The Safety and Efficacy of Intralymphatic Immunotherapy in Pollen Allergic Adolescents and Young Adults With Asthma

Study Overview
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Brief Summary
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The study evaluates the safety and efficacy of intralymphatic allergen-specific immunotherapy given to adolescents and young adults who are allergic to grass or birch pollen and have mild or moderate asthma. Patients will be treated with three intralymphatic injections; 1000 SQ-U x3 with 4-5 weeks interval, or placebo with 4-5 weeks interval. The patients receiving treatment will be given a fourth injection one year after the initial injections. The study is conducted in collaboration between Professor Lars Olof Cardell (ENT), prof Gunilla Hedlin (Pediatrics) and prof Marianne van Hage (Immunology).

Detailed Description
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30 patients with seasonal allergic rhinitis due to birch or grass pollen are included. Study subjects are randomized to intralymphatic injections with placebo or ALK Alutard 5-grasses / birch or placebo. The patients receiving treatment will be given a fourth injection one year after the initial injections.

Official Title
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The Safety and Efficacy of Intralymphatic Immunotherapy in Pollen Allergic Adolescents and Young Adults With Asthma: A Randomized Placebo-controlled Trial

Conditions
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Rhinitis, Asthma, Allergy

Intervention / Treatment
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* Drug: ALK Alutard birch or 5-grasses
* Drug: ALK diluent 0,3% human albumin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Allergic rhinitis due to grass or birch pollen Mild to moderate asthma with a positive methacholine challenge Accepted and signed informed consent. Exclusion Criteria: Previously subcutaneous immunotherapy (SCIT) with total symptom relief. Previously SCIT but no symptom improvement at all. Sensitizations to house dust mite or furry animals, with ongoing exposure and symptoms. Severe atopic dermatitis. Patients with significant diseases other than allergic rhinitis. A significant disease is defined as a disease which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study. Patients with a respiratory tract infection in the past 4 weeks prior to Visit 2. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception (i.e., oral contraceptives, intrauterine devices, diaphragm, or subdermal implants). Known autoimmune or collagen disease Cardiovascular disease Hepatic disease Known renal insufficiency Cancer Hematologic disease Chronic infectious disease Any medication with a possible side-effect of interfering with the immune response Previous immuno- or chemotherapy Disease or conditions rendering the treatment of anaphylactic reactions difficult (symptomatic coronary heart diseases, severe arterial hypertension and treatment with β-blockers) Major metabolic disease Known or suspected allergy to the study product Obesity with BMI > 30 since subcutaneous fat makes ultrasound imaging of lymph nodes harder which may risk the correct placement of injection. Patients who, in the opinion of the investigator, abuse alcohol or drugs within 2 years prior to Visit 1. Patients who have taken an investigational drug within 1 month or six half lives, whichever is greater, prior to Visit 1. Mental incapability of coping with the study Withdrawal of informed consent

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>ALK diluent 0,3% human albumin' | Drug: ALK diluent 0,3% human albumin<br>* Intralymphatic injection with 0.1 ml. 3 injections with 4-5 weeks interval<br>* Other names: Human albumin;|
| Experimental: Active treatment<br>Intervention: Drug ALK Alutard birch or 5-grasses. Grass pollen suspension or birch pollen suspension | Drug: ALK Alutard birch or 5-grasses<br>* Intralymphatic injection with 1000 units. 3 injections with 4-5 weeks interval (0,1 ml) and one additional booster injection with 1000 units before the second pollen season.<br>* Other names: ALK Alutard birch pollen or ALK Alutard grass pollen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Symptoms Score After Nasal Allergen Challenge | 0,1 ml of ALK Aquagen birch or timothy 10 000 SQU/ml is deposited in each nostril and allergy symptoms are recorded. Symptoms during NPTs were scored according to the Lebel scoring scale. Symtom scores at 5, 15, and 30 minutes after nasal administration of the allergenextract were summed to represent the symptom-score at each nasal challenge (at inclusion, 12 months after inclusion and for the active patients 24 months after inclusion). The scoring system identifies nasal, eye, and ear symptoms: rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus, watery eyes, and itchy ears, each graded on a scale from 0 to 3 points, and a total score was summarized after subtracting the starting score (min score is 0 and maximum score is 54 + the number of sneezes). Higher scores mean worse outcome. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change on Visual Analogue Scale (VAS | Treatment effect was evaluated by asking the patients to compare their allergic symptoms during the last pollen season with the pollen season before treatment on a visual analogue scale ranging from 0 (unchanged symptoms, no improvement) to 10 (total symptom relief, complete recovery). | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Change in Quality of Life | Difference before and after treatment in Quality of Life. Quality of life was assessed using the Juniper Asthma Quality of Life Questionnaire, giving a score ranging from 1 to 7, and a change in score of 0.5 points is considered clinically relevant. Lower value is considered worse outcome. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Change in Allergen-specific Serum Immunoglobulin E (IgE) Levels Compared to Before Treatment | Allergen-specific IgE levels were measured by ImmunoCAP (Thermo Scientific, Uppsala, Sweden) for birch (t3) and timothy grass (g6) pollen according to the manufacturer's instructions. A cutoff level ≥ 0.35 kUA/L was considered positive. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Change in Asthma Symptom Scores | Asthma control 4 weeks before follow-up was estimated with the asthma control test. The score is based on a questionnaire with 5 questions concerning the patients asthma. Each question can be given a score from 1 to 5 points. The answers for each question is added together, where a minimum score of 5 and a maximum score of 25 can be obtained. Higher scores indicate improved outcome and a score of 19 or less suggests poorly controlled asthma. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Change in Pulmonary Function Measurement (Spirometry) | FEV1 were measured according to international guidelines and results presented in % of predicted values according to the patients height, gender, age and weight. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Changes in Airway Inflammation Assessed by Exhaled Nitric Oxide | Nitric oxide in exhaled air, p.p.b. were measured according to international guidelines, and higher values indicate worse outcome. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Change in Symptom and Medication-score | Modified Symptom scores and Medication score were calculated taking into account the frequency: daily (4 points); every second day (3 points); 1 to 3 days per week (2 points); occasionally (1 point); never (0 points), for the following symptoms: blocked nose, rhinorrhea, fatigue, sneezing, and asthma symptoms, and for the following medications used: local and systemic antihistamines, nasal steroids, asthma medication, and eye drops. A minimum score of 0 and a maximum score of 20 points for symptoms and 16 points for medication could be obtained. Higher values indicate worse outcome. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Changes in Response to a Bronchial Challenge With Methacholine | Methacholine challenge to test the bronchial hyperresponsiveness in the airways of the included subjects. The subject will inhale increasing doses of methacholine. Spirometry is performed before and between each inhalation. The cumulative dose of methacholine needed to elicit at 20% decrease in FEV1 (PD20) is reported. Lower values indicate worse outcome. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). | 
| Change in Allergen-specific Serum Immunoglobulin (Ig) G and Ig4 Levels Compared to Before Treatment | Allergen-specific IgG and IgG4 level was measured by ImmunoCAP (Thermo Scientific, Uppsala, Sweden) for birch (t3) and timothy grass (g6) pollen according to the manufacturer's instructions. A cutoff 2 mg/L for IgG and 0.05 mg/L for IgG4 was considered positive. | At inclusion (pre-treatment), 12 months after inclusion (after first pollen season) and for the active treated patients 24 months after inclusion (after the second pollen season). |