The Influence of Nonspecific Immunostimulation on Changes in the Concentration of iNKT Cells

NCT04802616 | Completed Phase 3

• 1 other identifier: KE-0254/251/2020
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of the study is to assess the effect of polyvalent mechanical bacterial lysate (PMBL, Ismigen) on the clinical course of grass pollen-induced allergic rhinitis (using: total nasal symptom score, visual analogue scale, peak nasal inspiratory flow measurement) in children aged 5 to 17 and to assess changes in the concentration of iNKT cells under the influence of the therapy. Half of the 80 participants will receive PMBL while the other half will receive placebo.

Conditions

Allergic Rhinitis Due to Grass Pollen

Keywords

allergic rhinitis; seasonal allergic rhinitis; children; grass pollen season; bacterial lysate; iNKT cells

Outcome Measures

Primary Outcomes (8)

• Change in the severity of nasal SAR symptoms as assessed by total nasal symptom score (TNSS)

  The severity of nasal SAR symptoms (sneezing, runny nose, itchy nose and nasal congestion) will be recorded by parents of children in the daily patient diary using the following scale: 0 = absent (no symptom); 1 = mild (symptom present, easily tolerated); 2 = moderate (awareness of symptom, bothersome but tolerable); 3 = severe (symptoms hard to tolerate, interfere with daily activities and/or sleeping). The total nasal symptom score (sum of the 4 symptom scores) ranges from 0 (no symptoms) to 12 (worst symptoms). Weekly average TNSS values from the baseline period (before the grass pollen season) and obtained 1 month, 2 months, 3 months, 4 months and 5 months after initiating therapy will be used for statistical analysis.

  at baseline, at 1-month, at 2-months, at 3-months, at 4-months and at 5-months

• Change in the nasal obstruction using peak nasal inspiratory flow (PNIF)

  Assessment of the nasal obstruction during two site visits based on measurement of peak nasal inspiratory flow by Youlten Peak Flow Meter (Clement Clarke International, UK). The higher PNIF value, the smaller nasal obstruction.

  at baseline and at 3-months

• Change in the severity of nasal SAR symptoms as assessed by visual analogue scale (VAS)

  Assessment of the severity of nasal SAR symptoms during six visits (2 site visits and 4 telephone visits) with the use of visual analogue scale.The patient will be asked to indicate the severity of nasal SAR symptoms on a 100 mm visual analogue scale, where 0 is no symptoms and 100 the worst possible symptoms.

  at baseline, at 1-month, at 2-months, at 3-months, at 4-months and at 5-months

• iNKT1 cells concentration

  To assess the change in the level of iNKT1 cells (T-bet+IFN-γ+) in the blood.

  at baseline and at 3-months

• iNKT2 cells concentration

  To assess the change in the level of iNKT2 cells (GATA3+IL-4+) in the blood.

  at baseline and at 3-months

• iNKT10 cells concentration

  To assess the change in the level of iNKT10 cells (E4BP4+IL-10+) in the blood.

  at baseline and at 3-months

• iNKT17 cells concentration

  To assess the change in the level of iNKT17 cells (RORγt+IL-17+) in the blood.

  at baseline and at 3-months

• iNKTreg cells concentration

  To assess the change in the level of iNKTreg cells (FoxP3+) in the blood.

  at baseline and at 3-months

Secondary Outcomes (8)

• Frequency of oral H1-antihistamines use

  from baseline, up to the 5-month time point

• Frequency of intranasal corticosteroids use

  from baseline, up to the 5-month time point

• Incidence of treatment emergent adverse events [safety and tolerability]

  from baseline, up to the 5-month time point

• Incidence of treatment emergent adverse events leading to discontinuation [safety and tolerability]

  from baseline, up to the 5-month time point

• Time to discontinuation due to treatment emergent adverse events [safety and tolerability]

  From date of randomization until the date of occurrence of an adverse event leading to discontinuation, assessed up to 5 months

Study Arms (2)

Polyvalent mechanical bacterial lysate

EXPERIMENTAL

Treatment over 3 successive months with one daily sublingual tablet (7 mg of bacterial lysate) over 10 days followed by 20 days of rest.

Drug: Ismigen

Placebo

PLACEBO COMPARATOR

Treatment over 3 successive months with one daily sublingual tablet over 10 days followed by 20 days of rest.

