| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Seasonal allergic rhinitis and/or rhinoconjunctivitis with or without intermittent asthma due to birch pollen allergy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Seasonal allergic rhinitis and/or rhinoconjunctivitis ("Hay Fever") with or without intermittent asthma due to birch pollen allergy |
|
| 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 | 10066093 |
| E.1.2 | Term | Birch pollen 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 |
| The primary objective of the study is the proof of efficacy (superiority versus placebo) by means of the combined Symptom and Medication score (SMS) on nasal and ocular symptoms and their respective Rescue Medication score (RMS) for the perennial treatment regimen of Depigoid Birch 5000 DPP/mL versus placebo after 2 years of treatment and after 5 years comprising 3 years of treatment plus 2 years treatment-free follow-up. |
|
| E.2.2 | Secondary objectives of the trial |
Difference in SMS + RMS in eDiary only for 3rd year data
Differences in Symptom score (SS),RMS,SMS during 1.,3.,4. pollen
season (futility & interim analysis (FA, IA). Changed after 2nd-year IA:
3rd-year FA will not be performed
Difference in SMS incl. pulmonary symptoms
Differences in SMS,SS,RMS concern. non-asthmatic & asthmatic pts.
Difference in the RQLQ/AdolRQLQ scores
Difference in nos. of well days & hell days
Differences in immunol. parameters within the pts/between treatm.
groups
Disease-modifying effect after 5 yrs
Responder-analysis after 2 & 5 yrs
Differences in laboratory parameters (hemat./clinical chem.)
Differences in AEs throughout whole study duration incl. differences
between treatm. groups in severity levels of SRs,immediate & local
reactions,incl. calculation of ratios per injection
Differences in vital signs, physical examination, global evaluation
Differences between symptoms reported in the pat. diaries
Exam. of pharmacokinetics of Al(OH)3 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Examination of pharmacokinetics (PK) of aluminum hydroxide:
aluminum concentrations in plasma and urine before immunotherapy,
after the first maintenance dose, and after 1 year of treatment (PDCO
requirement).
See secondary objectives, last bullet (page 38 of the protocol).
This substudy will only be conducted with 24 patients in selected sites in Germany
|
|
| E.3 | Principal inclusion criteria |
Patients will be eligible for inclusion into the study only if all of the following criteria are met:
1. Availability of an appropriately signed and dated informed consent before any study-specific examination,
2. Aged 12 to 70 years at the screening visit (V0-SCR),
3. Clinical history of at least 2 years of seasonal allergic rhinitis and/or rhinoconjunctivitis with or without intermittent asthma due to birch pollen allergy that has required repeated use of symptomatic treatment,
4. Patients must have a minimum level of perception of symptoms from previous seasons defined as at least a moderate symptom level (i.e. a score of 2 on the 4-point Likert scale) in at least 2 symptom categories prior to randomization,
5. Lung function value ≥ 80% of the predicted normal value,
6. IgE-mediated sensitization has to be verified by:
• suggestive medical history, and
• specific IgE reactivity to birch pollen (CAP-RAST ≥ 2), and
• a positive SPT to birch pollen at screening or within 1 month of the screening visit. An SPT is considered positive if it results in a wheal diameter of at least 3.0 mm.
7. Internet access so that patients can complete the eDiary daily via internet during all 5 pollen seasons covered by the study protocol.
Special criteria for patients with co-allergies: For all patients with co-allergies as a result of sensitization against grass and/or weed pollen and/or perennial allergens (e.g. house dust mites, animal dander), all of the following inclusion criteria must be fulfilled:
8. Patients do not suffer from typical symptoms against co-allergens,
9. Specific CAP-RAST result to co-allergens less than the CAP-RAST result to birch pollen (the difference has to be ≥ 2). Alternatively, a currently performed (up to 1 month prior to the screening visit) negative CPT or NPT is acceptable and outweighs a high CA_-RAST test results against the respective co-allergen. Patients with co-allergies against animal dander may be randomized even if the CAP-RAST difference is < 2, but they must not be exposed to the specific allergen,
10. The result of the SPT against co-allergens is less than the result of the SPT against birch pollen. Alternatively, a currently performed (up to 1 month prior to the screening visit) negative CPT or NPT is acceptable and outweighs a positive SPT or CAP-RAST tets agains the respective co-allergen. |
|
| E.4 | Principal exclusion criteria |
A patient will not be eligible for inclusion in this study if any of the following criteria are met:
1. History of significant clinical manifestations of allergy as a result of sensitization against co-allergies, particularly—but not limited to—grass or weed pollen and perennial allergens (e.g. house dust mites, cat or dog).
2. History of anaphylactic reaction.
3. Moderate or severe persistent asthma (GINA 3 or 4).
4. Mild persistent asthma (GINA 2), according to the Global Initiative for Asthma Guidelines, necessitating treatment with inhaled glucocorticoids at a daily dose level of > 400 μg budesonide dose equivalents.
5. Lung function < 80% of the predicted normal value (for PEF: highest result of 3 measurements).
6. Acute or chronic inflammatory or infectious airway diseases including recurrent acute or chronic sinusitis.
7. Chronic structural diseases of the affected organs (e.g. eye, nose, lung).
8. History or presence of confirmed or potential diseases of the immune system including autoimmune diseases and immune deficiencies of actual clinical relevance.
9. Any disease that prohibits the use of adrenaline (e.g. hyperthyroidism).
10. Atopic dermatitis with SCORAD >40 in the past or at screening.
11. Any severe, uncontrolled disease or diseases that could increase the risk for patients
participating in the study, which include but are not limited to the following:
cardiovascular insufficiency, any severe or unstable lung diseases, endocrine diseases,
clinically significant renal or hepatic diseases, or hematological disorders.
