| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Immunoglobulin E Mediated Cow's Milk Allergy |
| Allergia al latte vaccino non Ig-E mediata |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cow's Milk Allergy |
| Allergia al latte vaccino |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011240 |
| E.1.2 | Term | Cow's milk allergy |
| E.1.2 | System Organ Class | 100000004870 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the diagnostic performance of DBV1605 for the diagnosis of non-Immunoglobulin E (IgE) mediated cow’s milk allergy (CMA) in children with symptoms suggestive of non-IgE mediated CMA based on the sensitivity and the specificity |
| Valutare le prestazioni diagnostiche di DBV1605 per la diagnosi di allergia al latte vaccino (CMA, Cow’s Milk Allergy) non immunoglobulina E (IgE) mediata nei bambini con sintomi che suggeriscono CMA non IgE mediata in base alla sensibilità e alla specificità. |
|
| E.2.2 | Secondary objectives of the trial |
• Estimate the specificity of DBV1605 in a control group of subjects;
• Assess the diagnostic performance of DBV1605 in different subgroups of interest;
• Assess the adhesion and application duration of the DBV1605 patch;
• Assess the safety of a single 48-hour application of DBV1605 |
- stimare la specificità di DBV1605 in un gruppo di controllo di soggetti;
- Valutare le prestazioni diagnostiche di DBV1605 in diversi sottogruppi di interesse;
• Valutare l'adesione e la durata di applicazione del cerotto DBV1605;
• Valutare la sicurezza di una singola applicazione di 48 ore di DBV1605. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female subjects aged 1 month to 5 years at Screening Visit,
• Subjects with a history of symptoms that are consistent with non-IgE mediated CMA as per Investigator's assessment, by either:
o Two or more gastrointestinal symptoms (vomiting, diarrhea, persistent distress/colic, regurgitation, constipation), that lasted at least 1 week within 1
month prior to Screening Visit
o Blood in stool,
• Subjects with any type of diet containing regular cow's milk protein (e.g. cow's milk consumption, cow's milk partial elimination, partially hydrolyzed milk) within 1 month prior to Screening Visit,
• Subjects with a negative cow's milk SPT: mean wheal diameter <3 mm and negative control <1 mm.
Subjects may be included in the disease group if they do not meet, among other criteria, any of the following exclusion criteria:
• Subjects with an established diagnosis of non-IgE mediated by a physician after appropriate diagnostic testing including cow's milk
protein challenge,
• Breast-fed subject at Screening Visit,
• Subjects with a history of confirmed food protein-induced enterocolitis syndrome,
• Subjects with a convincing history of IgE-mediated CMA.
CONTROL GROUP
Subjects may be included in the control group only if they meet, among other criteria, the following inclusion criteria:
• Male or female subjects aged 1 month to 5 years at Visit 1,
• Subjects having no medical history of any type of allergy, including no history of IgE-mediated allergic reactions to cow's milk and with no medical history of any food allergy in their family (parents, sibling),
• Subjects who tolerate at least 200 mL of cow's milk or equivalent dairy foods daily within 1 month prior to Visit 1.
• Subjects with negative cow's milk SPT: mean wheal diameter <3 mm and negative control <1 mm.
Subjects may be included in the control group if they do not meet, among other criteria, any of the following exclusion criteria:
• Subjects with history of persistent gastro-intestinal symptoms including vomiting, diarrhea, distress/colic, regurgitation, constipation, blood in stool, for at least 4 consecutive weeks within the previous year.
• Breast-fed subjects at Visit 1. |
• Soggetti di sesso maschile o femminile di et% compresa tra 1 mese e 5 anni alla visita di screening
• Soggetti con anamnesi di sintomi coerenti con CMA non IgE mediata come da valutazione dello sperimentatore:
o Due o pi) sintomi gastrointestinali (vomito, diarrea, malessere/colica persistente, rigurgito, stipsi), della durata di almeno 1 settimana nel mese precedente la visita di screening
o Sangue nelle feci
• Soggetti con qualsiasi tipo di dieta a base di proteine del latte vaccino (ad esempio consumo di latte vaccino, ad esclusione parziale di latte vaccino, latte parzialmente idrolizzato) nel mese precedente la
visita di screening
• Soggetti con SPT negativo per il latte vaccino: diametro medio del pomfo < 3 mm e controllo negativo < 1 mm
I soggetti possono essere inclusi nel gruppo di malattia se non soddisfano, tra gli altri, i seguenti criteri di inclusione:
• Soggetti con una diagnosi di CMA non IgE mediata accertata da un medico dopo test diagnostici appropriati, compreso il test di provocazione delle proteine del latte vaccino
• Soggetto allattato al seno alla visita di screening
• Soggetti con anamnesi di sindrome da enterocolite indotta da proteine alimentari confermata
• Soggetti con anamnesi convincente di CMA IgE mediata
Gruppo di controllo
I soggetti possono essere inclusi nel gruppo di controllo solo se soddisfano, tra gli altri, i seguenti criteri di inclusione:
• Soggetti di sesso maschile o femminile di et% compresa tra 1 mese e 5 anni alla visita 1
• Soggetti che non presentano anamnesi di alcun tipo di allergia, compresa l'anamnesi di reazioni allergiche IgE mediate al latte vaccino e privi di anamnesi di allergie alimentari in famiglia (genitori, fratelli e
sorelle)
• Soggetti che tollerano almeno 200 ml di latte vaccino o di alimenti lattiero-caseari equivalenti al giorno nel mese precedente alla visita 1
• Soggetti con un SPT negativo per il latte vaccino: diametro medio del pomfo < 3 mm e controllo negativo < 1 mm
I soggetti possono essere inclusi nel gruppo di controllo se non soddisfano, tra gli altri, i seguenti criteri di esclusione:
• Soggetti con anamnesi di sintomi gastrointestinali persistenti tra cui vomito, diarrea, malessere/colica, rigurgito, stipsi, sangue nelle feci, per almeno 4 settimane consecutive nell'anno precedente
• Soggetti allattati al seno alla visita 1 |
|
| E.4 | Principal exclusion criteria |
DISEASE GROUP
1 Subjects with an established diagnosis of non-IgE mediated CMA made by a physician after appropriate diagnostic testing including cow's milk protein challenge.
2 Breast-fed subjects at Screening Visit.
3 Subjects on a cow's milk protein-free diet including an AA-based formula or an extensively hydrolyzed formula within 1 month of
Screening Visit.
4 Subjects with a history of confirmed FPIES.
5 Any contraindication to a cow's milk challenge, in particular subjects with a history of severe anaphylactic reaction to cow's milk. Severe anaphylaxis is defined as Grade 3 of the Anaphylaxis Staging System, including:
• Severe hypoxia, persistent hypotension or more than 20% drop in blood pressure, neurological compromise, or
• Cyanosis or SpO2 = 92% at any stage, confusion, cardiovascular collapse, loss of consciousness, bradycardia, cardiac arrest.
6 Subjects with a convincing history of IgE-mediated CMA.
10 Known hypersensitivity to any of the DBV1605 components (except to milk proteins).
11 Known hypersensitivity to any component of the food challenge formula (except to milk proteins).
12 A history of any immunotherapy for CMA.
15 Any disorder in which epinephrine is contraindicated such as congenital cardiac malformation, uncontrolled hypertension, or serious ventricular arrhythmias.
17 Intake of leukotriene receptor antagonists or 5-lipooxygenase inhibitors within 30 days prior to Screening Visit.
18 Treatment with antihistamines within 1 to 7 days (depending on halflife and specified in APPENDIX 3) prior to Screening Visit or inability to discontinue antihistamines for the minimum wash-out periods required prior to SPT or food challenges.
19 Treatment with topical steroid applied on the back within 30 days prior to Screening Visit. |
DISEASE GROUP
1 Subjects with an established diagnosis of non-IgE mediated CMA made by a physician after appropriate diagnostic testing including cow's milk protein challenge.
2 Breast-fed subjects at Screening Visit.
3 Subjects on a cow's milk protein-free diet including an AA-based formula or an extensively hydrolyzed formula within 1 month of
Screening Visit.
4 Subjects with a history of confirmed FPIES.
5 Any contraindication to a cow's milk challenge, in particular subjects with a history of severe anaphylactic reaction to cow's milk. Severe anaphylaxis is defined as Grade 3 of the Anaphylaxis Staging System, including:
• Severe hypoxia, persistent hypotension or more than 20% drop in blood pressure, neurological compromise, or
• Cyanosis or SpO2 = 92% at any stage, confusion, cardiovascular collapse, loss of consciousness, bradycardia, cardiac arrest.
6 Subjects with a convincing history of IgE-mediated CMA.
10 Known hypersensitivity to any of the DBV1605 components (except to milk proteins).
11 Known hypersensitivity to any component of the food challenge formula (except to milk proteins).
12 A history of any immunotherapy for CMA.
15 Any disorder in which epinephrine is contraindicated such as congenital cardiac malformation, uncontrolled hypertension, or serious ventricular arrhythmias.
17 Intake of leukotriene receptor antagonists or 5-lipooxygenase inhibitors within 30 days prior to Screening Visit.
18 Treatment with antihistamines within 1 to 7 days (depending on halflife and specified in APPENDIX 3) prior to Screening Visit or inability to discontinue antihistamines for the minimum wash-out periods required prior to SPT or food challenges.
19 Treatment with topical steroid applied on the back within 30 days prior to Screening Visit. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The sensitivity and the specificity of DBV1605 based on skin reactivity readings after 48 hours and 72 hours will be compared to the results of the DBPCFC in subjects of the disease group. |
La sensibilità e la specificità di DBV1605 basate sulle letture della reattività cutanea dopo 48 ore e 72 ore
saranno confrontate con i risultati del test DBPCFC nei soggetti del gruppo di malattia. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The DBV1605 patch test will be considered positive if, after 48 hours and/or 72 hours following application:
• The skin reactivity under the control patch is rated Grades 0 or 1, and
• The skin reactivity under the active patch is rated at least 1 grade higher than the control patch.
