Intralymphatic Immunotherapy in Increasing Doses, After Subcutaneous Immunotherapy

Intralymphatic Immunotherapy in Increasing Doses up to 10 000 SQ-U -a Human Randomized Clinical Trial

The study evaluates the safety and effect of intralymphatic allergen specific immunotherapy in increasing doses. Patients that have already undergone subcutaneous immunotherapy will be treated with three intralymphatic injections in increasing doses; 1000 SQ-U, 3000 SQ-U and 10 000 SQ-U, or placebo.

Study Overview

• Status: Completed
• Conditions: Rhinitis, Allergic
• Intervention / Treatment: Drug: ALK diluent; Drug: ALK Alutard birch or 5-grasses

Detailed Description

38 patients with seasonal allergic rhinitis that have recently (within 20 months) ended a full subcutaneous immunotherapy protocol with birch or grass allergen with improvement but not full symptom relief are recruited. Study subjects are randomized to intralymphatic injections with placebo or ALK Alutard 5-grasses or birch.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Sweden
  • Borås, Sweden, 501 82
    • Allergy Unit, Södra Älvsborgs Hospital
  • Malmö, Sweden, 205 02
    • ENT department, Skånes University Hospital Malmö and Lund
  • Stockholm, Sweden, 141 86
    • ENT department, Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-55
• Accepted and signed informed consent.
• Recently (within 20 months) ended a full 3 year program with subcutaneous immunotherapy (SCIT) with amelioration of symptoms but not full symptom relief.

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 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
• Perennial pulmonary disease including asthma
• 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, apart from SCIT
• 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: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: ALK diluent; Human albumin	Drug: ALK diluent; 0,3% human albumin; Other Names: Human albumin
Active Comparator: ALK Alutard birch or 5-grasses; Grass pollen suspension or birch pollen suspension	Drug: ALK Alutard birch or 5-grasses; 3 injections with 4-5 weeks interval.; Other Names: ALK Alutard birch pollen or ALK Alutard grass pollen; ATC-code V01AA, V04CL and V07AB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total daily symptoms and medications score	Difference between active and placebo group in total daily symptoms and medications score during the pollen season.	5-7 months after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement on Visual Analogue Scale (VAS)	Difference in improvement on VAS between active and placebo group.	During pollen season and recalled after pollen season, approximately 1 year after the start of treatment.
Change in skin prick test reactivity	Tested with ALK Soluprick. Measured as the wheal area in millimeter for birch- or grass pollen.	4-8 weeks after treatment, 9-12 months after treatment
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.	4-8 weeks after treatment, 9-12 months after treatment
Difference between active and placebo group in Quality of Life measured with Juniper Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)	At peak pollen season after treatment.	Up to 7 months after treatment.
Difference between active and placebo group in Quality of Life measured with Sino Nasal Outcome Test -22 (SNOT-22)	At peak pollen season after treatment.	Up to 7 months after treatment.
Change in allergen specific S- antibody levels.	IgE, IgG, IgG4	4-8 weeks after treatment, 9-12 months after treatment
Incidence of adverse events graded as mild-moderate-severe		From first injection to 30 days after last injection.

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Karolinska University Hospital; Skane University Hospital; Sodra Alvsborgs Hospital
• Investigators: Principal Investigator: Lars Olaf Cardell, Professor, Karolinska University Hospital

Publications and helpful links

General Publications

• Hellkvist L, Hjalmarsson E, Weinfeld D, Dahl A, Karlsson A, Westman M, Lundkvist K, Winqvist O, Georen SK, Westin U, Cardell LO. High-dose pollen intralymphatic immunotherapy: Two RDBPC trials question the benefit of dose increase. Allergy. 2022 Mar;77(3):883-896. doi: 10.1111/all.15042. Epub 2021 Aug 29.
• Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, McCormack SJ, Simard JJ, Wuthrich B, Crameri R, Graf N, Johansen P, Kundig TM. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17908-12. doi: 10.1073/pnas.0803725105. Epub 2008 Nov 10.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: January 23, 2016
• First Submitted That Met QC Criteria: February 5, 2016
• First Posted (Estimate): February 10, 2016

Study Record Updates

• Last Update Posted (Actual): September 4, 2019
• Last Update Submitted That Met QC Criteria: September 3, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Hypersensitivity, Immediate; Otorhinolaryngologic Diseases; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Rhinitis; Rhinitis, Allergic
• Other Study ID Numbers: 2015-001259-63

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes