| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients Suffering from Mite-Induced Allergic Rhino-Conjunctivitis Without or With Controlled Asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients Suffering from Mite-Induced Allergic Inflammation of the Conjunctiva and Rhinitis Without or With Controlled Asthma |
|
| 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 | 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 |
| The objective of this clinical trial is to determine the optimal effective and safe dose of tablet-based ‘sublingual specific immunotherapy’ (SLIT) with the monomeric allergoid LAIS® dermatophagoides sublingual tablets, administered once daily (o.d.), to adults with mite-induced ARC undergoing allergen-specific provocation with Titrated Nasal Provocation Test (TNPT) and natural ‘in-field’ allergen exposure. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female (not breastfeeding, with negative pregnancy test and using either a highly effective method of contraception during the entire study or being post-menopausal for at least 1 year or sterilized women) outpatients, 18–64 years old.
2. Moderate to severe mite-induced ARC of at least 2 years according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines.
3. Positive specific SPT (wheal size diameter of <2 mm for negative control AND wheal size diameter of >=3 mm for histamine control AND wheal size diameter of >= 3 mm larger than saline control) at screening for Der. f. or Der. p.
4. Serum specific IgE to Der. f. or Der. p. (>0.7 kU/l).
5. Positive nasal provocation test at V1: mean LSS, as total score of applied allergen dosages divided by the number of allergen dosages, ≥5.
6. Subject must be willing and able to comply with the trial protocol
7. Written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Allergen Immunotherapy (AIT) within the previous five years with mite-extracts and any current immunotherapy with another allergen.
2. Clinically relevant hypersensitivity to any of the excipients used in LAIS® mites sublingual tablets, in placebo tablets, in the rescue medications (prednisone, desloratadine, mometasone) and/or SPT and/or NPT solutions (lactose monohydrate, cellulose microcrystalline, silica colloidal anhydrous, magnesium stearate, sodium carboxymethyl cellulose, silicon dioxide, carmellose sodium, glycerol, citric acid monohydrate, sodium citrate dihydrate, polysorbate 80, benzalkonium chloride, maize starch, hypromellose, hydro treated vegetable oil (Type 1), titanium dioxide, macrgol 400, indigocarmin-aluminiumsalt, phenol, sodiumphospate dihydrate, disodium phosphate dodecahydrate, sodium chloride, human albumin) and/or active substances of the rescue medication (prednisone, desloratadine, mometasone).
3. Clinically relevant co-sensitization(s) (moderate to severe symptoms of ARC/asthma against co-allergens), e.g. to seasonal pollen and/or any animal hair and dander, if regularly exposed and/or as demonstrated in SPT.
4. Co-sensitizations with the allergen reaction to co-allergens having a wheal size diameter larger than that of house dust mite allergens in SPT.
5. Asthma requiring treatment other than short-acting inhaled ß2- agonists and low-dose inhaled corticosteroids [e.g. Step 2 (patients receiving Leucotriene receptor antagonists (LTRA) to Step 5, GINA- definition 2018] at screening and/or severe asthma or history of uncontrolled/partly controlled asthma within 3 months prior to screening.
6. Subjects with reduced lung function forced expiratory volume in 1 second (FEV1) <80% of the predicted value at screening.
7. Symptoms of or treatment for acute inflammation of the nose, upper respiratory tract infection, acute sinusitis, acute otitis media, active tuberculosis or other relevant infectious process within 14 days of the first baseline TNPT visit.
8. Clinically relevant nasal polyps, history of surgery either of paranasal sinus or of nasal turbinates, and/or elective maxillofacial surgery within 6 months before planned treatment start (randomization).
9. Diagnosis of choanal atresia, chronic rhinosinusitis with nasal polyps, septal perforation, severe septal deviation, atrophic rhinitis, adenoids obstructing nasal ventilation.
10. History of anaphylaxis Grade 3 or 4 according to Ring et al. (2014).
11. History of recurrent (defined as at least 2 or more episodes) generalized urticaria during the last 2 years.
12. History of immunotherapy-induced facial and/or neck angioedema or a family (parents and siblings) history of hereditary angioedema.
13. Any clinically relevant chronic disease (e.g. cystic fibrosis, emphysema, malignancy, malabsorption or malnutrition, renal or hepatic abnormality, chronic infections, or any other diseases that, in the opinion of the investigator, would interfere with the trial evaluations or the safety of the subjects).
14. Systemic disease affecting the immune system (e.g., insulin dependent diabetes, severe active autoimmune disease, immune complex disease or immune deficiency disease).
15. Contraindications to adrenaline (e.g. heart rhythm disorders, hyperthyroidism, Parkinson symptoms, glaucoma).
16. Concurrent use of prohibited medication(s) or inadequate wash-out of medication prior to SPT/NPT. Other medications will be permitted, if they are not expected to interfere with the ability of the patient to participate in the study and provided they have been on a stable regimen (i.e., the same daily dosage and route of administration) for 4 weeks prior to screening.
17. Immunosuppressive treatment (ATC code L04 or L01) within 3 months prior to the screening visit.
18. Treatment with antidepressant medication with antihistaminic effect (e.g. doxepin, mianserin).
19. Treatment with antipsychotic medications with antihistaminic effect (e.g. chlorpromazine, levomepromazine, clozapine, olanzapine, thioridazine)
20. Treatment with anti-IgE drugs (e.g. omalizumab) within 130 days/5 half-lives (whichever is the longest before 1st dosing).
21. Treatment with systemic β-blockers.
22. Use of an investigational drug within 30 days/5 half-lives of the drug (whichever is the longest prior to screening).
23. Direct family members of the investigator or trial staff, defined as the investigator's/staff's spouse, parent, child, grandparent, or grandchild.
24. History of alcohol or drug abuse.
25. Severe oral inflammation or oral wounds at randomization.
26. Risk of non-compliance with study procedures.
27. Patients with total symptoms score ≥3 during TNPT evoked by non-active substance (control solution).
28. Any vaccination within two weeks before treatment start (V2) and within one week before TNPT.
29. Severe psychiatric, psychological, or neurological disorders
30. Persons who are in an institution as a result of an administrative or judicial order. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change over time (final TNPT vs baseline TNPT) in the mean Lebel’s Symptoms Score (LSS) in response to mite provocation for 3 verum groups compared to placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| baseline TNPT (V1) and final TNPT (V10) |
|
| E.5.2 | Secondary end point(s) |
Change over time (difference interim TNPT vs baseline TNPT) in the mean Lebel’s Symptoms Score (LSS) in response to mite provocation for 3 verum groups compared to placebo and between active groups for dose-response evaluation.
Percentage of subjects with at least 10-fold increase in the dose eliciting a positive nasal provocation test for 3 verum groups compared to placebo.
Mean Lebel’s Symptoms Score (LSS) in interim TNPT and final TNPT in the 3 verum groups compared to placebo (comparison between groups in the LSS).
Change over time (difference final TNPT and interim TNPT vs baseline TNPT) in PNIF in response to mite provocation (the highest between the two evaluations at 10min and 45 min from the last dose administered) for the 3 verum groups compared to placebo.
Change over time (difference final TNPT and interim TNPT vs baseline TNPT) in VAS for 4 nasal symptoms and cumulative VAS (maximal 400 mm, 100 mm per symptom) in response to mite provocation in the 3 verum groups compared to placebo.
Mean Combined Symptom-Medication score (CSMS, range 0-6), mean dSS, and mean dMS in the 3 verum groups compared to placebo during the period 1st November to 31st December 2019 of diary documentation.
Mean change from baseline (2 weeks run-in) of the CSMS in the period 1st November to 31st December 2019 of diary documentation in the 3 verum groups compared to placebo.
VAS score for 4 nasal symptoms and cumulative VAS (maximal 400 mm, 100 mm per symptom) in the three verum groups compared to placebo at each control visit.
Safety data obtained by physical examination, vital signs, laboratory variables and spirometry (FEV1, FEV1/FVC, PEF and optinal MEF 25,50,75% and or MEF25-75)
Number of events and number of subjects affected by TEAEs and SAEs, local and systemic reactions, as well as analyses of early (occurring within 30 min after IMP intake) or delayed reactions (occurring later than 30 min after IMP intake).
Serum specific immunoglobulin (sIg) E and G4 levels for Der. f. and Der. p before treatment in V0 and after treatment in V10 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.: interim TNPT (V7/V8/V9) and baseline TNPT (V1)
2.:final TNPT (V10), interim TNPT (V7/V8/V9) and baseline TNPT (V1)
3.: interim TNPT (V7/V8/V9) and final TNPT (V10)
4.: final TNPT (V10), interim TNPT (V7/V8/V9) and baseline TNPT (V1)
5.: final TNPT (V10), interim TNPT (V7/V8/V9) and baseline TNPT (V1)
6.: during the period 1st November -31st December 2019 of diary documentation.
7.: baseline (2 weeks run-in) and in the period 1st November to 31st December of diary documentation
8.: V4-V9
9.: V0-V10
10.: V0-V10
11.: V0 and after treatment in V10 |
|
| 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 | Yes |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| multi-centre, dose-finding |
|
| 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 | 4 |
| 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 | 30 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
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