Peanut Allergy
Conditions
Brief summary
The PEPITES study evaluates the efficacy and safety of Viaskin Peanut 250 µg peanut protein to induce desensitization to peanut in peanut-allergic children 4 through 11 years of age after a 12-month treatment by epicutaneous immunotherapy (EPIT).
Detailed description
This is a 12-month, Phase III, double-blind, placebo-controlled, randomized study to assess the efficacy and safety of Viaskin Peanut, dosed at 250µg peanut protein (per patch) in peanut-allergic children from 4 through 11 years of age. The overall maximum study duration for each subject is approximately 61 weeks (6-week screening period, 12-month treatment period and 2-week follow-up period). During the screening period, subjects will undergo a first screening visit and an entry double-blind, placebo-controlled food challenge (DBPCFC) to peanut to confirm their allergy and their entry peanut eliciting dose (ED). The starting dose of the challenge will be 1 mg peanut protein and will escalate up to a highest dose of 300mg peanut protein. Subjects who react at or below the dose of 300mg peanut protein are considered eligible. Randomization of eligible subjects will occur in a 2:1 ratio to Viaskin Peanut dosed at 250µg peanut protein (active treatment) or placebo. Subjects will be stratified at randomization by their entry/screening DBPCFC ED in 1 of the following 2 strata and by study center: * Stratum 1: children with a screening ED of 1mg, 3mg or 10mg; * Stratum 2: children with a screening ED of 30mg, 100mg or 300mg. Subjects will apply a Viaskin patch containing either peanut protein or placebo daily for a period of 12 months. At Month 12, a post-treatment DBPCFC to peanut will be performed, with a starting dose of 1 mg peanut protein with escalation up to a highest dose of 2,000 mg peanut protein. This evaluation will help determine the primary efficacy endpoint of this pivotal study.
Interventions
BIOLOGICALViaskin Peanut 250mcg
Peanut extract cutaneous patch
BIOLOGICALPlacebo
Cutaneous patch containing an inactive deposit manufactured to mimic peanut extract
Sponsors
DBV Technologies
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Male or female children aged 4 through 11 years; 2. Physician-diagnosis of peanut allergy or children with a well documented medical history of IgE-mediated symptoms after ingestion of peanut and currently following a strict peanut-free diet, but without a physician diagnosis; 3. Peanut-specific IgE level (ImmunoCAP system) \>0.7 kU/L; 4. Positive peanut skin prick test (SPT) with a largest wheal diameter: * ≥6 mm for children 4 through 5 years of age at Visit 1, * ≥8 mm for children 6 years and above at Visit 1; 5. Positive DBPCFC at ≤300 mg peanut protein. Main
Exclusion criteria
1. History of severe anaphylaxis to peanut with any of the following symptoms: hypotension, hypoxia, neurological compromise (collapse, loss of consciousness or incontinence); 2. Generalized dermatologic disease 3. Diagnosis of mast cell disorders, including mastocytosis or uricaria pigmentosa as well as hereditary or idiopathic angioedema; 4. Diagnosis of asthma that fulfills any of the following criteria: * Uncontrolled persistent asthma as defined by National Asthma Education and Prevention Program Asthma guidelines 2007 or by Global Initiative for Asthma guidelines 2015, * Asthma treated with either a high daily high dose of inhaled corticosteroid or with a combination therapy of a medium or high daily dose of inhaled corticosteroid with a long acting inhaled β2 agonist or with a combination therapy of a high daily dose of inhaled corticosteroid with a long acting inhaled β2 agonist. Asthmatic subjects treated with a medium daily dose of inhaled corticosteroids are eligible. Intermittent asthmatic subjects who require intermittent use of inhaled corticosteroids for rescue are also eligible, * Two or more systemic corticosteroid courses for asthma in the past year or 1 oral corticosteroid course for asthma within 3 months prior to Visit 1, or during screening period, * Prior intubation/mechanical ventilation for asthma within 1 year prior to Visit 1, or during screening; 5. Receiving β-blocking agents, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers or tricyclic antidepressant therapy; 6. Received anti-tumor necrosis factor drugs or anti-IgE drugs (such as omalizumab) or any biologic immunomodulatory therapy within 1 year prior to Visit 1, during screening period or during study participation; 7. Use of systemic long-acting corticosteroids within 12 weeks prior to Visit 1 and/or use of systemic short-acting corticosteroids within 4 weeks prior to Visit 1 or during screening; 8. Prior or concomitant history of any immunotherapy to any food; 9. Receiving or planning to receive any aeroallergen immunotherapy during their participation in the study. Aeroallergen immunotherapy must be discontinued at the time of Visit 1; 10. Any disorder in which epinephrine is contraindicated such as coronary artery disease, uncontrolled hypertension, or serious ventricular arrhythmias.