E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Allergic rhinitis/rhinoconjunctivitis (ARC) caused by house dust mite (HDM) allergy. |
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E.1.1.1 | Medical condition in easily understood language |
House dust mite (HDM) allergy. |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001724 |
E.1.2 | Term | Allergic rhinitis (excl hay fever) |
E.1.2 | System Organ Class | 100000004855 |
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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 assess clinical efficacy of 50,000 AUeq/mL (0.5 mL) PM SCIT, compared to placebo, in patients suffering from HDM-induced ARC, measured by the combined symptom and medication score (CSMS(n)) during the last 8 weeks of approximately 1 year treatment. For this primary CSMS(n) evaluation, the symptom score of the CSMS(n) will be based on nasal symptoms only. |
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E.2.2 | Secondary objectives of the trial |
• To assess clinical efficacy of PM, compared to placebo, measured by the: o dSS(n) (mean individual daily symptom scores, nasal symptoms only) assessed during the last 8 weeks of the approximately 1 year treatment period; o dMS (mean daily medication score) assessed during the last 8 weeks of the approximately 1 year treatment period; o Difference in NPT (nasal provocation test) at the end of study compared to baseline. • To determine the onset of efficacy based on CSMS(n) for PM vs placebo. • To compare the proportion of ‘symptom-free days’ (i.e. days without nasal symptoms) and ‘troubled days’ (i.e. days with CSMS(n) ≥ 1.5), assessed during the last 8 weeks of the approximately 1 year treatment period. • To assess the effect of PM, compared to placebo, on Quality of Life (QoL) after approximately 1 year of treatment. • To assess the effect of PM, compared to placebo, on serum specific immunoglobulin levels.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients who signed their informed consent form. 2. Patients aged ≥18 and ≤65 years at signing of informed consent form. 3. Patients with moderate to severe HDM-induced allergic rhinitis or rhinoconjunctivitis (based on ARIA classification) for at least one year prior to screening; with or without concomitant asthma (asthma must be controlled (GINA 2010)). 4. Patients with a history of concomitant asthma must have an FEV1 >70% of predicted value, at screening. Patients without a history of asthma must have an FEV1 >70% or a PEF >80% of predicted value at screening. 5. Patient that reported a mean CSMS(n) ≥1.5 during the baseline period . 6. Patients that are willing and capable to complete an e-diary daily during 12 weeks of the study (≥60% compliance in e-diary completion during the 14 days baseline period). 7. Patients with a positive SPT for HDM D. pter or D. far (mean wheal diameter ≥3 mm compared to negative control; for negative control a reaction up to 2 mm is allowed; histamine control should be positive (mean wheal diameter ≥3 mm) assessed during screening or a documented positive response obtained within one year before screening. 8. Patients with an allergen specific serum IgE (ssIgE) level for HDM D. pter or D. far of ≥0.7 U/mL assessed during screening. 9. Patients with a positive NPT for HDM D. pter extract during screening (Lebel score ≥6 at 10,000 AU/mL), test should be postponed if baseline score is ≥ 3 or if negative control is > 3.
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E.4 | Principal exclusion criteria |
1. Patients with concomitant sensitization i.e. positive SPT (mean wheal diameter ≥3 mm compared to negative control; negative control should be negative; histamine control should be positive (mean wheal diameter ≥3 mm)) to other allergens than HDM, if they have expected clinically relevant symptoms related to the other allergen, overlapping with either the 8-week efficacy assessment period and/or the screening/baseline period, based on the judgement of the investigator. 2. Patients sensitized and symptomatic to pets, that will be regularly exposed to pets during the study period. 3. Patients with a history of anaphylaxis with cardio-respiratory symptoms (food allergy, drugs or an idiopathic reaction). 4. Patients who received immunotherapy (SCIT or SLIT) with HDM allergens within the past 5 years. 5. Patients with unsuccessful allergen-specific immunotherapy (SCIT or SLIT) within the past 5 years (e.g., but not limited to, prematurely stopped immunotherapy due to non-compliance, AEs, or lack of therapeutic effect). 6. Patients who undergo allergen-specific immunotherapy (SCIT or SLIT) with other allergens than HDM during the study period (screening up to EoS). 7. Patients who participated in a clinical interventional study within the last 3 months (e.g. new investigational drug or biological) or in an observational study within the last 30 days (e.g. post marketing study), or plans on participating in another clinical trial during the duration of this study, at the discretion of the investigator. 8. Patients that (will) receive any vaccination (including influenza vaccine) one week before start of treatment and/or during the up-dosing phase. 9. Patients undergoing any immunosuppressive treatment (e.g. anti-IgE therapy) within the last 6 months prior to inclusion and up to EoS. 10. Patients suffering from severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs. 11. Patients suffering from active malignancies or any malignant disease during 5 years prior to screening. 12. Patients suffering from any chronic or acute disease that in the opinion of the investigator might place the patient at an additional risk, including but not limited to the following: clinically significant abnormal ECG at screening or cardiovascular insufficiency, any severe or unstable lung diseases, endocrine disorders, clinically significant renal or hepatic diseases, haematological disorders, severe atopic dermatitis. 13. Patients suffering from any disease with a contra-indication for the use of epinephrine/adrenaline (e.g. hyperthyroidism, glaucoma). 14. Patients receiving treatment with systemic corticosteroids, nasal corticosteroids, antihistamines during the indicated timeframe as listed in Table 4. 15. Patients receiving treatment with systemic or local beta-blockers (including beta-blocker containing eye drops) any time during the study. 