/hpf STANDARD_DEVIATION 29.52 | 60.93 Eos/hpf STANDARD_DEVIATION 49.39 | 64 Eos/hpf STANDARD_DEVIATION 44.5 |
| 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 15 Participants | 5 Participants | 20 Participants |
| Region of Enrollment United States | 15 participants | 5 participants | 20 participants |
| Sex: Female, Male Female | 5 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 5 |
| other Total, other adverse events | 15 / 15 | 5 / 5 |
| serious Total, serious adverse events | 0 / 15 | 1 / 5 |
Outcome results
Primary
Change in Eosinophils/High Power Field at End of Double-blind (DB) (Per Protocol Patients)
Esophageal biopsy samples will be obtained prior to randomization and after completion of treatment. Intraepithelial eosinophils will be counted in all high powered fields (HPFs) using light microscopy. A HPF will be counted only if at least half of the field is occupied by tissue. The maximum eosinophil count per HPF will be reported for each esophageal biopsy site (at each of 2 levels). The maximum eosinophil count for each patient will be calculated from either level. For the final outcome, mean from each individual patients maximum eosinophil count/hpf along with standard deviation will be calculated.
Time frame: Month 11(end of double blind phase)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Change in Eosinophils/High Power Field at End of Double-blind (DB) (Per Protocol Patients) | -26.86 Eosinophils (Eos)/high power field | Standard Deviation 22.53 |
| Viaskin Placebo | Change in Eosinophils/High Power Field at End of Double-blind (DB) (Per Protocol Patients) | 42.5 Eosinophils (Eos)/high power field | Standard Deviation 31.82 |
Primary
Change in Maximum Esophageal Eosinophil Count From Baseline to End of Double-blind Treatment. (Intent to Treat Population)
Esophageal biopsy samples will be obtained prior to randomization and after completion of treatment. Intraepithelial eosinophils will be counted in all high powered fields (HPFs) using light microscopy. A HPF will be counted only if at least half of the field is occupied by tissue. The maximum eosinophil count per HPF will be reported for each esophageal biopsy site (at each of 2 levels). The maximum eosinophil count for each patient will be calculated from either level. For the final outcome, mean from each individual patients maximum eosinophil count/hpf along with standard deviation will be calculated.
Time frame: From baseline to month 11 (end of double blind phase)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Change in Maximum Esophageal Eosinophil Count From Baseline to End of Double-blind Treatment. (Intent to Treat Population) | -10.8 Eosinophils (Eos)/high power field (HPF) | Standard Deviation 37.73 |
| Viaskin Placebo | Change in Maximum Esophageal Eosinophil Count From Baseline to End of Double-blind Treatment. (Intent to Treat Population) | -24.2 Eosinophils (Eos)/high power field (HPF) | Standard Deviation 63 |
Secondary
Endoscopy Score (Per Protocol Patients)
Upper endoscopies with biopsies (2 each of proximal and distal, plus any inflamed areas) will be completed before and after each treatment period. Each endoscopy will be scored using a validated standardized measure which examines 4 major esophageal features (rings, furrows, exudates and edema) and the presence of minor features of narrow caliber esophagus, feline esophagus, stricture and crepe paper esophagus. Each feature is graded: 0-none, 1 mild, 2-moderate, 3-severe. The scores including both major and minor criteria are summed. Total score is presented and lower score is better. The range is from 0-12
Time frame: Month 11 (end of double blind phase)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Endoscopy Score (Per Protocol Patients) | 1.43 score on a scale | Standard Deviation 1.51 |
| Viaskin Placebo | Endoscopy Score (Per Protocol Patients) | 3 score on a scale | Standard Deviation 1.41 |
Secondary
Eosinophilic Esophagitis Symptom Score (Intent to Treat Population)
Symptoms of Eosinophilic Esophagitis range from abdominal pain, gastroesophageal reflux, vomiting, and difficult swallowing. Investigator assessment of the subject's symptoms was completed on a 4-point Likert scale for 3 separate symptoms (vomiting, abdominal pain and dysphagia). Investigator assessment of the subject's symptoms was completed on a 4-point Likert scale for 3 separate symptoms (vomiting, abdominal pain and dysphagia). (0-none, 1-mild, 2-moderate, 3-severe, ). Total score is reported with a range of 0 to 9. A lower score is better.
