E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of seasonal grass pollen-induced rhinoconjunctivitis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Ear, nose and throat diseases [C09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019170 |
E.1.2 | Term | Hay fever |
E.1.2 | System Organ Class | 100000004870 |
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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 demonstrate the clinical efficacy of grass pollen-ASIT+™ (gpASIT+™) following subcutaneous administration to patients suffering from grass pollen-induced allergic rhinoconjunctivitis, as assessed with the combined symptom and medication score (CSMS) during the peak of the grass pollen season in Year 1 (2019). |
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E.2.2 | Secondary objectives of the trial |
· To confirm the clinical efficacy of gpASIT+™ as assessed with the CSMS during the entire grass pollen seasons in Year 1 (2019) and Year 2 (2020);
· To confirm the clinical efficacy of gpASIT+™ as assessed with the Rhinoconjunctivitis Total Symptom Score (RTSS) and subscores, the Rescue Medication Score (RMS) and the rate of “well days”, during the grass pollen seasons (both peaks and entire seasons) in Year 1 (2019) and Year 2 (2020);
· To confirm the safety and clinical tolerability of gpASIT+™ treatment after the first and second treatment courses;
· To confirm the induction of key immunological effects in serum after treatment with gpASIT+™ after the first and second treatment courses;
· To assess patients’ quality of life and the health economics impact of treatment with gpASIT+™ during the grass pollen seasons in Year 1 (2019) and Year 2 (2020);
Additional objectives detailed in the Study Protocol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria - Year 1
1) Female or male patients aged 18 to 64 years (inclusive);
2) Signed and dated Informed Consent Form (ICF) by a legally competent patient;
3) Good physical and mental health according to medical history, physical examination and vital signs;
4) Female patients who are:
a. Not of childbearing potential, defined as: amenorrhea or post-menopausal (natural spontaneous amenorrhea for at least 12 months, or at least 6 weeks following surgical menopause), OR
b. Naturally or surgically sterile (hysterectomy; bilateral salpingectomy or oophorectomy; bilateral tubal ligation with surgery at least 6 weeks prior to study screening), OR
c. Non-pregnant, non-lactating with negative blood pregnancy test at the Screening visit and using at least one of the following contraceptive methods:
i. Stable hormonal contraceptive for ≥90 days prior to the study (if <90 days prior to the study, additional use of a double barrier method is required until 90 days are reached) and for ≥3 weeks after the final injection, OR
ii. Placement of an intrauterine device (IUD) or intrauterine hormone-releasing
system, OR
iii. Successful male sterilisation of the sole sexual partner (patient must verbally
confirm that appropriate post-vasectomy documentation of the absence of sperm in the ejaculate was provided), OR
iv. True abstinence when in line with the preferred and usual lifestyle of the patient. Periodic abstinence such as calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception.
5) Allergy diagnosis:
a. A clinical history of moderate to severe grass pollen-induced SARC for at least 2 pollen seasons, requiring treatment with either antihistamines or nasal corticosteroids during the 2017 and 2018 grass pollen seasons and with symptoms interfering with usual daily activities or with sleep, as defined according to Allergic Rhinitis and its Impact on Asthma (ARIA) classification of rhinitis (Bousquet et al. 2001; Brozèk et al. 2017, see Chapter VIII.3.2) AND
b. A positive SPT (wheal diameter ≥3 mm) to grass pollen mixture, histamine wheal ≥3 mm, sodium chloride (NaCl) control reaction <2 mm AND
c. Specific IgE against grass pollen ≥0.7 kU/L.
6) For asthmatic patients, confirmed diagnosis of well-controlled asthma according to Global Initiative for Asthma (GINA; 2018) guidelines (Steps 1 to 3, see Chapter VIII.3.2).
Inclusion criteria (Year 2; extension)
Patients must meet all the following inclusion criteria in order to participate in the extension part of the study:
1) Signed and dated Informed Consent Form by a legally competent patient;
2) Good physical and mental health according to medical history, physical examination and vital signs;
3) Female patients who are still fulfilling the non-child-bearing conditions defined in the inclusion criteria for Year 1;
4) For asthmatic patients, confirmed diagnosis of well-controlled asthma according to GINA 2018 guidelines (Steps 1 to 3);
5) Patients having received at least one injection of the investigational product before the first season. |
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E.4 | Principal exclusion criteria |
Exclusion Criteria - Year 1
1) Diagnosis of mastocytosis;
2) Previous (within the last 5 years) immunotherapy with grass allergens;
3) Ongoing immunotherapy with grass allergens or any other allergens;
4) Patients with any history of anaphylaxis due to any cause;
5) Patients with a history of hypersensitivity to the excipients of the investigational product;
6) Patients with a forced expiratory volume in 1 second (FEV1) <80% of the predicted value (European Community for Steel and Coal [ECSC]) or with a peak expiratory flow (PEF) <70% of the individual optimum value at the Screening visit
7) History of being intubated with mechanical ventilator support or in intensive care unit for asthma at any point in the patient’s life;
8) History of emergency visit or hospital admission for asthma in the previous 12 months;
9) Clinical history of moderate to severe allergic rhinitis, as defined according to the ARIA classification of rhinitis, due to tree pollen near or overlapping the grass pollen season;
10) Clinical history of moderate to severe allergic rhinitis as defined according to the ARIA classification of rhinitis caused by an allergen to which the participant is regularly exposed;
11) Patients with a history of significant renal disease or chronic hepatic disease;
12) Patients with a malignant disease;
13) Patients with history of systemic disease affecting the immune system such as autoimmune diseases, immune complex disease or immunodeficiency, or with any chronic disease which may impair the patient’s ability to participate in the trial (e.g. severe congestive heart failure, active gastric ulcer, inflammatory bowel disease, uncontrolled diabetes mellitus, etc.);
14) Patients requiring concomitant medications such as beta-blocking, angiotensin receptor antagonist or angiotensin-converting enzyme inhibitor treatment; antidepressant drugs with potent antihistamine properties i.e. tricyclic antidepressants (e.g. doxepin, amitriptyline, desipramine, imipramine, etc.); anti-IgE antibodies, mast cell stabilisers, anti-leukotriene agents or anti-interleukin treatment (e.g. anti-interleukin 5); corticosteroids (oral, topical or
nasal); or H1 anti-histaminic drugs;
15) Patients with any contraindication for the use of adrenaline;
16) Patients with (repeated) laboratory abnormalities according to Common Terminology Criteria for Adverse Events higher than Grade 2 at Screening;
17) Patients with known positive serology for Human Immunodeficiency Virus-1/2, Hepatitis B Virus or Hepatitis C Virus;
18) Patients having received a vaccine, corticoids or immunosuppressive medications with significant systemic effect within 1 month before trial entry;
19) Patients being in any relationship with or being dependent on the Sponsor, Contract Research Organisation (CRO) and/or Investigator;
20) Inability to understand instructions, attend planned visits and/or complete study documents or assessments, including unreliable patients such as those with known alcoholism or drug abuse or with a history of a severe psychiatric disorder, as well as patients unwilling to give informed consent or to abide by the requirements of the protocol;
21) Simultaneous participation in other clinical trials or previous participation within 30 days before inclusion;
22) Patients who have been committed to an institution by virtue of an order issued by either the judicial or the administrative authorities.
Exclusion criteria (Year 2; extension)
Patients meeting any of the following exclusion criteria cannot participate in the extension part of the study:
1) Diagnosis of mastocytosis;
2) Ongoing immunotherapy with grass allergens or any other allergens started since previous season;
3) Patients with a FEV1 <80% of the predicted value (ECSC) at the Screening visit;
4) History of emergency visit or hospital admission for asthma since the previous season;
5) Patients diagnosed since the previous season with:
a. A significant renal or hepatic disease;
b. A malignant disease;
c. A systemic disease affecting the immune system such as autoimmune diseases, immune complex disease or immunodeficiency;
d. Any chronic disease which may impair the patient’s ability to participate in the trial (e.g. severe congestive heart failure, active gastric ulcer, inflammatory bowel disease, uncontrolled diabetes mellitus, etc.);
e. A contraindication for the use of adrenaline.
6) Patients requiring concomitant medications such as:
a. Vaccination;
b. Systemic corticosteroids other than those provided as rescue medication (concomitant inhaled corticosteroid treatment is allowed for asthma control);
c. Systemic immunosuppressive medications (e.g. methotrexate or ciclosporin A);
- Complete list of Exclusion Criteria Year 2 detailed in the Study Protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the average daily CSMS collected during the peak of the grass pollen season in Year 1. The daily CSMS is the sum of the daily symptom score and the daily RMS calculated from the data recorded in the eDiary. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Over the peak of the grass pollen season. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints for Year 1 are:
• CSMS over the entire grass pollen season;
• RTSS (i.e. the sum of ESS and NSS) over the peak period and the entire grass pollen season; RMS over the peak period and the entire grass pollen season;
• Symptom subscores (ESS and NSS) over the peak period and the entire grass pollen season;
• TSS (the sum of the ESS, NSS and lung symptom score) over the peak period and the entire grass pollen season (in asthmatic patients only);
• Use of rescue medication to relieve asthma symptoms over the peak period and the pollen season;
• Number (%) of “well days” over the peak period and the entire grass pollen season;
• RQLQ(S);
• PGE assessment.
Secondary efficacy endpoints and analysis for Year 2
With the exception of the secondary analysis, the same statistical analyses will be used for both Year 1 and Year 2.
The first efficacy endpoint for Year 2 will be the average daily CSMS collected during the peak of the grass pollen season in Year 2. An analysis of covariance (ANCOVA) similar to the one run for Year 1 will be applied. The LS mean from the ANCOVA and the corresponding two-sided 95% CI of the difference of LS means between the two treatment groups will be presented. If the 20% difference (0.30 in absolute value) is within the 95% CI, then the study will be declared positive
because the observed treatment effect of Year 1 could be considered as sustained.
The second efficacy analysis will be the evaluation of change within the gpASIT+™ group assessed through a paired comparison (repeated ANOVA) between Year 1 and Year 2 which allows a reliable assessment of efficacy improvement between the first and second season.
To explore the change of the CSMS scores over the two pollen seasons in the non-treated group, the same analysis will be repeated within the placebo group. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Over the peak period and the entire pollen season |
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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 | Yes |
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 | 27 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 23 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 23 |
E.8.9.2 | In all countries concerned by the trial days | 0 |