16. Patients suffering from moderate to severe nasal obstructive disease such as polyps, septum deviations, etc. 17. Patients suffering from clinically significant chronic sinusitis or ocular infection. 18. Female patients of child-bearing potential who are pregnant, lactating or using inadequate contraceptive measures. Contraceptive measures and other events/measures preventing pregnancy considered adequate are: 1) hormonal contraceptives (i.e. combined estrogen and progesteron containing preparations as well as progesteron-only preparations associated with inhibition of ovulation) such as contraceptive pills, transdermal patches, intrauterine device (IUD), intrauterine system (IUS) implant, or vaginal ring (started at least 4 weeks prior to IMP administration); 2) surgical female participant sterilization (removal of the uterus or ovaries or tubal ligation (”tied tubes”)); 3) postmenopausal (12 consecutive months without a period) for at least 2 years; 4) male partner sterilization (vasectomy with documentation of azoospermia) prior to the female patient's entry into trial and is the sole sexual partner for that female patient; 5) sexual abstinence or having no sexual relationship with a man. *In general, it is recommended to continue the use of contraceptive for at least 3 months after the last dose of study medication, this is therefore also applicable for the current study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the Combined Symptom (nasal symptoms only) and Medication Score CSMS(n). The primary evaluation of the CSMS(n) includes only nasal symptoms; itchy nose, sneezing, runny nose, and blocked nose (all rated from 0-3), and the medication score; 1 for oral and/or topical antihistamines, 2 for intranasal corticosteroids, and 3 for oral corticosteroids. The eye symptoms will not be taken into account in the primary evaluation, because these are less relevant for HDM induced allergies (23). The scores from the four nasal symptoms are added and divided by 4 to a total daily symptom score (dSS(n)) from 0-3. The medication score can reach a maximum of 3 and the total daily medication score ranges from 0-3. The CSMS(n) will range from 0-6.
The EAACI has recently published a position paper on the use of the CSMS as a primary end-point in allergen immunotherapy trials.
Baseline CSMS(n) will be determined during a period of 14 days during the screening period . After randomization, the e-diary will be filled out during two separate periods of 1 week (this will be skipped for patients that are suffering from any co-allergy during these periods), and during the last part of the study patients will be asked to fill in the symptom and medication e-diary on a daily basis for a period of 8 weeks. Timing of this 8 weeks period depends on the randomization date of the patients. For details on the timing of this efficacy period, please refer to the SoE (Table 1). Scores for each of these periods will be averaged. The mean CSMS(n) is the mean of the non-missing daily scores during the period considered. Patients will be asked to fill in their CSMS(n) daily on a fixed time window. For the primary endpoint the data collected during the last 8 weeks of the approximately 1 year treatment period will be used.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Difference in mean CSMS(n) (nasal symptoms only) between PM vs. placebo treatment group, will be assessed during the last 8 weeks of the approximately 1 year treatment period. |
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E.5.2 | Secondary end point(s) |
Efficacy • dSS(n) (nasal symptoms only), measured during the last 8 weeks of the approximately 1 year treatment period. • dMS measured during the last 8 weeks of the approximately 1 year treatment period. • Difference in change from baseline in NPT outcome (Lebel score). • Onset of efficacy based on CSMS(n), measured during the two one-week periods during treatment and during the last 8 weeks of the approximately 1 year treatment period. • Proportion of ‘symptom-free days’ (i.e. days without nasal symptoms) and ‘troubled days’ (i.e. days with CSMS(n) ≥ 1.5), assessed during the last 8 weeks of the approximately 1 year treatment period. • QoL measured with the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ-S) and EQ-5D-5L questionnaire, for all patients; and an additional asthma control questionnaire (ACQ, for patients with concomitant asthma only) as measured at the end of treatment. • Difference from baseline in serum specific immunoglobulin levels (IgE, IgG, IgG4) between PM and placebo, during and after treatment.
Safety • Safety and tolerability assessed by: o local and systemic reactions o (serious) adverse events o blood safety biochemistry/haematology parameters (including aluminium content) o urinalysis (including aluminium content) o vital signs o ECG in PM compared to placebo, as measured before, during and after treatment.
Exploratory • Difference in CSMS (nasal and conjunctival symptoms) between PM and placebo, measured during the last 8 weeks of the approximately 1 year treatment period. • dSS (nasal and conjunctival symptoms), measured during the last 8 weeks of the approximately 1 year treatment period. • Difference in QoL measured with the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ-S) and EQ-5D-5L questionnaire, for all patients; and an additional asthma control questionnaire (ACQ, for patients with concomitant asthma only) as measured two times points during treatment. • Difference in mean CSMS(n) between PM and placebo with sufficient HDM exposure at the patients’ home measured both at screening and at the end of the study. . Clinical efficacy of PM, compared to placebo, on asthma parameters (e.g. asthma related concomitant medication, asthma related adverse events and lung function)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy and exploratory endpoints: During the two one week periods, during the 8 week period at the end of the study and at the end of treatment study visit. Safety: During the complete 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 | Yes |
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
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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 | 8 |
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 | 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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |