Study of Efficacy and Safety of Omalizumab in Severe Japanese Cedar Pollinosis Adult and Adolescent Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study was to demonstrate the efficacy and safety of omalizumab compared with placebo, on top of SoC (anti-histamine and nasal corticosteroid) in adult and adolescent patients with severe Japanese cedar pollinosis, whose symptoms were inadequately controlled despite the current recommended therapies (nasal corticosteroids plus one or more medications out of anti-histamine, leukotriene receptor antagonist, or prostaglandin D2/thromboxane A2 receptor antagonist) in the previous 2 Japanese cedar pollen seasons.

Official Title
-----------------
A 12 Week, Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Omalizumab in Adult and Adolescent Patients With Inadequately Controlled Severe Japanese Cedar Pollinosis Despite the Current Recommended Therapies

Conditions
-----------------
Seasonal Allergic Rhinitis

Intervention / Treatment
-----------------
* Drug: Omalizumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: A clinical history of Japanese cedar pollinosis defined by the following Took nasal corticosteroid plus one or more medications out of antihistamine (second generation), leukotriene receptor antagonist, or prostaglandin D2 thromboxane A2 receptor antagonist in Japanese cedar pollen seasons in 2016 and 2017. Had inadequately controlled symptoms of Japanese cedar pollinosis lasting at least one week in the Japanese cedar pollen season in 2017 despite the nasal corticosteroid plus one or more medications out of anti-histamine (second generation), leukotriene receptor antagonist, or prostaglandin D2/thromboxane A2 receptor antagonist (regardless of having perennial allergic rhinitis or not) Serum cedar pollen-specific Immunoglobulin E (IgE) levels of ≥ score of 3 by CAP/RAST-FEIA, ImmunoCAP or MAST at the screening epoch. Developing a symptom of Japanese cedar pollinosis during the period from first observational day in cedar pollen in Kanto area to initial drug administration (Visit 101), as defined by the following Having any nasal or ocular symptom (≥ score of 1 in sneezing, rhinorrhea, nasal congestion, itchy eye or watery eye) in at least 2 days or Having both any nasal symptom (≥ score of 1 in sneezing, rhinorrhea, nasal congestion) and any eye symptom (≥ score of 1 in itchy eye or watery eye) in at least one day, which is confirmed by patient e-diary (unless a symptom is clearly consider to take place due to other than Japanese cedar pollinosis/allergic rhinitis (e.g., upper respiratory tract infection, or common cold)). Body weight and serum total IgE level at screen epoch within the dosing table range; body weight of ≥ 20 to ≤ 150 kg and serum total IgE levels of ≥ 30 to ≤ 1500 IU/mL at a maximum. Exclusion Criteria: With an active rhinitis other than allergic rhinitis (e.g acute or chronic rhinitis, idiopathic rhinitis). With an active nose disease other than allergic rhinitis (e.g., acute or chronic rhinosinusitis or deflected septum) which is expected to affect the evaluation of efficacy of the study drug judged by the investigator. With elevated serum IgE levels for reasons other than allergy (e.g., parasite infections, hyperimmunoglobulin E syndrome, Wiskott-Aldrich Syndrome or clinical allergic bronchopulmonary aspergillosis). With a severe asthma treated with high dose inhaled corticosteroid (≥ 800 μg/day fluticasone propionate or an equivalent for aged ≥ 16 to <75 years, > 200 μg/day for aged ≥ 12 to <16 years). Who are receiving operative treatment for allergic rhinitis (e.g., electrocoagulation, laser surgery, 80% trichloroacetic acid chemo-surgery, inferior turbinectomy or posterior nasal neurectomy) within 1 years prior to the screening epoch.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omalizumab<br>Eligible patients randomized to this arm received omalizumab subcutaneously for 12 weeks | Drug: Omalizumab<br>* Omalizumab were administered by subcutaneous injection. Dose (75 to 600 mg) and dosing frequency (every 2 or 4 weeks) were determined by serum total IgE level (IU/mL) and body weight (kg) measured at the screening epoch according the dosing table.<br>|
| Placebo Comparator: Placebo<br>Eligible patients randomized to this arm received placebo subcutaneously for 12 weeks | Drug: Placebo<br>* Placebo were administered by subcutaneous injection. Dose (75 to 600 mg) and dosing frequency (every 2 or 4 weeks) were determined by serum total IgE level (IU/mL) and body weight (kg) measured at the screening epoch according the dosing table.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Nasal Symptom Score | Nasal symptoms (sneezing, rhinorrhea and nasal congestion) were recorded by the patient everyday in their e-Diary, on a scale of 0 (none) to 4 (intense/severe). Nasal symptom score (0-12 point) consisted of score for severity of sneezing (0-4 point), rhinorrhea (0-4 point) and nasal congestion (0-4 point). Severe symptom period: The three weeks where the cumulative value of the mean daily nasal symptom score is the maximum. The three weeks must also meet one of the following criteria: 2) ≥ 70% of the period with concomitant use of fluticasone propionate is included in this three weeks. 