Drug: Placebo

Interventions

Ismigen DRUG

Sublingual tablets containing 7 mg of bacterial lysate from the following bacteria: Staphylococcus aureus, Haemophilus influenzae serotype B, Klebsiella pneumoniae, Klebsiella ozaenae, Neiserria catarrhalis, Streptococcus viridans, Streptococcus pyogenes, Streptococcus pneumoniae (6 strains: TY1/EQ11, TY2/EQ22, TY3/EQ14, TY5/EQ15, TY8/EQ23, TY47/EQ24).

Also known as: Polyvalent mechanical bacterial lysate (PMBL)

Polyvalent mechanical bacterial lysate

Placebo DRUG

Matched tablets without any active substance.

Placebo

Eligibility Criteria

• Age: 5 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children of both genders aged 5 to 17 years.
• Children with grass pollen-induced allergic rhinitis recognized and treated according to current ARIA (Allergic Rhinitis and its Impact on Asthma) recommendations.
• Positive skin prick test to grass pollen allergens or positive specific IgE (defined as ≥ class 2, ≥ 0,70 kU/l) against timothy grass pollen allergens.
• Proper use of polyvalent mechanical bacterial lysate sublingual tablets.
• Not using drugs to alleviate the symptoms of allergic rhinitis in the last 7 days prior to enrollment in the study: intranasal glucocorticosteroids, intranasal, oral and ophthalmic antihistamines, intranasal and oral alpha-mimetics, intranasal anticholinergics, antileukotrienes and cromones.
• Written informed consent obtained from parents/guardians before any study related procedures are performed.

You may not qualify if:

• Patient received mechanical bacterial lysate immunostimulation within the previous 12 months before randomisation visit.
• Patient received chemical bacterial lysate immunostimulation within the previous 6 months before randomisation visit.
• Patient received oral/subcutaneous allergen-immunotherapy within the previous 3 years before the start of the study.
• Other chronic conditions of the nose or nasal sinuses.
• Severe nasal septum deviation.
• Acute respiratory infection in the 2 weeks prior to randomization visit.
• Treatment with systemic corticosteroids within the last 6 months before the start of the study.
• History of transfusion of blood, blood components or blood products.
• Pregnant or breastfeeding woman.
• Other chronic, uncontrolled diseases of the respiratory tract, gastrointestinal tract, urinary system, hematological diseases, immunodeficiency, cancer, cystic fibrosis.

Sponsors & Collaborators

• Medical University of Lublin: lead

Study Sites (1)

Department of Pulmonary Diseases and Children Rheumatology, Medical University of Lublin

Lublin, 20-093, Poland

Location

Related Publications (15)

• Janeczek K, Emeryk A, Rachel M, Duma D, Zimmer L, Poleszak E. Polyvalent Mechanical Bacterial Lysate Administration Improves the Clinical Course of Grass Pollen-Induced Allergic Rhinitis in Children: A Randomized Controlled Trial. J Allergy Clin Immunol Pract. 2021 Jan;9(1):453-462. doi: 10.1016/j.jaip.2020.08.025. Epub 2020 Aug 26.

  PMID: 32858239 BACKGROUND

• Janeczek KP, Emeryk A, Rapiejko P. Effect of polyvalent bacterial lysate on the clinical course of pollen allergic rhinitis in children. Postepy Dermatol Alergol. 2019 Aug;36(4):504-505. doi: 10.5114/ada.2019.87457. Epub 2019 Aug 30. No abstract available.

  PMID: 31616231 BACKGROUND

• Banche G, Allizond V, Mandras N, Garzaro M, Cavallo GP, Baldi C, Scutera S, Musso T, Roana J, Tullio V, Carlone NA, Cuffini AM. Improvement of clinical response in allergic rhinitis patients treated with an oral immunostimulating bacterial lysate: in vivo immunological effects. Int J Immunopathol Pharmacol. 2007 Jan-Mar;20(1):129-38. doi: 10.1177/039463200702000115.

  PMID: 17346436 BACKGROUND

• Meng Q, Li P, Li Y, Chen J, Wang L, He L, Xie J, Gao X. Broncho-vaxom alleviates persistent allergic rhinitis in patients by improving Th1/Th2 cytokine balance of nasal mucosa. Rhinology. 2019 Dec 1;57(6):451-459. doi: 10.4193/Rhin19.161.

