Efficacy and Safety Evaluation for the Treatment of HDM Induced Allergic Asthma and Rhinitis/Rhinoconjunctivitis

Prospective, Randomised, DBPC, Double-dummy, Multicenter CT of Efficacy and Safety With IT in Patients With Controlled Mild to Moderate Allergic Asthma and Rhinitis/Rhinoconjunctivitis, Allergic to D. Pteronyssinus and/or D. Farinae.

Prospective, randomized, placebo-controlled, multicenter of 3 active treatment groups, compared to 1 placebo group, for the determination of the efficacy and safety of subcutaneous immunotherapy in patients with mild to moderate asthma and rhinitis/rhinoconjunctivitis (intermittent or persistent) allergic to Dermatophagoides pteronyssinus and/or Dermatophagoides farinae.

Study Overview

• Status: Not yet recruiting
• Conditions: Perennial Allergic Rhinitis; Allergic Asthma; Allergic Rhinoconjunctivitis; House Dust Mite Allergy
• Intervention / Treatment: Biological: Placebo subcutaneous; Biological: MM09 allergoid-mannan conjugates subcutaneous (3.000 UTm/mL); Biological: Placebo sublingual; Biological: MM09 allergoid-mannan conjugates Sublingual (3.000 UTm/mL); Biological: MM09 allergoid-mannan conjugates Sublingual (9.000 UTm/mL)

Detailed Description

Prospective multicenter randomized double-dummy clinical trial of three active treatment groups compared to one placebo group. The principal objective of the clinical trial is the determination of the efficacy and safety of subcutaneous immunotherapy in patients with mild to moderate asthma and rhinitis/rhinoconjunctivitis (intermittent or persistent) allergic to Dermatophagoides pteronyssinus and/or Dermatophagoides farinae.

The primary efficacy endpoint will be the symptom score and medication consumption required for the control of asthma and rhinitis/rhinoconjunctivitis symptoms.

The study design consists of 3 active treatment groups and one placebo group. The trial population will include 400 subjects between the age of 12 and 60 years that will receive the treatment during 12 months.

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Miguel Casanovas, MD, PhD; Phone Number: 0034 912908942; Email: mcasanovas@inmunotek.com

Study Locations

• Spain
  • A Coruña, Spain, 15006
    • Hospital Universitario A Coruña
    • Contact: Antonio Parra Arrondo, MD, PhD
  • Alicante, Spain, 03010
    • Hospital General Universitario de Alicante
    • Contact: Luis Moral, MD, PhD
  • Alicante, Spain, 03015
    • Centro Médico Quiron Salud Alicante
    • Contact: Angel Ferrer, MD, PhD
  • Melilla, Spain, 52006
    • Clínica RUSADIR
    • Contact: Oliver Alexis Muñoz Daga, MD, PhD
  • Málaga, Spain, 29010
    • Hospital Universitario Regional de Malaga
    • Contact: Carmén Rondón, MD, PhD
  • Málaga, Spain, 29004
    • Hopital Quirón Salud Málaga
    • Contact: Leticia Herrero Lifona, MD, PhD
  • Málaga, Spain, 29005
    • Clinica del Dr.Pérez Estrada Cornejo
    • Contact: Manuel Pérez Estrada Cornejo, MD. PhD
  • Pontevedra, Spain, 36071
    • Complexo Hospitalario Universitario de Pontevedra
  • Valencia, Spain, 46026
    • Hospital Univeristario y Politécnico La Fe
  • Vila-real, Spain, 12540
    • Hospital Universitario de La Plana
    • Contact: Francisco David El-Qutob López, MD. PhD
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital universitario de Elche
  • Baleares
    • Ibiza, Baleares, Spain, 07800
      • Policlínica Nuestra Sra del Rosario
      • Contact: Silvia Martínez Blanco, MD, PhD
  • Barcelona
    • Esplugues De Llobregat, Barcelona, Spain, 08950
      • Hospital Sant Joan de Déu
      • Contact: Adriana Machinena, MD. PhD
    • Terrassa, Barcelona, Spain, 08227
      • Hospital de Terrassa
      • Contact: Marta Viñas, MD. PhD
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Hospital Universitario de Navarra
      • Contact: Ana Isabel Tabar Purroy, MD. PhD
  • Santa Cruz De Tenerife
    • San Cristóbal de La Laguna, Santa Cruz De Tenerife, Spain, 38320
      • Hospital Universitario de Canarias
      • Contact: Inmaculada Sánchez Machin, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed and dated Informed Consent Form (ICF).
2. Female or male aged 12 to 60 years, both included.
3. Confirmed clinical history of inhalation allergy (mild-moderate controlled intermittent or persistent asthma according to the definition of GEMA 5.0 and GINA 2020 and intermittent or persistent rhinitis / rhinoconjunctivitis according to the ARIA classification, caused by Dermatophagoides pteronyssinus and / or Dermatophagoides farinae). The asthma diagnosis will be valid up to 24 months prior to signing the informed consent.
4. Positive skin prick test (wheal major diameter ≥ 5 mm) to a standardized allergen extract of Dermatophagoides pteronyssinus and/or Dermatophagoides farinae.
5. Specific IgE against a complete extract of D. pteronyssinus and/or D. farinae or any of the molecular components of allergenic sources with a value ≥ 3.5 kU/L.
6. Women of childbearing age must have a urine pregnancy test negative result before enrolling the study.
7. Women of childbearing age must commit to using an adequate contraception method.
8. Capable of complying with dosage regimen.
9. Owning a smartphone to register symptoms and medication consumption.
10. A negative skin prick test to other aeroallergens with specific IgE < 3.5 kU/L with no clinical relevance.