12. Active malignant disease during the 5 years prior to study enrollment.
13. Any significant abnormal laboratory parameter or alteration in vital signs that could increase the risk for the study patient.
14. Abuse of alcohol, drugs, or medication within 1 year prior to study enrollment.
15. Severe psychiatric, psychological, or neurological disorders.
16. Ongoing or past full courses of SIT against birch pollen within the last 5 years.
17. Topical and systemic treatment with β-blockers.
18. Concomitant treatment with substances interfering with the immune system beginning 1 week prior to start of treatment.
19. Specific immunotherapy courses against other allergens (must be terminated at least 6 months prior to start of treatment).
20. Use of tranquillizers or psychoactive drugs that have an effect on (nor-) adrenaline within 1 week prior to Visit 1-1.
21. Use of systemic corticosteroids within 3 months prior to Visit 1-1.
22. Immunization with vaccines within 7 days prior to Visit 1-1.
23. Treatment with antihistamines for any reason other than allergic symptoms due to birch pollen allergy.
24. Patients with hypersensitivity to excipients of the IMP.
25. Changed residence between geographical regions since the last birch pollen season or not staying in the geographical region during the pre-determined birch pollen season.
26. Patients expected to be non-compliant and/or uncooperative.
27. Exposure to any investigational drug within one month or 6 half lives of the drug (whichever is longer).
28. Patients who have already participated in this study.
29. Patients who are employees of the study site, first-degree relatives, or partners of the investigator(s).
30. Any donation of germ cells, blood, organs, or bone marrow during the course of the study.
31. Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study.
32. Nursing (lactating) women or women with a positive pregnancy test at the screening visit.
Women of childbearing potential must be using highly effective contraception during
participation in this clinical study. A highly effective method of birth control is defined as
one that results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives and some intrauterine devices (IUDs) used from 8 weeks prior to the start of treatment, as well as sexual abstinence, or vasectomized partner.
33. Persons who are jurisdictionally or governmentally institutionalized.
Any waiver of these inclusion and exclusion criteria is strongly discouraged by the sponsor. If for unanticipated reasons and on an exceptional basis any criterion is waived, it must be approved by the investigator and the sponsor on a case-by-case basis prior to enrolling the patient. The waiver must not compromise the safety of the patient in any way. This must be documented by both the sponsor and the investigator. In accordance with local regulations the investigator may be required to notify the IRB/EC and the sponsor may be required to notify local regulatory agencies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary analysis variable is the mean integrated combined Symptom and Rescue Medication score (SMS) standardized to the total duration of the yearly pollen exposition time. It will be calculated separately for each year (resp. pollen season) after start of treatment. The SMS represents the sum of the mean daily Symptom score (SS) of rhinitis/ rhinoconjunctivitis/asthma symptoms plus the mean daily Rescue Medication score (RMS).
The following 6 symptoms for allergic rhinoconjunctivitis will be scored: nasal itching, sneezing, rhinorrhea, nasal obstruction, ocular itching/grittiness/redness and ocular tearing. The symptoms will be scored according to the recommendations at the Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases (Doc Ref: CHMP/EWP/18504/2006)
Within the Rescue Medication scoring system, score points are allocated per application of each single rescue medication product used in this study to treat the characteristic allergy related symptoms. The RMS is defined as the mean of the daily RMS during the pollen season.
Data of both scores are documented by the patients by means of a web-based electronic diary (eDiary) . Daily rhinitis and/or rhinoconjunctivitis and/or asthma symptoms, intake of rescue medication as well as the patient’s judgment (once weekly) of the effect of the study medication and the single rescue medications taken will be recorded. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Symptoms and rescue medication consumption will be captured via patient diary during birch pollen seasons (country-spec. approx. 2-3 months between Feb.-Jun) in the years pertaining to both the treatment and follow-up periods (years 1 to 5). |
|
| E.5.2 | Secondary end point(s) |
• Symptom score (SS)
• Rescue medication score (MS)
• Combined symptom and rescue medication score (SMS) including pulmonary symptoms: breathlessness, wheezing, cough, tightness in chest captured according to the same scoring system like the nasal/ocular symptoms.
• Rhinitis QoL scores (AdolRQLQ + RQLQ)
• IgE, IgG1 and IgG4 levels
• Number of well days and hell days
• Subjects (%) suffering from different severity levels of systemic reactions
• Subjects (%) suffering from immediate local reactions (≥ 5 cm in diameter)
• Subjects (%) suffering from delayed local reactions (≥ 10 cm in diameter)
• Ratio of systemic reactions per injection
• Ratio of local reactions per injection
• Pharmacokinetics of Aluminiumhydroxid (subgroup of 24 patents only): Aluminium concentrations in plasma and urine
• Investigators and patients global evaluation
• Disease modifying effect (% of patients who develop asthma or allergic symptoms against allergens other than birch pollen)
• Number of responders
• Adverse Events
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Symptoms and rescue medication score, well days, hell days: : during birch pollen seasons (country-spec. approx. 2-3 months between Feb.-Jun) in the years pertaining to both the treatment and follow-up periods (years 1 to 5).
Rhinitis QoL: once per birch pollen season (mid-season)
IgE, IgG1 and IgG4 levels: at baseline and at the visit after the expected end of the birch pollen seasons during the treatment and follow-up periods.
Pharmacokinetics of Aluminiumhydroxid: before immunotherapy, after the 1st maintenance dose and after 1 year of treatment
Investigators and patients global evaluation: after 5 years
Disease modifying effect: after 5 years
Number of responders : once per birch pollen season
Adverse events, systemic reactions, local reaction: throughout 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 | No |
| 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 |
|
| 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
|
| The end of the study is defined by the 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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