Time frame: Total Symptom Score at End of DB Phase, Month 11
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Eosinophilic Esophagitis Symptom Score (Intent to Treat Population) | 1.07 units on a scale | Standard Deviation 1.49 |
| Viaskin Placebo | Eosinophilic Esophagitis Symptom Score (Intent to Treat Population) | 1.40 units on a scale | Standard Deviation 1.14 |
Secondary
Eosinophils Per HPF at End of Double Bind Protocol (Per Protocol) Patients
Maximum Eosinophils/HPF after milk reintroduction at the end of double bind phase
Time frame: End of DB Phase, at 11 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Eosinophils Per HPF at End of Double Bind Protocol (Per Protocol) Patients | 25.57 Eos/hpf | Standard Deviation 31.19 |
| Viaskin Placebo | Eosinophils Per HPF at End of Double Bind Protocol (Per Protocol) Patients | 95 Eos/hpf | Standard Deviation 63.64 |
Secondary
Esophageal Endoscopy Score (ITT)
Upper endoscopies with biopsies (2 each of proximal and distal, plus any inflamed areas) will be completed before and after each treatment period. Each endoscopy will be scored using a validated standardized measure which examines 4 major esophageal features (rings, furrows, exudates and edema) and the presence of minor features of narrow caliber esophagus, feline esophagus, stricture and crepe paper esophagus. Each feature is graded: 0-none, 1 mild, 2-moderate, 3-severe. The scores are summed including both minor and major criteria. Total score is presented and lower score is better. The range is from 0-12
Time frame: At end of DB phase, at 11 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Esophageal Endoscopy Score (ITT) | 1.93 score on a scale | Standard Deviation 1.58 |
| Viaskin Placebo | Esophageal Endoscopy Score (ITT) | 1.60 score on a scale | Standard Deviation 1.67 |
Secondary
Pediatric Eosinophil Esophagitis Symptom Score (PP Population)
Pediatric Eosinophilic Esophagitis Symptom Score at end of DB phase using the validated Pediatric Eosinophilic Esophagitis Symptom Score (PEESS).The PEESS® is a 20 question survey asking patient symptom intensity and frequency on a 5 point scale (0 to 4) for each question for the preceding month. Therefore, the total score can range from 0 to 80. The total score is reported and lower score is better.
Time frame: Month 11, End of Double Blind Placebo Control
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Pediatric Eosinophil Esophagitis Symptom Score (PP Population) | 12.2 score on a scale | Standard Deviation 8.57 |
| Viaskin Placebo | Pediatric Eosinophil Esophagitis Symptom Score (PP Population) | 17 score on a scale | Standard Deviation 1.41 |
Secondary
Pediatric Eosinophilic Esophagitis Symptom Score (ITT)
Measure of Pediatric Eosinophilic Esophagitis symptom Score (PEESS) at the end of DB phase for the Intent to Treat Population The PEESS® is a 20 question survey asking patient symptom intensity and frequency on a 5 point scale (0 to 4) for each question for the preceding month. Therefore, the total score can range from 0 to 80. The total score is reported and lower score is better
Time frame: Month 11, end of Double Blind Phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Viaskin Milk 500 mcg | Pediatric Eosinophilic Esophagitis Symptom Score (ITT) | 11.15 units on a scale | Standard Deviation 11.07 |
| Viaskin Placebo | Pediatric Eosinophilic Esophagitis Symptom Score (ITT) | 13.2 units on a scale | Standard Deviation 7.33 |