  PMID: 31403136 BACKGROUND

• Han L, Zheng CP, Sun YQ, Xu G, Wen W, Fu QL. A bacterial extract of OM-85 Broncho-Vaxom prevents allergic rhinitis in mice. Am J Rhinol Allergy. 2014 Mar-Apr;28(2):110-6. doi: 10.2500/ajra.2013.27.4021.

  PMID: 24717947 BACKGROUND

• Liu C, Huang R, Yao R, Yang A. The Immunotherapeutic Role of Bacterial Lysates in a Mouse Model of Asthma. Lung. 2017 Oct;195(5):563-569. doi: 10.1007/s00408-017-0003-8. Epub 2017 May 4.

  PMID: 28474108 BACKGROUND

• Esposito S, Soto-Martinez ME, Feleszko W, Jones MH, Shen KL, Schaad UB. Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence. Curr Opin Allergy Clin Immunol. 2018 Jun;18(3):198-209. doi: 10.1097/ACI.0000000000000433.

  PMID: 29561355 BACKGROUND

• Emeryk A, Bartkowiak-Emeryk M, Raus Z, Braido F, Ferlazzo G, Melioli G. Mechanical bacterial lysate administration prevents exacerbation in allergic asthmatic children-The EOLIA study. Pediatr Allergy Immunol. 2018 Jun;29(4):394-401. doi: 10.1111/pai.12894.

  PMID: 29575037 BACKGROUND

• Kronenberg M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol. 2005;23:877-900. doi: 10.1146/annurev.immunol.23.021704.115742.

  PMID: 15771592 BACKGROUND

• Carnaud C, Lee D, Donnars O, Park SH, Beavis A, Koezuka Y, Bendelac A. Cutting edge: Cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J Immunol. 1999 Nov 1;163(9):4647-50.

  PMID: 10528160 BACKGROUND

• Oki S, Miyake S. Invariant natural killer T (iNKT) cells in asthma: a novel insight into the pathogenesis of asthma and the therapeutic implication of glycolipid ligands for allergic diseases. Allergol Int. 2007 Mar;56(1):7-14. doi: 10.2332/allergolint.R-06-137. Epub 2007 Jan 29.

  PMID: 17259804 BACKGROUND

• Bennstein SB. Unraveling Natural Killer T-Cells Development. Front Immunol. 2018 Jan 9;8:1950. doi: 10.3389/fimmu.2017.01950. eCollection 2017.

  PMID: 29375573 BACKGROUND

• Gupta RK, Gupta K, Dwivedi PD. Pathophysiology of IL-33 and IL-17 in allergic disorders. Cytokine Growth Factor Rev. 2017 Dec;38:22-36. doi: 10.1016/j.cytogfr.2017.09.005. Epub 2017 Nov 11.

  PMID: 29153708 BACKGROUND

• Coomes SM, Kannan Y, Pelly VS, Entwistle LJ, Guidi R, Perez-Lloret J, Nikolov N, Muller W, Wilson MS. CD4+ Th2 cells are directly regulated by IL-10 during allergic airway inflammation. Mucosal Immunol. 2017 Jan;10(1):150-161. doi: 10.1038/mi.2016.47. Epub 2016 May 11.

  PMID: 27166557 BACKGROUND

• Janeczek K, Kowalska W, Zarobkiewicz M, Suszczyk D, Mikolajczyk M, Markut-Miotla E, Morawska-Michalska I, Bakiera A, Tomczak A, Kaczynska A, Emeryk A, Rolinski J, Piotrowska-Weryszko K. Effect of immunostimulation with bacterial lysate on the clinical course of allergic rhinitis and the level of gammadeltaT, iNKT and cytotoxic T cells in children sensitized to grass pollen allergens: A randomized controlled trial. Front Immunol. 2023 Jan 17;14:1073788. doi: 10.3389/fimmu.2023.1073788. eCollection 2023.

  PMID: 36733480 DERIVED

MeSH Terms

Conditions

Rhinitis, Allergic; Rhinitis, Allergic, Seasonal

Interventions

Broncho-Vaxom

Condition Hierarchy (Ancestors)

Rhinitis; Nose Diseases; Respiratory Tract Diseases; Respiratory Hypersensitivity; Otorhinolaryngologic Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 15, 2021
• First Posted: March 17, 2021
• Study Start: March 22, 2021
• Primary Completion: September 30, 2021
• Study Completion: October 29, 2021
• Last Updated: April 5, 2022

Record last verified: 2021-08

Locations

PL (1)