| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Birch Pollen-induced Allergic Rhinoconjunctivitis |
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| E.1.1.1 | Medical condition in easily understood language |
| Allergic Rhinoconjunctivitis induced by birch pollen |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 | 10001728 |
| E.1.2 | Term | Allergic rhinoconjunctivitis |
| E.1.2 | System Organ Class | 100000004853 |
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| 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 demonstrate clinical efficacy of STALORAL® Birch 300 IR on ARC symptoms and rescue medication use during BPS2 of the trial, in children and adolescents with birch pollen-induced ARC. |
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| E.2.2 | Secondary objectives of the trial |
To assess the effect of STALORAL® Birch 300 IR on symptoms and medications along with rhino-conjunctivitis-associated QOL score during BPS2 of the trial, in children and adolescents with ARC.
•To assess combined ARC symptoms and medications score during the worst birch pollen period, each year.
•To assess combined ARC symptoms and medications scores over 2 consecutive birch pollen seasons.
•To assess individual symptoms and medication scores over 2 consecutive birch pollen seasons.
•To assess changes in the ARIA classification.
To assess OAS over 2 consecutive birch pollen seasons.
•To assess QOL of patients over 2 consecutive birch pollen seasons.
•To assess the patient’s immunological status over 2 consecutive birch pollen seasons.
•To assess the health-economic parameters over 2 consecutive birch pollen seasons.
DUE TO CHARACTERS LIMITATIONS, PLEASE SEE OTHER SECONDARY OBJECTIVES IN PROTOCOL REDLINE VERSION FOR CHANGES. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The patient must fulfil the following inclusion criteria to be eligible for the trial:
1. Able to sign and date the informed consent/assent form prior to any trial-specific procedure. Patients may check a box on the assent form if they are unable to provide a signature.
(Parents and/or authorised legal representative(s) will have to give written informed consent for minors in their custody.)
2. Covered by a health insurance system as per local regulation.
Demographics and Medical History
3. Aged ≥5 to ≤17 years old at the randomisation visit.
4. Documented, physician diagnosed, clinically relevant history of moderate to severe ARC induced by birch pollen (with or without asthma) despite having received treatment with symptom-relieving medication during at least 1 previous birch pollen season for ages 4 through 6 or at least 2 previous birch pollen seasons for ages 7 through 17 years at screening.
5. A Retrospective ARC Total Symptom Score (TSS), based on the previous birch pollen season ≥ 12 out of a maximum possible score of 18 AND a retrospective score of at least 30 on a general VAS (0-100) on the severity of symptoms as evaluated by the patient or by the parent/authorised legal representative if the patient is not able to perform the assessment, at screening. Retrospective ARC TSS (TSS0-18) is rated the same way as Daily Symptom Score (DSS) (DSS0-18).
Screening Tests and Evaluations
6. Positive Skin Prick Test (SPT) to Betula pendula at screening visit (the SPT is considered positive if it results in a wheal diameter ≥ 3.0 mm [with positive control (histamine) ≥ 3.0 mm and negative control = 0 mm]). The Sponsor will accept to include patients who have a documented positive SPT in their medical records if this SPT was performed during the previous 6 months preceding the screening visit at the same investigational site in which they are enrolled.
7. Positive specific Immunoglobulin E (IgE) to pollen allergens of Betula pendula at screening (CAP-RAST birch pollen allergens specific IgE ≥ 0.7 kU/L).
8. Negative urine pregnancy test on all female patients of childbearing potential or who have had their first menarche prior to randomisation.
Lifestyle Considerations
9. Internet access at home or via a portable device so that patients or the parent/authorised legal representative can complete the e-Diary in a dedicated application on a mobile phone daily via internet. Patients will start scoring at randomisation, i.e., 4 months before the pollen season. |
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| E.4 | Principal exclusion criteria |
1. Any clinical deterioration of asthma (i.e., asthma exacerbation) that resulted in emergency procedure/treatment or treatment with systemic corticosteroids within 3 months prior to randomisation.
2. For patients ≥7 years old:
Reduced lung function at randomisation defined as Forced Expiratory Volume in 1 second (FEV1) < 70% of the predicted value. For patients with asthma, this is assessed on the patient’s usual asthma controller medication*. The following wash-out periods apply for as needed asthma reliever medication at least a 6-hour wash-out of Short-Acting Beta Agonists (SABAs), a 12 hour wash-out of Long-Acting Beta Agonists (LABAs) and a 24h wash-out for ultra-LABAs and 5 days or 5 half lives for Inhaled Corticosteroids.
*In order to ensure that the asthmatic patients with a mild to moderate asthma status are controlled by treatment steps 1, 2 or 3 in accordance with the Global Initiative for Asthma (GINA 2022), the proper continuous asthma treatment i.e., "controller" is maintained. Only the asthma "reliever" medications must be stopped before performing spirometry. If an asthma medication is used as both ''controller'' and ''reliever'', such as inhaled corticosteroids (in combination with formoterol [LABA]) it must not be stopped before performing spirometry.
3. Severe or uncontrolled asthma or asthma treated with asthmatic therapies consistent with steps 4 or 5 as defined by Global Initiative for Asthma (GINA) 2022 received within 12 months prior to entry in the trial. Eligible asthmatic patients will be those with mild and moderate
asthma controlled by treatment(s) consistent GINA 2022 treatment with Steps 1, 2 or 3.
4. Severe oral inflammations such as oral lichen planus, oral ulcerations or oral mycosis.
5. Acute or chronic inflammatory or infectious upper airway diseases (excepted mild to moderate asthma) including recurrent acute or chronic sinusitis.
6. History of eosinophilic oesophagitis or with current severe or persistent gastroesophageal symptoms including dysphagia or chest pain that, in the opinion of the investigator, may constitute an increased safety concern..
7. A relevant history of systemic allergic reaction (e.g., anaphylaxis with cardiorespiratory symptoms, generalised urticaria or severe facial angioedema) that, in the opinion of the Investigator, may constitute an increased safety concern.
8. Any disease that prohibits the use of adrenaline (e.g., hyperthyroidism).
9. Any severe,uncontrolled disease that, upon Investigator judgment, could increase the risk for trial patients (including but not limited to cardiovascular insufficiency, any severe or unstable lung diseases, endocrine diseases,clinically significant renal or hepatic diseases, haematological disorders, diseases of the immune system including autoimmune diseases [upon the Investigator's judgment based on the benefit/risk assessment] and immune deficiencies of current clinical relevance, active malignancies).
Screening Tests and Evaluations
10. A documented clinically relevant history of seasonal ARC symptoms caused by an allergen source,other than tree pollen from the birch homologous group, with a season overlapping the BPS.
11. A documented clinically relevant history of perennial ARC symptoms caused by an allergen source such as animal dander to which the patient is exposed during the BPS.
12. Any significant abnormal laboratory parameter or alteration in vital signs that could increase the risk for the patient, in the opinion of the Investigator.
Medication
13. Ongoing treatment with prohibited treatment as listed in Section 8.2.3 or any allergen immunotherapy product including Specific Immunotherapy (SIT) or past full courses of SIT against birch pollen terminated for less than 5 years or past courses of SIT for other allergens terminated for less than 6 months prior to start of randomization.
14. Patients requiring continuous treatment with systemic corticosteroids for any indications.
15. Patients requiring continuous treatment with β-blockers or with Monoamine Oxidase Inhibitors (MAOIs).
16. Treatment with an immunosuppressive (ATC code L04 or L01) within 3 months prior to the screening visit.
17. Hypersensitivity to any excipients of the IMP or placebo,or contraindication to the use of RMs (i.e., antihistamine and nasal corticosteroids).
18. Patients following a strict low sodium diet as the IMP treatment contains 590 mg of sodium chloride per vial in a 10 mL solution.
19. Inability to adhere to the washout periods as defined by the protocol,with respect to screening and to refrain from using the medications indicated until after the trial is complete.
20. Patients who would be likely to require prohibited concomitant therapy during the trial or who are anticipated to require using of such agents during the trial. Any medication given for an AE will be permitted.
Other
DUE TO CHARACTERS LIMITATIONS, PLEASE SEE OTHER EXCLUSION CRITERIA IN PROTOCOL REDLINE VERSION FOR CHANGES. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the average ARC TCS (TCS0-38) over the entire BPS2.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The key secondary endpoints will be hierarchical endpoints:
• The average CSMS (CSMS0-6) over the entire BPS2.
• The average ARC DSS (DSS0-18) over the entire BPS2.
• The average ARC DMS (DMS0-20) over the entire BPS2
• The rhino-conjunctivitis-associated functional problems as measured with the RQLQ(S) average overall score for adolescents aged between 12 to 17 years over the entire BPS2.
