Safety and Efficacy Study of Intralymphatic Allergen-specific Immunotherapy

Study Overview
=================
Brief Summary
-----------------
Allergen-specific immunotherapy (ASIT) is commonly used to treat patients with allergic rhino-conjunctivitis and asthma, and it is the only proven treatment that affects the long-term development of allergic rhinitis and asthma. The current treatment regime of ASIT requires numerous subcutaneous allergen injections and takes several years to complete. Hence, there is a need to develop more convenient protocols for induction of allergen tolerance. Emerging evidence suggest that by targeting of antigen presenting cells within the lymph nodes the immunogenicity of the allergen can be enhanced and the number of injections can be reduced. The purpose of this study is to evaluate whether intralymphatic administration of ASIT is a safe and effective treatment for patients with pollen-induced allergic rhinitis. The long term goal is to provide a base for a more efficient administration of ASIT, which will reduce both the dose necessary and the number of clinic visits associated with the conventional subcutaneous ASIT. The investigators will make an attempt to reproduce the results of a recent human study of intralymphatic ASIT (clinicaltrials.gov; NCT00470457) in a Swedish clinical setting. The first part of the study is completed and published (PMID: 23374268)

Detailed Description
-----------------
In the first part of the study safety and clinical efficacy of ALK Alutard Birch or 5-grass have been evaluated in a RCT with 50 patients. Active patients recieve 3 injections with 1000 SQ-U ALK Alutard or 5-grasses in a lymph node in the groin. Dose interval 4 weeks. This part of the study is completed and published (PMID: 23374268) In the second part of the study 60 patients participates in a RCT with intralymphatic injections with both ALK Alutard Birch AND ALK Alutard 5-grasses. The injections are given intralymphatically with one allergen in each groin with 30 minutes observation between injections. Dose and dose interval are the same as in the first part of the study; the active group recieves 1000 SQ-U ALK Alutard Birch in right groin and 1000 SQ-U 5-grasses in left groin. The injections are given 3 times with 4 weeks interval. Enrollment and treatment is completed and the results will be evaluated in the autumn 2015.

Official Title
-----------------
Intralymphatic Allergen-specific Immunity as a New Administration Route for Treatment of Pollen-induced Allergic Diseases

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

Intervention / Treatment
-----------------
* Drug: ALK Alutard Birch and/or 5-grasses
* Drug: ALK Diluent


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-50, Seasonal allergic symptoms for birch and/or grass verified by skin prick test, Accepted informed consent Exclusion Criteria: Pregnancy or nursing Autoimmune or collagen disease (known) Cardiovascular disease Perennial pulmonary disease Hepatic disease Renal disease Cancer Any medication with a possible side-effect of interfering with the immune response Previous immuno- or chemotherapy Chronic diseases Other upper airway disease (non-allergic sinusitis, nasal polyps, chronic obstructive and restrictive lung disease) 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 Alcohol or drug abuse Mental incapability of coping with the study Withdrawal of informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ALK Alutard Birch and/or 5-grasses<br>3 intralymphatic injections with dose 1000 SQ-U and dose interval 4 weeks. | Drug: ALK Alutard Birch and/or 5-grasses<br>* 3 intralymphatic injections of 1000 SQ-U birch and/or grass allergen with 4 weeks interval. The substance used for the three intralymphatic injections is ALK-alutard SQ Betula verrucosa® and ALK-alutard SQ 5-grasses ® under ATC-code V01AA, V04CL and V07AB which is a depot formulation for subcutaneous use.<br>* Other names: ALK Alutard Betula Verrucosa and ALK Alutard 5-grasses;|
| Placebo Comparator: ALK diluent<br>3 intralymphatic injections with dose interval 4 weeks. | Drug: ALK Diluent<br>* This placebo group will receive 3 injections of 0.3% human albumin instead of active substance<br>* Other names: Human albumin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in subjective allergic symptoms following nasal allergen provocation | The study subjects will be intranasally challenged with allergen and symptom score questionnaires are filled out pre-provocation and 5, 10 and 30 min post-provocation. | Before treatment, an average of 4 weeks after completed treatment and 6-9 months after treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Registration of adverse event |  | from the first injection to 30 days after the last injections has been given | 
| Effects on quality of life | SNOT-22 questionnaire | During peak pollen season which will be up to 5 months (birch) and 6 months (grass) after completed treatment | 
| Effects on quality of life | Juniper RQLQ questionnaires | During peak pollen season which will be up to 5 months (birch) and 6 months (grass) after completed treatment | 
| Change in medicine consumption during pollen season | After the pollen season patients report to what extension they have been using medications; more, the same or less. The mediacations asked about are antihistamine tablets, antihistamine eye drops, nasal steroid, steroid tablets, b2-bronchodilator inhalation, leucotrien receptor antagonist, nasal or ocular sodium chromoglycates. | 6-9 months after treatment. | 
| Change in symptoms at pollen season | After the pollen season at the 6-9 months follow up patients recall the pollen season and rates the improvement on an arbitrary scale ranging 0-10 with 0 as no improvement at all and 10 total symptom relief. | 6-9 months after treatment. | 
| Short term improvement of skin reactivity | Skin prick test | Before treatment, an average of 4 weeks after completed treatment and 6-9 months after treatment. | 
| S-IgE Birch |  | Before treatment, approximately 4 weeks after completed treatment and 6-9 months after treatment | 
| S-IgE Grass |  | Before treatment, approximately 4 weeks after completed treatment and 6-9 months after treatment | 
| S-IgG4 Grass |  | Before treatment, approximately 4 weeks after completed treatment and 6-9 months after treatment | 
| S-IgG4 Birch |  | Before treatment, approximately 4 weeks after completed treatment and 6-9 months after treatment |