2) ≥ 70% of this three weeks includes the period with concomitant use of fluticasone propionate. If not, severe symptom period was extended at a minimum to meet one of the criteria above. The severe symptom period will be defined as: the three weeks where the cumulative value of the mean daily nasal symptom score will be the maximum. | Severe symptom period (from 23Feb2018 to 24March2018) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Ocular Symptom Score and Mean Nasal Ocular Symptom Score | Ocular symptoms (itchy and watery eye) were recorded by the patient everyday in their e-Diary, on a scale of 0 (none) to 4 (intense/severe). Ocular symptom score (0-8 point) consisted of score for severity of itchy eye (0-4 point) and watery eye (0-4 point). Nasal ocular symptom score consisted of nasal symptom score and ocular symptom score. Nasal ocular symptom score is the sum of nasal symptom score (0-12) and ocular symptom score (0-8) 0 presents no nasal ocular symptom and 20 presents worse outcome. | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Mean Nasal Symptom Medication Score, Mean Ocular Symptom Medication Score, and Mean Nasal Ocular Symptom Medication Score | Medication scores were given for fluticasone propionate (nasal, 2 point), fexofenadine hydrochloride (oral, 1 point), tramazoline hydrochloride (nasal, 1 point), and levocabastine hydrochloride (ocular, 1 point). Symptom medication score consisted of severe symptom period. Nasal symptom medication score is the sum of nasal symptom score and medication score (fexofenadine hydrochloride, fluticasone propionate, tramazoline hydrochloride) Ocular symptom medication score is the sum of ocular symptom score and medication score (fexofenadine hydrochloride, levocabastine hydrochloride) Nasal ocular symptom medication score is the sum of nasal symptom score, ocular symptom score and medication score (fexofenadine hydrochloride, fluticasone propionate, tramazoline hydrochloride, levocabastine hydrochloride). | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Mean Score for Severity of Sneezing, Rhinorrhea and Nasal Congestion | Symptoms of sneezing, rhinorrhea and nasal congestion were evaluated on a scale of 0 (none) to 4 (intense/severe). | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Mean Score for Severity of Itchy and Watery Eye | Symptoms of itchy and watery eye were evaluated on a scale of 0 (none) to 4 (intense/severe). | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Mean Score for Impairment of Daily Activities | Impairment of daily activities were evaluated on a scale of 0 (none) to 4 (intense/severe). | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Number of Symptom Free Days | Nasal symptom free days (days with all nasal symptoms are not more than mild in severity) during the severe symptom period. Ocular symptom free days (days with all ocular symptoms are not more than mild in severity) during the severe symptom period. | Severe symptom period (from 23Feb2018 to 24March2018) | 
| Completely Nasal Symptom Free Patients | Completely nasal symptom free patients is the number of patients who were nasal symptom free (all nasal symptoms were not more than mild in severity) on all non-missing days and had nasal symptom scores for at least 26 days during the 30 days of severe symptom period. | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Rescue Medication Score | Rescue medication scores were given for tramazoline hydrochloride (nasal, 1 point) and levocabastine hydrochloride (ocular, 1 point). Rescue medication score for nasal is medication score for Tramazoline hydrochloride, Rescue medication score for ocular is medication score for Levocabastine hydrochloride and Rescue medication score for nasal and ocular is the sum of medication score for Tramazoline hydrochloride and Levocabastine hydrochlorid | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Rescue Medication Free Days | Number of days with no rescue medication (tramazoline hydrochloride, levocabastine hydrochloride). Nasal ocular rescue medication free days were defined as the days with no use of tramazoline hydrochloride (nasal rescue medication) and levocabastine hydrochloride (ocular rescue medication). | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Number of Rescue Medication Used | Amount number of rescue medication used (a total number of times used). | Severe symptom period (from 23Feb2018 to 24Mar2018) | 
| Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ, No1) Score | Nasal and eye symptoms (JRQLQ I) included 6 categories: Runny nose, Sneezing, Nasal congestion, Itchy nose, itchy eyes and watery eyes, on a 5-point scale of 0 to 4 (no symptoms to very severe symptoms). JRQLQ I score was a mean of these 6 categories. JRQLQ II included 17 items on a 5-point scale, 0 to 4 (no significant problem to very greatly). JRQLQ II scores was a mean of these 17 items. Overall face scale (JRQLQ III) evaluated overall symptoms, condition and feelings on a 5-point scale from 0 to 4 (fine to crying). Evaluation visit was defined as follows independently for each evaluation item and for each patient: 1) If there was a single visit during the severe symptom period, the visit was the evaluation visit. 2) If there were ≥ 2 visits during the severe symptom period and a) if Visit 105 was one of them, Visit 105 was the evaluation visit; b) if Visit 105 was outside the period, the closest visit to Visit 105 during the period was the evaluation visit. | Evaluation Visit, one visit during severe symptom period (23-Feb-2018 to 24-Mar-2018) for each patient | 
| Number of Participants With Anti-omalizumab Antibodes | Number of participants with antibodies against the Fab and Fc region of omalizumab in serum. | Prior to first dosing (Day 1), At follow-up investigation which were conducted 20/22 weeks after 12 week-treatment epoch | 
| Serum Trough Omalizumab Concentration | Blood samples were collected Prior to first dosing (Day 1), at Day 29, Day 57, Day 85 and follow-up investigation which were conducted 20/22 weeks after 12 week-treatment epoch | Prior to first dosing (Day 1), at Day 29, Day 57, Day 85 and 24 weeks after last dose | 
| Free IgE and Total IgE | Blood samples were collected Prior to first dosing (Day 1), at Day 29, Day 57, Day 85 and follow-up investigation were conducted 20/22 weeks after 12 week-treatment epoch | Day 1, at Day 29, Day 57, Day 85 and 24 weeks after last dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cryptomeria, omalizumab, seasonal allergic rhinitis