| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Birch Pollen-induced Allergic Rhinoconjunctivitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Allergic Rhinoconjunctivitis induced by birch pollen |
|
| 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 |
|
| 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 Allergic Rhino-Conjunctivitis (ARC) symptoms and rescue medication use during the second birch pollen season of the trial, in children and adolescents with birch pollen-induced ARC |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary: Assess the effect of STALORAL® Birch 300 IR on symptoms and medications along with rhinoconjunctivitis-associated quality of life during the second birch pollen season
Other:
• Assess combined ARC symptoms and medications score during the worst birch pollen period, each year and over two consecutive pollen seasons
• Assess changes in the ARIA classification
• Assess individual symptoms and medication scores, asthma status and control, Oral Allergy Syndrome (OAS), quality of life of patients, patient immunological status, health-economic parameters, patient medication compliance over two consecutive pollen seasons
• Assess an exploratory symptom and medication score over two consecutive birch pollen seasons
• Evaluate the safety and clinical tolerability of STALORAL® Birch 300 IR in children and adolescents 5 to 17 years old with birch pollen associated ARC
• Setup a serum bank to improve the knowledge of the allergic disease and of the mechanisms of immunotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to sign and date the informed consent/assent prior to any trial-specific procedure.
(Parents and/or authorised legal representatives will have to give written informed consent for minors in their custody. Children and adolescents will be asked to sign an assent form, dependent on country-specific requirements and Investigator assessment.)
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 based on the previous birch pollen season ≥ 12 out of a maximum possible score of 18 as evaluated by the patient or by the parent/authorised legal representative 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.
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 IgE to pollen allergens of Betula pendula at screening (CAP-RAST birch pollen allergens specific IgE ≥ 0.7 kU/L).
8. Patients with non-clinically relevant co-sensitization to other inhalant allergens such as e.g., grass/rye, mites or animal dander can be enrolled, but only if:
-the CAP-class with the referring allergen has to be at least 2 CAP-classes below the CAP-class for birch, and/or
-the SPT-wheal has to be 2 mm smaller than the SPT-wheal for birch, and
-clinical symptoms* and exposure to these allergens during the 2 IMP treatment periods are not anticipated (based on the clinical judgement and medical records) e.g., by not having regular contact the respective animal such as cat at home.
*Relevant clinical symptoms of respiratory allergy are 4 nasal symptoms (runny nose, blocked nose, sneezing, itchy nose), associated or not to 2 eye related items (itchy eyes, watery eyes), associated or not to asthma (mainly cough, wheezing, shortness of breath).
9. Negative urine pregnancy test on all female patients who have had their menarche prior to randomisation.
Lifestyle Considerations
10. Internet access at home or via a portable device so that patients or the parent/authorised legal representative can complete the eDiary daily via internet during the birch pollen seasons covered by the trial protocol.
|
|
| E.4 | Principal exclusion criteria |
Medical history
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 for ultra LABAs, 24 h 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 is 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 spirometry.
Note: This criterion does not need to be fulfilled if the patient is <7 years old, as s/he cannot perform reproducible FEV1 manoeuvres despite coaching and is not considered as having a diagnosis of asthma.
3. Uncontrolled asthma 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 with GINA 2022 treatment Steps 1, 2 or 3.
4. 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.
Note: Patients with fever, flu or an upper respiratory tract infection at Visit 1 (screening visit) must be treated appropriately. They can be randomised at Visit 2 (randomisation visit) only if the infectious episode is resolved.
6. History of eosinophilic oesophagitis.
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 and immune deficiencies of current clinical relevance, active malignancies).
Screening Tests and Evaluations
10. 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
11. Ongoing treatment with any allergy 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.
12. Patients requiring continuous treatment with systemic corticosteroids for any indications.
13. Patients requiring continuous treatment with β-blockers or with Monoamine Oxidase Inhibitors (MAOIs).
14. Treatment with an immunosuppressive (ATC code L04 or L01) within 3 months prior to the screening visit.
15. Hypersensitivity to any excipient of the IMP/Placebo or contraindication to the use of rescue medications (i.e., antihistamine and nasal corticosteroids).
16. Patients following a strict low sodium diet as the trial treatment contains 590 mg of sodium chloride per vial in a 10 mL solution. |
Other
17. Breastfeeding females (lactating)
18. Sexually active females of childbearing potential or who have had their first menarche prior to randomisation who are not taking and/or willing to use either 1 highly effective contraceptive method or 2 clinically accepted contraceptive method until the end of the trial (depending on the local regulation):
-Abstinence
-Acceptable highly effective methods of contraception
19. Participation in any clinical trial within 30 days prior to the screening visit.
20. Change in residence between geographical regions since the last birch pollen season or anticipated relocation away from the geographical region during the pre-determined birch pollen seasons for more than 2 weeks.
21. Patients who are non-compliant and/or uncooperative, in the Investigator’s opinion.
22. Possible dependency of the patient or patient s’ parents/authorised legal representative(s) on Sponsor or Investigators/sub-Investigators or trial personnel.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The average ARC Total Combined Score (TCS0-38) is defined as the average of the daily (non-missing) ARC TCS0-38.
The daily ARC TCS0-38 is the sum of the ARC Daily Symptom Score (0-18) (DSS0-18) and the ARC Daily Medication Score (0-20) (DMS0-20) and thus ranges from 0 to 38 points: TCS0-38 = DSSS0-18 + DMS0-20.
• The DSS0-18 is the sum of 6 ARC symptoms scores with 4 rhinitis related items (runny nose, blocked nose, sneezing, itchy nose) and 2 eye related items (itchy eyes, watery eyes): each symptom is rated on a 4- point scale from 0 to 3:
- 0 = No symptom;
- 1 = Mild symptoms, i.e., sign/symptom clearly present, but minimal awareness, easily tolerated;
- 2 = Moderate symptoms, i.e., definite awareness of sign/symptom that is bothersome but tolerable;
- 3 = Severe symptoms, i.e., sign/symptom that is hard tolerate, that causes interference with activities of daily living and/or sleeping.
• The DMS0-20 is based on rescue medication intake (oral antihistamine tablets scored 0 or 6, ocular antihistamines scored 0 to 6 and nasal corticosteroids scored 0 to 8) and ranges from 0 to 20.
• Note: Oral corticosteroids are prohibited rescue medication for the management of ARC in the frame of the trial. However, in the event of asthma exacerbation, oral corticosteroids may be prescribed. If so, they will be considered as concomitant treatments to manage an adverse event and a DMS of 20 on each day of intake will be imputed to patients who took oral corticosteroids.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary Efficacy variables:
• The average ARC Combined Symptom Medication Score (CSMS0-6) is defined as the average of the daily (non-missing) ARC CSMS0-6 with CSMS0-6 defined as: CSMS0-6= DSS0-3 +DMS0-3
- The DSS0-3 is calculated as the average of the 6 scores for each individual ARC symptom (runny nose, blocked nose, sneezing, itchy nose, itchy eyes, watery eyes) rated on a 4- point scale from 0 to 3 (0 = None; 1 = Mild; 2 = Moderate; 3 = Severe).
- The DMS0-3 is based on rescue medication intake and ranges from 0 to 3 (0=No rescue medication taken; 1=antihistamine as eye drops and/or oral form; 2=nasal corticosteroid; 3= oral corticosteroid as a concomitant treatment to manage asthma exacerbation, if the case arises).
• The average DSS0-18 calculated as the average of the daily (non-missing) DSS0-18
• The average DMS0-20 calculated as the average of the daily (non-missing) DMS0-20.
• The overall RQLQ(S) score and the overall PRQLQ score, calculated as the mean of responses.
Other secondary Efficacy variables:
• The average ARC TCS0-38 and the average CSMS0-6 will also be analysed to answer other secondary efficacy endpoints.
• The Proportion of Symptom-Controlled Days (PSCD2-0) calculated as the proportion of days during the birch pollen season with no rescue medication intake (DMS0-20=0) and controlled symptoms (DSS0-18 ≤2).
• Controlled patient (CP), i.e., patient with 25%, 50% or 75% of symptom-controlled days (CP25, CP50 and CP75 based on PSCD2-0) during the birch pollen season
• The Proportion of Not-Controlled Days (PNCD) calculated as the proportion of days during the birch pollen season with one of the following:
- at least one individual symptom score = 2 and DMS0-20>0, or
- at least two individual symptom scores = 2 whatever the DMS0-20, or
- at least one individual symptom score = 3 whatever the DMS0-20.
• The 6 average individual ARC symptom scores (scale 0-3) for runny nose, blocked nose, sneezing, itchy nose, itchy eyes, watery eyes rated as defined above, calculated as the average of the daily (non-missing) individual symptom scores.
• The average DSS0-18 and the average DMS0-20 as well as the average DSS0-3 and the average DMS0-3 will also be analysed to answer other secondary efficacy endpoints.
• The average Visual Analogue Scale score (VAS score) of the intensity of rhinoconjunctivitis symptoms is calculated as the average of the daily (non-missing) VAS scores during the birch pollen season. The score ranges from 0 to 100.
• The rescue medication intake for each patient (Yes/No).
• The proportion of days with rescue medication.
• ARIA classes.
• Asthma (yes/no).
• Severity of asthma: mild/moderate/severe as per classification by the Global Initiative for Asthma (GINA) 2022.
• The ACQ total score, corresponding to the mean of the scores obtained for each of the 7 questions of the questionnaire.
• The ACQ score per dimension.
• OAS: absence / presence.
• The individual domain RQLQ(S) and PRQLQ scores calculated as the means of the items in each domain.
• The patient’s health state described by the EQ-5D-Y or the EQ-5D-Y proxy using 5 dimensions and a VAS score.
• The overall PAQLQ score corresponding to the mean of all 23 responses and the individual domain scores corresponding to the means of the items in those domains.
Other variables:
• Immunological markers [serum IgE (total, specific to birch pollen, specific to Bet v 1) and IgG4 (specific to birch pollen and specific to Bet v 1)].
• Health-economic variables will be:
- days at school or work lost due to ARC for the patients
- working days lost for the parents due to their child’s ARC
- ARC-related extra-visits to the physician
- days of allergic asthma-related hospitalisation.
• Treatment compliance: excellent, good, poor (and reasons for poor compliance).
Exploratory variables:
• The exploratory mixed combined symptom and medication score mCSMS0-100 as defined by the ARIA-EAACI task force. The mCSMS0-100 is based on the VAS for global allergy symptoms and is weighted according to the patient rescue medication use and to the VAS level.
Safety variables:
• Adverse events (including severity and relatedness to treatment).
• Adverse events of special interest (Anaphylactic reactions including anaphylactic shocks; Severe laryngo-pharyngeal reactions; Autoimmune disorders; Eosinophilic oesophagitis; Tooth and oral/mucosal discolouration).
• Routine laboratory tests.
• Weight, physical examinations and vital signs.
• Pulmonary function (FEV1 measured by spirometry).
• Laboratory investigations (haematology, clinical biochemistry, immunological parameters).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of first pollen season
End of the study |
|
| 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 | 10 |
| 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
|
| last visit of the last patient |
|
| 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 | 20 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
Print