The rhino-conjunctivitis-associated functional problems as measured with the PRQLQ average overall score for children between 6 to 11 years over the entire BPS2.
Other secondary
The average ARC TCS0-38 over the worst birch pollen period during BPS1 and during BPS2.
• The average ARC CSMS0-6 over the worst birch pollen period during BPS1 and during BPS2.
• The average ARC TCS0-38 over BPS1.
• The average ARC CSMS0-6 over BPS1.
• The PSCD 2-0 (PSCD2-0) over BPS1 and over BPS2.
• Patients reaching 25%, 50% and 75% of PSCD2-0 over BPS1 and over BPS2.
The PNCD (PNCD2-0) over BPS1 and over BPS2.
• The average ARC symptom score for each of the 6 individual symptoms (runny nose, blocked nose, sneezing, itchy nose, itchy eyes, watery eyes) over BPS1 and over BPS2.
• The average ARC DSS0-18 over BPS1.
• The average ARC DMS0-20 over BPS1.
• The average DSS0-3 over BPS1 and BPS2.
• The average DMS0-3 over BPS1 and BPS2.
• The average VAS score (range 0-100) of the intensity of rhinoconjunctivitis symptoms over BPS1 and over BPS2.
• Patients with rescue medication intake over BPS1 and over BPS2.
The proportion of days with rescue medication intake over BPS1 and over BPS2.
• Patients with a shift in the ARIA classification from baseline to BPS1 and/or to BPS2.
• Patients with asthma (yes/no) over BPS1 and BPS2.
• Severity of asthma as per classification by the GINA over BPS1 and BPS2.
• ACQ total score over BPS1 and BPS2 in children aged 6-17 years.
• ACQ score per dimension over BPS1 and BPS2 in children aged 6-17 years.
• Patients with OAS (yes/no) over BPS1 and BPS2.
• The average overall RQLQ(S) score for adolescents between 12 to 17 years over BPS1.
• The average overall PRQLQ score for children between 6 to 11 years over BPS1.
• The average RQLQ(S) individual domain scores for adolescents between 12 to 17 years over BPS1 and over BPS2.
• The average PRQLQ individual domain scores for children between 6 to 11 years over BPS1 and over BPS2.
• The health-related QOL (HRQoL) as measured with EQ-5D-Y score over BPS1 and over BPS2 for children between 8 to 17 years.
• The HRQoL as measured with EQ-5D-Y proxy score over BPS1 and over BPS2 for children under 8.
• Functional problems in asthmatic patients as measured with overall PAQLQ(S) score over BPS1 and over BPS2 in asthmatic patients aged 7 to 17 years old at randomisation.
• Serum birch-specific levels of IgE and IgG4 over BPS1 and over BPS2.
• Number of days at school/work lost due to ARC for the patients.
• Number of working days lost for the parents due to their child’s ARC.
• Number of ARC-related extra-visits to the physician.
• Number of days of allergic asthma-related hospitalization.
• Compliance level over BPS1 and over BPS2.
• Reason for poor compliance over BPS1 and BPS2.
• The average mCSMS0-100 over BPS1 and over BPS2.
• AEs (including severity and relatedness to treatment).
• AESI (anaphylactic reactions including anaphylactic shocks; severe laryngo-pharyngeal reactions; autoimmune disorders; eosinophilic oesophagitis; tooth and oral/mucosal discolouration, and AEs leading to patient’s withdrawal).
• Routine laboratory tests.
• Weight, physical examinations, and vital signs.
• Pulmonary function (FEV1 measured by spirometry).
• Laboratory investigations (haematology, clinical biochemistry, immunological parameters).
Exploratory
• The average mCSMS0-100 over BPS1 and over BPS2.
Safety
• AEs (including severity and relatedness to treatment).
• AESI (anaphylactic reactions including anaphylactic shocks; severe laryngo-pharyngeal reactions; autoimmune disorders; eosinophilic oesophagitis; tooth and oral/mucosal discolouration, and AEs leading to patient’s withdrawal).
• Routine laboratory tests.
• Physical examinations, and vital signs.
• Pulmonary function (FEV1 measured by spirometry).
Laboratory investigations (haematology, clinical biochemistry, immunological parameters).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of first pollen season
End of the study |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| last visit of the last patient |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 23 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 31 |
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