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Percentages of Treatment Responders at Month 12; Analyzed in the Overall Population | At Month 12 | The Double-Blind Placebo-Controlled Food Challenges (DBPCFCs) to determine Eliciting Dose (ED) were performed at screening and Month 12, with each challenge occurring over 2 days. The participant was gradually fed increasing amounts of standardized blinded oral formulas containing either peanut protein (during 1 of the 2 days of the challenge), or without any peanut protein (during the other day of the challenge). A participant was defined as a treatment responder if: * ED was ≥300 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 1), or * ED was ≥1,000 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 2). Participants with missing treatment response at Month 12 were imputed as non-responders. The percentage of treatment responders at Month 12 is presented. Analysis of the difference in response rates between treatment groups is presented in the subsequent statistical analysis table. Analysis was performed in the overall population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Percentages of Treatment Responders at Month 12; Analyzed in Each Screening Eliciting Dose (ED) Subgroup | At Month 12 | The Double-Blind Placebo-Controlled Food Challenges (DBPCFCs) to determine Eliciting Dose (ED) were performed at screening and Month 12, with each challenge occurring over 2 days. The participant was gradually fed increasing amounts of blinded oral formulas containing either peanut protein (during 1 of the 2 days of the challenge), or without any peanut protein (during the other day of the challenge). A participant was defined as a treatment responder if: * ED was ≥300 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 1), or * ED was ≥1,000 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 2). Participants with missing treatment response at Month 12 were imputed as non-responders. The percentage of treatment responders at Month 12 is presented below. Analysis of the difference in response rates between treatment groups is presented in the subsequent statistical analysis table. Analysis was performed for each separate screening ED subgroup. |
| Cumulative Reactive Dose (CRD) of Peanut Protein at Baseline and Month 12 | Baseline and Month 12 | The CRD was calculated as the sum of all doses given (including any repeated and partial doses). The median CRD of peanut protein at baseline and Month 12 is presented. Analysis was performed using the modified baseline observation carried forward method to impute missing data at Month 12. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time | Baseline and Months 3, 6 and 12 | Venous blood samples were drawn to assess peanut-specific IgE levels at baseline and Months 3, 6 and 12. The median relative changes from baseline in IgE levels for each timepoint are presented. Relative change from baseline=100×(value at the visit-value at baseline)/value at baseline. |
| Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time | Baseline and Months 3, 6 and 12 | Venous blood samples were drawn to assess peanut-specific IgG4 levels at baseline and Months 3, 6 and 12. The median relative changes from baseline in IgG4 levels for each timepoint are presented. Relative change from baseline=100×(value at the visit-value at baseline)/value at baseline. |
Countries
Australia, Canada, Germany, Ireland, United States
Participant flow
Recruitment details
This Phase III study was conducted in participants aged 4 to 11 years old with peanut allergy at 31 active centers in Australia, Canada, Germany, Ireland and USA. Participants were randomized in a 2:1 ratio to receive DBV712 250 micrograms (μg) (Viaskin® Peanut 250 μg) or placebo.
Pre-assignment details
A total of 500 participants signed an informed consent form and were enrolled in the study: 144 were screened failed and 356 were eligible and randomized in a 2:1 ratio to receive DBV712 250µg (n=238) or placebo (n=118). Maximum study duration for each participant was approximately 61 weeks (6-week screening period, 53-week treatment period and 2-week follow-up period).
Participants by arm
| Arm | Count |
|---|---|
| DBV712 250 μg Participants applied 1 new DBV712 250 μg patch for 24 hours (±4 hours) every day for 12 months. The application duration was progressively increased to a duration of 24 hours daily over a 15-day period (6 hours during the first week, 12 hours during the second week and 24 hours from the third week onwards). | 238 |
| Placebo Participants applied 1 new placebo patch for 24 hours (±4 hours) every day for 12 months. The application duration was progressively increased to a duration of 24 hours daily over a 15-day period (6 hours during the first week, 12 hours during the second week and 24 hours from the third week onwards). | 118 |
| Total | 356 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Screening Period | Adverse Event | 0 | 0 | 1 |
| Screening Period | Inclusion/Exclusion Failure | 0 | 0 | 117 |
| Screening Period | Other not specified | 0 | 0 | 3 |
| Screening Period | Withdrawal by Subject | 0 | 0 | 23 |
| Treatment and Follow-up Periods | Adverse Event | 4 | 0 | 0 |
| Treatment and Follow-up Periods | Lost to Follow-up | 3 | 3 | 0 |
| Treatment and Follow-up Periods | Non-compliance with the investigational product (IP) | 2 | 0 | 0 |
| Treatment and Follow-up Periods | Other | 3 | 1 | 0 |
| Treatment and Follow-up Periods | Physician Decision | 0 | 1 | 0 |
| Treatment and Follow-up Periods | Withdrawal by Subject | 13 | 6 | 0 |
Baseline characteristics
| Characteristic | DBV712 250 μg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 7.4 years STANDARD_DEVIATION 2.11 | 7.3 years STANDARD_DEVIATION 2.3 | 7.3 years STANDARD_DEVIATION 2.17 |
| Age, Customized 4 to 5 years | 55 Participants | 32 Participants | 87 Participants |
| Age, Customized 6 to 11 years | 183 Participants | 86 Participants | 269 Participants |
| Race/Ethnicity, Customized Asian | 19 Participants | 8 Participants | 27 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 24 Participants | 12 Participants | 36 Participants |
| Race/Ethnicity, Customized White | 194 Participants | 96 Participants | 290 Participants |
| Screening Eliciting Dose (ED) Subgroup Screening ED Subgroup 1 | 41 Participants | 20 Participants | 61 Participants |
| Screening Eliciting Dose (ED) Subgroup Screening ED Subgroup 2 | 197 Participants | 98 Participants | 295 Participants |
| Sex: Female, Male Female | 89 Participants | 49 Participants | 138 Participants |
| Sex: Female, Male Male | 149 Participants | 69 Participants | 218 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 238 | 0 / 118 | 0 / 500 |
| other Total, other adverse events | 222 / 238 | 96 / 118 | 83 / 500 |
| serious Total, serious adverse events | 10 / 238 | 6 / 118 | 9 / 500 |
Outcome results
Primary
Difference in Percentages of Treatment Responders at Month 12; Analyzed in the Overall Population
The Double-Blind Placebo-Controlled Food Challenges (DBPCFCs) to determine Eliciting Dose (ED) were performed at screening and Month 12, with each challenge occurring over 2 days. The participant was gradually fed increasing amounts of standardized blinded oral formulas containing either peanut protein (during 1 of the 2 days of the challenge), or without any peanut protein (during the other day of the challenge). A participant was defined as a treatment responder if: * ED was ≥300 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 1), or * ED was ≥1,000 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 2). Participants with missing treatment response at Month 12 were imputed as non-responders. The percentage of treatment responders at Month 12 is presented. Analysis of the difference in response rates between treatment groups is presented in the subsequent statistical analysis table. Analysis was performed in the overall population.
Time frame: At Month 12
Population: The Intent-to-Treat (ITT) population was comprised of all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DBV712 250 μg | Difference in Percentages of Treatment Responders at Month 12; Analyzed in the Overall Population | 35.3 percentage of participants |
| Placebo | Difference in Percentages of Treatment Responders at Month 12; Analyzed in the Overall Population | 13.6 percentage of participants |
Comparison: Analysis of the difference in response rates between DBV712 250 μg group and Placebo group and 2-sided Newcombe 95% confidence interval (CI). P-value was obtained from a 2-sided 5% test to evaluate the null hypothesis of no difference in response rates between treatment groups using the Wald method. Clinical relevance was evaluated based on the lower bound of the Newcombe 95% CI of the difference in response rates ≥15%.p-value: <0.00195% CI: [12.4, 29.8]Wald
Secondary
Cumulative Reactive Dose (CRD) of Peanut Protein at Baseline and Month 12
The CRD was calculated as the sum of all doses given (including any repeated and partial doses). The median CRD of peanut protein at baseline and Month 12 is presented. Analysis was performed using the modified baseline observation carried forward method to impute missing data at Month 12.
Time frame: Baseline and Month 12
Population: The Intent-to-Treat (ITT) population was comprised of all participants who were randomized.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DBV712 250 μg | Cumulative Reactive Dose (CRD) of Peanut Protein at Baseline and Month 12 | Baseline | 144.0 mg |
| DBV712 250 μg | Cumulative Reactive Dose (CRD) of Peanut Protein at Baseline and Month 12 | Month 12 | 444.0 mg |
| Placebo | Cumulative Reactive Dose (CRD) of Peanut Protein at Baseline and Month 12 | Baseline | 144.0 mg |
| Placebo | Cumulative Reactive Dose (CRD) of Peanut Protein at Baseline and Month 12 | Month 12 | 144.0 mg |
Comparison: The treatment effect was estimated using the Hodges-Lehmann estimate of the difference in median CRDs at Month 12.p-value: <0.00195% CI: [130, 317]Wilcoxon rank-sum test
Secondary
Difference in Percentages of Treatment Responders at Month 12; Analyzed in Each Screening Eliciting Dose (ED) Subgroup
The Double-Blind Placebo-Controlled Food Challenges (DBPCFCs) to determine Eliciting Dose (ED) were performed at screening and Month 12, with each challenge occurring over 2 days. The participant was gradually fed increasing amounts of blinded oral formulas containing either peanut protein (during 1 of the 2 days of the challenge), or without any peanut protein (during the other day of the challenge). A participant was defined as a treatment responder if: * ED was ≥300 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 1), or * ED was ≥1,000 mg peanut protein at Month 12 DBPCFC (for screening ED subgroup 2). Participants with missing treatment response at Month 12 were imputed as non-responders. The percentage of treatment responders at Month 12 is presented below. Analysis of the difference in response rates between treatment groups is presented in the subsequent statistical analysis table. Analysis was performed for each separate screening ED subgroup.