The DBV1605 patch test will be considered negative if after both 48 hours and 72 hours:
• The skin reactivity under the control patch is rated Grades 0 or 1, and
• The skin reactivity under the active patch is rated the same grade as the control patch or 1 grade lower than the control patch. |
Il test epicutaneo DBV1605 sarà considerato positivo se, dopo 48 ore e/o 72 ore dall'applicazione:
• La reattività cutanea sotto il cerotto di controllo è classificata di grado 0 o 1, e
• La reattività cutanea sotto il cerotto attivo è classificata di almeno 1 grado superiore rispetto al cerotto di controllo.
Il test epicutaneo DBV1605 sarà considerato negativo se, dopo 48 ore e/o 72 ore:
• La reattività cutanea sotto il cerotto di controllo è classificata di grado 0 o 1, e
• La reattività cutanea sotto il cerotto attivo è classificata dello stesso grado del cerotto di controllo o 1
grado inferiore al cerotto di controllo. |
|
| E.5.2 | Secondary end point(s) |
In the disease group of subjects:
• DBV1605 sensitivity and specificity after readings at 48 hours;
• DBV1605 sensitivity and specificity after readings at 72 hours;
• DBV1605 sensitivity and specificity considering the test positive if, after 48 hours and/or 72 hours following application:
o The skin reactivity under the control patch is rated Grades 0 or 1, and
o The skin reactivity under the active patch is rated at least 2 grades
higher than the control patch.
In addition, other indicators of DBV1605 diagnostic performance could be explored, and subgroups could be considered for the analysis. The following secondary analyses will be conducted in the control group to confirm the results observed in the disease group:
• DBV1605 specificity after readings at 48 hours and 72 hours in the control group.
The adhesion of DBV1605 will be assessed with:
• The proportions of patches with adhesion scored Grade 0 or 1 and the proportions of patches with adhesion scored higher than 1 at application;
• The proportions of patches with adhesion scored Grade 0 or 1 and the proportions of patches with adhesion scored higher than 1 at removal.
The duration of DBV1605 application will be assessed with:
• The proportions of patches without detachment of the occlusive chamber as assessed by the parents/guardians at different timepoints:
24 hours ±1 hour, 36 hours ±1 hour and 48 hours ±1 hour;
• The proportions of patches present at the application site more than 36 hours after application, excluding voluntary removal;
• The mean duration of patch application until removal or detachment |
Nel gruppo dei soggetti affetti da malattia:
• Sensibilità e specificità di DBV1605 dopo le letture a 48 ore
• Sensibilità e specificità di DBV1605 dopo le letture a 72 ore
• Sensibilità e specificità di DBV1605 considerando il test positivo se, dopo 48 ore e/o 72 ore dall'applicazione:
o La reattività cutanea sotto il cerotto di controllo è classificata di grado 0 o 1, e
o La reattività cutanea sotto il cerotto attivo è classificata di almeno 2 gradi superiore rispetto al cerotto di controllo.
Inoltre, potrebbero essere esplorati altri indicatori delle prestazioni diagnostiche di DBV1605, e potrebbero essere presi in considerazione per l'analisi, se del caso, sottogruppi che saranno dettagliati nel Piano di analisi statistica (SAP, Statistical Analysis Plan).
Nel gruppo di controllo saranno condotte le seguenti analisi secondarie per confermare i risultati osservati nel gruppo di malattia:
• Specificità di DBV1605 dopo le letture a 48 e 72 ore nel gruppo di controllo L'adesione di DBV1605 sarà valutata con:
• Le percentuali di cerotti con adesione che hanno ottenuto un punteggio di grado 0 o 1 e le percentuali di cerotti con adesione che hanno ottenuto un punteggio superiore a 1 all'applicazione
• Le percentuali di cerotti con adesione che hanno ottenuto un punteggio di grado 0 o 1 e le percentuali di cerotti con adesione che hanno ottenuto un punteggio superiore a 1 alla rimozione
La durata dell'applicazione di DBV1605 sarà valutata con:
• Le percentuali di cerotti senza distacco della camera occlusiva valutate dai genitori/tutori in diversi punti temporali: A 24 ore ±1 ora, a 36 ore ±1 ora e a 48 ore ±1 ora
• Le percentuali di cerotti presenti sul sito di applicazione più di 36 ore dopo l'applicazione, esclusa la rimozione volontaria
• La durata media dell'applicazione del cerotto fino alla rimozione o al distacco |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DBV1605 sensitivity and specificity readings at after 48 hours and 72 hours. The test will be considered positive if, after 48 hours and/or
72 hours following application:
o The skin reactivity under the control patch is rated Grades 0 or 1, and
o The skin reactivity under the active patch is rated at least 2 grades higher than the control patch. |
DBV1605 sensitivity and specificity readings at after 48 hours and 72 hours. The test will be considered positive if, after 48 hours and/or
72 hours following application:
o The skin reactivity under the control patch is rated Grades 0 or 1, and
o The skin reactivity under the active patch is rated at least 2 grades higher than the control patch. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| active and control patch of the same IMP |
| active and control patch of the same IMP |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Lithuania |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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