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

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

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)".

Study Overview

• Status: Completed
• Conditions: Asthma; Allergy; Rhinitis
• Intervention / Treatment: Drug: ALK diluent 0,3% human albumin; Drug: ALK Alutard birch or 5-grasses

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; ALK diluent 0,3% human albumin'	Drug: ALK diluent 0,3% human albumin; Intralymphatic injection with 0.1 ml. 3 injections with 4-5 weeks interval; Other Names: Human albumin
Experimental: Active treatment; Intervention: Drug ALK Alutard birch or 5-grasses. Grass pollen suspension or birch pollen suspension	Drug: ALK Alutard birch or 5-grasses; 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.; Other Names: ALK Alutard birch pollen or ALK Alutard grass pollen

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: Karolinska Institutet

Publications and helpful links

General Publications

• Patterson AM, Bonny AE, Shiels WE 2nd, Erwin EA. Three-injection intralymphatic immunotherapy in adolescents and young adults with grass pollen rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2016 Feb;116(2):168-70. doi: 10.1016/j.anai.2015.11.010. Epub 2015 Dec 17. No abstract available.
• Witten M, Malling HJ, Blom L, Poulsen BC, Poulsen LK. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy? J Allergy Clin Immunol. 2013 Nov;132(5):1248-1252.e5. doi: 10.1016/j.jaci.2013.07.033. Epub 2013 Sep 13. No abstract available.
• Hylander T, Latif L, Petersson-Westin U, Cardell LO. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis. J Allergy Clin Immunol. 2013 Feb;131(2):412-20. doi: 10.1016/j.jaci.2012.10.056.
• Senti G, Crameri R, Kuster D, Johansen P, Martinez-Gomez JM, Graf N, Steiner M, Hothorn LA, Gronlund H, Tivig C, Zaleska A, Soyer O, van Hage M, Akdis CA, Akdis M, Rose H, Kundig TM. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012 May;129(5):1290-6. doi: 10.1016/j.jaci.2012.02.026. Epub 2012 Mar 30.
• Hylander T, Larsson O, Petersson-Westin U, Eriksson M, Kumlien Georen S, Winqvist O, Cardell LO. Intralymphatic immunotherapy of pollen-induced rhinoconjunctivitis: a double-blind placebo-controlled trial. Respir Res. 2016 Jan 27;17:10. doi: 10.1186/s12931-016-0324-9.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2013
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: December 6, 2017
• First Submitted That Met QC Criteria: January 8, 2018
• First Posted (Actual): January 9, 2018

Study Record Updates

• Last Update Posted (Actual): September 28, 2020
• Last Update Submitted That Met QC Criteria: September 25, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Otorhinolaryngologic Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Asthma; Rhinitis
• Other Study ID Numbers: DNR 2012/701 EPN Lund

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No