Time frame: At Month 12
Population: The Intent-to-Treat (ITT) population was comprised of all participants who were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DBV712 250 μg | Difference in Percentages of Treatment Responders at Month 12; Analyzed in Each Screening Eliciting Dose (ED) Subgroup | Screening ED subgroup 1 | 39.0 percentage of participants |
| DBV712 250 μg | Difference in Percentages of Treatment Responders at Month 12; Analyzed in Each Screening Eliciting Dose (ED) Subgroup | Screening ED subgroup 2 | 34.5 percentage of participants |
| Placebo | Difference in Percentages of Treatment Responders at Month 12; Analyzed in Each Screening Eliciting Dose (ED) Subgroup | Screening ED subgroup 1 | 20.0 percentage of participants |
| Placebo | Difference in Percentages of Treatment Responders at Month 12; Analyzed in Each Screening Eliciting Dose (ED) Subgroup | Screening ED subgroup 2 | 12.2 percentage of participants |
Comparison: Screening ED subgroup 1:~Analysis of the difference in response rates between DBV712 250 μg group and Placebo group and 2-sided Newcombe 95% CI. P-value was obtained from a 2-sided 5% test to evaluate the null hypothesis of no difference in response rates between treatment groups using the Wald method. Clinical relevance was evaluated based on the lower bound of the Newcombe 95% CI of the difference in response rates \>0.p-value: 0.10595% CI: [-6.4, 38.4]Wald
Comparison: Screening ED subgroup 2:~Analysis of the difference in response rates between DBV712 250 μg group and Placebo group and 2-sided Newcombe 95% CI. P-value was obtained from a 2-sided 5% test to evaluate the null hypothesis of no difference in response rates between treatment groups using the Wald method. Clinical relevance was evaluated based on the lower bound of the Newcombe 95% CI of the difference in response rates \>0.p-value: <0.00195% CI: [12.1, 30.8]Wald
Other Pre-specified
Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time
Venous blood samples were drawn to assess peanut-specific IgE levels at baseline and Months 3, 6 and 12. The median relative changes from baseline in IgE levels for each timepoint are presented. Relative change from baseline=100×(value at the visit-value at baseline)/value at baseline.
Time frame: Baseline and Months 3, 6 and 12
Population: The Intent-to-Treat (ITT) population was comprised of all participants who were randomized. Only those with non-missing data were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DBV712 250 μg | Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time | Month 3 | 78.716 Percent of change |
| DBV712 250 μg | Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time | Month 6 | 39.716 Percent of change |
| DBV712 250 μg | Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time | Month 12 | 2.858 Percent of change |
| Placebo | Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time | Month 3 | 16.964 Percent of change |
| Placebo | Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time | Month 6 | 4.605 Percent of change |
| Placebo | Relative Change From Baseline in Peanut-specific Immunoglobulin E (IgE) Over Time | Month 12 | -6.919 Percent of change |
Other Pre-specified
Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time
Venous blood samples were drawn to assess peanut-specific IgG4 levels at baseline and Months 3, 6 and 12. The median relative changes from baseline in IgG4 levels for each timepoint are presented. Relative change from baseline=100×(value at the visit-value at baseline)/value at baseline.
Time frame: Baseline and Months 3, 6 and 12
Population: The Intent-to-Treat (ITT) population was comprised of all participants who were randomized. Only those with non-missing data were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DBV712 250 μg | Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time | Month 3 | 127.778 Percent of change |
| DBV712 250 μg | Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time | Month 6 | 258.491 Percent of change |
| DBV712 250 μg | Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time | Month 12 | 513.487 Percent of change |
| Placebo | Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time | Month 3 | 14.286 Percent of change |
| Placebo | Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time | Month 6 | 11.492 Percent of change |
| Placebo | Relative Changes From Baseline in Peanut-specific Immunoglobulin G4 Subtype (IgG4) Over Time | Month 12 | 10.496 Percent of change |