Exclusion Criteria:

1. Previous immunotherapy to any of the tested allergen during the last 5 years or any desensitization process in the last 2 years (ITO, milk, egg, ...) or currently receiving immunotherapy with any other allergen.
2. Positive skin prick test to other aeroallergens, except for intermittent symptoms due to temporary exposition to dander.
3. Those cases in which AIT would be a contraindication according to the criteria of European Allergy and Clinical Immunology Immunotherapy Subcommittee.
4. Uncontrolled or severe asthma and/or FEV1 <70% despite pharmacological treatment by the time of enrolment.
5. Intake of β-blockers.
6. Use of immunosuppressive or biological drug.
7. Unstable patients by the time of enrolment (acute exacerbation asthma, respiratory infection, fever, acute pruritus, etc).
8. Patients who have suffered chronic urticaria during the last 2 years, severe anaphylaxis, or family history of angioedema.
9. Having any contraindication for the use of adrenaline (hyperthyroidism, heart disease, high blood pressure).
10. Other severe diseases not related to allergic asthma or rhinitis that could interfere in the study treatment or the follow-up (epilepsy, psychomotor agitation, diabetes, malformations, nephropathy) according to medical criteria.
11. Autoimmune diseases (thyroiditis, lupus, etc.), tumoral diseases or immunodeficiencies.
12. Participants that the investigator believes could not comply with the study protocol or have serious psychiatric disorders.
13. Known allergy to any of the ingredients of the study medication except for mites.
14. Lower respiratory tract diseases different from asthma as bronchiectasis or chronic obstructive pulmonary disease.
15. Breast-feeding or pregnant women.
16. Being immediate family of the investigator.
17. Concurrent participation in other clinical trials or prior participation within 30 days prior to inclusion.
18. History of serious systemic reactions, including food, Hymenoptera venom, medications, etc.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group I: MM09 allergoid-mannan conjugates SC (3.000 UTm/mL) + sublingual placebo; Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 3,000 UTm/mL subcutaneous immunotherapy + sublingual placebo. Subcutaneous active treatment will be administered once a month for 12 months. Sublingual placebo will be administered daily (2 subsequent administrations) for 12 months.	Biological: MM09 allergoid-mannan conjugates subcutaneous (3.000 UTm/mL); Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 3.000 UTm/mL for subcutaneous administration.; Biological: Placebo sublingual; The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.
Experimental: Group II: MM09 allergoid-mannan conjugates SL (3.000 UTm/mL) + subcutaneous placebo; Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan sublingual immunotherapy at 3.000 UTm/mL + subcutaneous placebo. Sublingual active treatment will be administered daily (2 subsequent administrations) for 12 months. Subcutaneous placebo will be administered once a month for 12 months.	Biological: Placebo subcutaneous; The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.; Biological: MM09 allergoid-mannan conjugates Sublingual (3.000 UTm/mL); Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 3.000 UTm/mL for sublingual administration.
Experimental: Group III: MM09 allergoid-mannan conjugates SL (9.000 UTm/mL) + subcutaneous placebo; Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan sublingual immunotherapy at 9.000 UTm/mL + subcutaneous placebo. Sublingual active treatment will be administered daily (2 subsequent administrations) for 12 months. Subcutaneous placebo will be administered once a month for 12 months.	Biological: Placebo subcutaneous; The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.; Biological: MM09 allergoid-mannan conjugates Sublingual (9.000 UTm/mL); Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 9.000 UTm/mL for sublingual administration.
Placebo Comparator: Group IV: Placebo; Mixture of sublingual placebo + subcutaneous placebo. Sublingual placebo will be administered daily (2 subsequent administrations) for 12 months. Subcutaneous placebo will be administered once a month for 12 months	Biological: Placebo subcutaneous; The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.; Biological: Placebo sublingual; The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSMS: Combined Symptoms and Medication Score	Evaluation of the number of symptoms and the consumption of medication necessary for the control of such symptoms in asthma and rhinitis / rhinoconjunctivitis of each subject during the trial, of the groups with each other and with respect to placebo. - The endpoint for each asthma and rhinitis / rhinoconjunctivitis symptom will be as follows: 0 = No symptoms; 1 = Mild; 2 = Moderate; 3 = Severe Total daily symptom score = 0-3 The asthma medication will be scored based on the therapeutic step in which drugs are included in the GEMA 5 guide. The rhinitis / rhinoconjunctivitis medication score: 0 = No medication; 1 = oral or topical (eyes or nose) non-sedative H1 antihistamines (H1A); 2 = intranasal corticosteroids (INS) with / without H1A; 3 = oral corticosteroids with/without (INS), with/without H1A Total daily medication score = 0-3	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Asthmatic exacerbations	Time elapsed until the first appearance of asthmatic exacerbations, number, duration and severity.	12 months
Consumption of health resources	For each patient, the number of times that due to allergy symptoms has done the following will be counted: have visited the family doctor; have made an unscheduled visit to the specialist; has gone to the emergency room; has been hospitalized; have needed to contact the doctor by phone	12 months
Asthma symptom-free days	Number of days that subjects have no symptoms related to asthma	12 months
Rhinitis / rhinoconjunctivitis symptom-free days	Number of days that subjects have no symptom related to rhinitis / rhinoconjunctivitis.	12 months
Asthma medication-free days	Number of days that subjects need no medication for treatment of asthma.	12 months
Rhinitis / rhinoconjunctivitis medication-free days	Number of days that subjects need no medication for treatment of Rhinitis / rhinoconjunctivitis.	12 months
Respiratory function_FEV1	Measurement of Forced Expiratory Volume in 1 Second (FEV1) %	Baseline, month 6, month 12
Respiratory function_PEF	Peak Expiratory Flow (PEF) [velocity]	Baseline, month 6, month 12
Clinical benefit	Time to onset of clinical benefit	12 months
Immunological parameters	Analyses of total and specific IgE, specific IgE index / total IgE, specific IgG4 and Anti-Saccharomyces cerevisiae (ASCA) IgA&IgG.	12 months
Quality of life associated with asthma (AQLQ)	The quality of life associated with asthma will be measured using the Asthma Quality of Life Questionnaire (AQLQ). AQLQ consists of 32 items and 4 domains (limitations in activities, symptoms, emotional and environmental). Each item is scored from 1=no impairment to 7=severe impairment.	12 months
Quality of life associated with rhinoconjunctivitis (RQLQ)	The quality of life associated with rhinoconjunctivitis will be measured using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RQLQ it consists of 28 items (questions) and 7 domains (Activities, sleep, general symptoms, practical problems, nose symptoms, eye and emotional symptoms). The score of each item for all domains, except for the emotional one, ranges from "0=Nothing bothered me" to "6=It has bothered me a lot". The emotional domain score ranges from "0=Never" to "6=Always".	Baseline, month 6, month 12
Questionnaire for asthma control (ACQ)	Asthma control will be measured following the ACQ questionnaire. The ACQ questionnaire consists of 7 questions (ACQ-7) or 6 questions (ACQ-6). In questions 1-6, patients recall their experience during the last 7 days and answer using a scale of 7 points (from "0 = fully controlled" to "6 = extremely poorly controlled"). The seventh question, which refers to the% FEV1 of the reference value, must be completed by an employee of the site. The questionnaire score is the mean of the 7 responses (ACQ-7) or 6 responses (ACQ-6). The interpretation of the scores is as follows: Less than or equal to 0.75: Adequate control of asthma From 0.75 to 1.50: Partially controlled asthma More than 1.50: Inadequate asthma control	12 months
Visual Analogue Scale (VAS)	Visual Analogue Scale in which the subject has to indicate in a straight line of 10 cm how he/she feels regarding to his allergy symptoms. Being left side "0 = very bad" and right side "10 = very well". VAS scale will also be completed by the investigator answering how he/she thinks that the patient feels.	12 months
Safety parameters	Global rate and severity of AE per administration and per subject	12 months
Number of Local Adverse Reactions	Local adverse reactions are those that appear at the site of the administration. They are classified into: Immediate (it appears during the first 30 minutes from the administration of investigational product) and Late (it appears after the first 30 minutes from the administration of investigational product)	12 months
Number of Systemic Adverse Reactions	Systemic adverse reactions are those that appear in other parts of the body other than the site of administration.Their severity will be classified following the indications proposed by the World Allergy Organization (WAO) in 2010.	12 months

Collaborators and Investigators

• Sponsor: Inmunotek S.L.
• Collaborators: BioClever 2005 S.L.; NTS hub S.L
• Investigators: Principal Investigator: Ana Isabel Tabar Purroy, MD. PhD, Hospital Universitario de Navarra

Publications and helpful links

General Publications

• Sirvent S, Soria I, Cirauqui C, Cases B, Manzano AI, Diez-Rivero CM, Reche PA, Lopez-Relano J, Martinez-Naves E, Canada FJ, Jimenez-Barbero J, Subiza J, Casanovas M, Fernandez-Caldas E, Subiza JL, Palomares O. Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1. J Allergy Clin Immunol. 2016 Aug;138(2):558-567.e11. doi: 10.1016/j.jaci.2016.02.029. Epub 2016 Apr 13.
• Soria I, Alvarez J, Manzano AI, Lopez-Relano J, Cases B, Mas-Fontao A, Canada FJ, Fernandez-Caldas E, Casanovas M, Jimenez-Barbero J, Palomares O, Vinals-Florez LM, Subiza JL. