Phase IIIb Double-Blind Placebo-Controlled Trial of Betula Pollen Extract in Pediatric Birch Pollen-Induced Allergic Rhinoconjunctivitis with or without Asthma
- Trial ID
- 2023-509833-38-00
- Protocol
- YOBI/SL79.22
- Sponsor
- Stallergenes
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the clinical efficacy of **STALORAL® Birch 300 IR** on symptoms of Allergic Rhinoconjunctivitis (ARC) and the use of rescue medication during the second birch pollen season (BPS2) in children and adolescents aged 5 to 17 years with birch pollen-induced ARC. This is clinically relevant as it aims to provide evidence for the effectiveness of STALORAL® Birch 300 IR in managing symptoms and reducing the need for additional medication in this population, potentially improving patient outcomes and quality of life.
Secondary objectives include:
- Assessing the effect of STALORAL® Birch 300 IR on symptoms, medication use, and rhinoconjunctivitis-associated quality of life (QOL) score during BPS2.
- Evaluating combined ARC symptoms and medication scores during the worst birch pollen period each year and over two consecutive birch pollen seasons.
- Assessing individual symptoms and medication scores over two consecutive birch pollen seasons.
- Evaluating changes in the ARIA classification.
- Assessing asthma status and control over two consecutive birch pollen seasons.
- Evaluating Oral Allergy Syndrome (OAS) over two consecutive birch pollen seasons.
- Assessing the quality of life of patients over two consecutive birch pollen seasons.
- Evaluating the patient's immunological status over two consecutive birch pollen seasons.
Participants
The clinical trial focuses on evaluating the efficacy of **STALORAL® Birch 300 IR** in children and adolescents diagnosed with **birch pollen-induced allergic rhinoconjunctivitis**. The study population comprises both male and female participants aged between 5 and 17 years. Participants are required to have a documented history of moderate to severe allergic rhinoconjunctivitis induced by birch pollen, with or without asthma, and must have experienced symptoms despite previous treatment. The trial includes individuals who have a positive skin prick test to Betula pendula and specific Immunoglobulin E (IgE) to birch pollen allergens. Participants must have internet access to complete an e-Diary application daily. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a multi-national, **Phase IIIb**, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of STALORAL Birch 300 IR in children and adolescents aged 5 to 17 years with **birch pollen-induced allergic rhinoconjunctivitis**, with or without asthma. The trial employs a randomized design where participants are assigned to receive either the active treatment or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the study's double-blind nature. The trial is expected to conclude by July 31, 2025, with recruitment having commenced on September 20, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as a documented history of moderate to severe allergic rhinoconjunctivitis induced by birch pollen and a positive skin prick test to Betula pendula. Following randomization, participants will be involved in the study for a maximum treatment period of 13 months. During this time, they will attend regular follow-up visits to monitor safety and efficacy outcomes, including the assessment of symptoms and rescue medication use. The primary efficacy endpoint is the average allergic rhinoconjunctivitis total combined score over the entire birch pollen season 2 (BPS2).
The study includes an end-of-study visit, where final assessments are conducted to evaluate the overall impact of the treatment. Participants are expected to complete daily electronic diaries to record symptoms, which will be used to assess secondary endpoints such as the average combined symptom and medication score and the average daily symptom score over BPS2. The expected length of participant involvement is approximately 13 months, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that warrant discontinuation. The trial aims to provide robust data on the clinical efficacy of STALORAL Birch 300 IR in the target population, contributing to the understanding of its therapeutic potential in managing birch pollen-induced allergic rhinoconjunctivitis.
Treatment
The clinical trial involves the administration of **STALORAL Birch 300 IR/ml**, an **oromucosal solution** containing **betula pollen extract** as the active substance. This experimental medication is designed for **sublingual use** and is administered at a maximum daily dose of 300 BAU (Bioequivalent Allergy Units). The treatment period extends up to 13 weeks. The solution is provided by Stallergenes and is intended to evaluate its efficacy in managing symptoms of birch pollen-induced allergic rhinoconjunctivitis in children and adolescents aged 5 to 17 years. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment regimen.
Additionally, the study includes a **placebo** group receiving a solution identical in appearance to the STALORAL Birch 300 IR/ml but devoid of the active substance. The placebo is also administered as an oromucosal solution for sublingual use, following the same dosing schedule and treatment period as the experimental group. This comparator treatment is essential for maintaining the double-blind nature of the trial, allowing for an unbiased assessment of the experimental medication's efficacy and safety.
Another formulation, **STALORAL Birch 10 IR/ml and 300 IR/ml**, is also utilized in the trial. This oromucosal solution contains the same active substance, **betula pollen extract**, and is administered sublingually. The dosing regimen and treatment duration are consistent with the other formulations, ensuring uniformity across the study. The inclusion of this formulation allows for a comprehensive evaluation of the medication's effects at varying concentrations, contributing to the overall assessment of its therapeutic potential.
Efficacy
The efficacy of the clinical trial will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the average **Allergic Rhinoconjunctivitis Combined Symptom and Medication Score (ARC TCS)** over the entire Birch Pollen Season 2 (BPS2). Secondary endpoints include the average Combined Symptom and Medication Score (CSMS), the average ARC Daily Symptom Score (DSS), and the average ARC Daily Medication Score (DMS) over the entire BPS2. Additionally, rhinoconjunctivitis-associated functional problems will be evaluated using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)) for adolescents aged 12 to 17 years and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) for children aged 6 to 11 years, with average overall scores calculated over the entire BPS2.
These efficacy parameters will be measured and collected using validated scales and questionnaires. The assessments will be conducted throughout the trial period, with data collection occurring at specified intervals to ensure comprehensive evaluation of the treatment's impact. The analysis of these parameters will provide insights into the clinical efficacy of STALORAL® Birch 300 IR in managing symptoms and reducing the need for rescue medication in children and adolescents with birch pollen-induced allergic rhinoconjunctivitis, with or without asthma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.)
- Covered by a health insurance system as per local regulation.
- Demographics and Medical History - Aged ≥5 to ≤17 years old at the randomisation visit.
- 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.
- A Retrospective ARC Total Symptom Score (TSS), based on the previous birch pollen season of at least 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 - 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.
- Positive specific Immunoglobulin E (IgE) to pollen allergens of Betula pendula and Bet v 1 at screening (CAP-RAST birch pollen allergens and Bet v 1 specific IgEs ≥ 0.7 kU/L).
- Negative urine pregnancy test on all female patients of childbearing potential or who have had their first menarche prior to randomisation.
- Lifestyle Considerations - 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.
Exclusion Criteria
- Medical History - 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.
- 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 asneeded 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) 24h wash-out for ultra-LABAs and 5 days or 5 halflives 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.
- 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.
- Severe oral inflammations such as oral lichen planus, oral ulcerations or oral mycosis.
- Acute or chronic inflammatory or infectious upper airway diseases (excepted mild to moderate asthma) including recurrent acute or chronic sinusitis.
- 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.
- 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.
- Any disease that prohibits the use of adrenaline (e.g., hyperthyroidism).
- 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. 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.
- 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.
- 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 - 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 randomisation.
- Patients requiring continuous treatment with systemic corticosteroids for any indications.
- Patients requiring continuous treatment with β-blockers or with Monoamine Oxidase Inhibitors (MAOIs).
- Treatment with an immunosuppressive (ATC code L04 or L01) within 3 months prior to the screening visit.
- Hypersensitivity to any excipient of the IMP/placebo, or contraindication to the use of RMs (i.e., antihistamine and nasal corticosteroids).
- Patients following a strict low sodium diet as the IMP treatment contains 590 mg of sodium chloride per vial in a 10 mL solution.
- 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.
- 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.For other exclusion criteria, please refer to the section 7.2 of the Protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 20 Sept 2023 | 36 |
 Bulgaria | Not Recruiting | 20 Sept 2023 | 65 |
 Finland | Not Recruiting | 20 Sept 2023 | 45 |
 France | Not Recruiting | 20 Sept 2023 | 32 |
 Germany | Not Recruiting | 20 Sept 2023 | 105 |
 Hungary | Not Recruiting | 20 Sept 2023 | 63 |
 Latvia | Not Recruiting | 20 Sept 2023 | 23 |
 Lithuania | Not Recruiting | 20 Sept 2023 | 37 |
 Poland | Not Recruiting | 20 Sept 2023 | 173 |
 Romania | Not Recruiting | 20 Sept 2023 | 54 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo - Staloral birch, oromucosal solution | Placebo | N/A | — | — | — | N/A |
STALORAL Birke 10 IR/ml und 300 IR/ml, Lösung zur Anwendung in der Mundhöhle | Test | LÖSUNG ZUR ANWENDUNG IN DER MUNDHÖHLE | SUBLINGUAL USE | 300 | 13 | PRD418226 |
STALORAL Birke 300 IR/ml, Lösung zur Anwendung in der Mundhöhle | Test | LÖSUNG ZUR ANWENDUNG IN DER MUNDHÖHLE | SUBLINGUAL USE | 300 | 13 | PRD418225 |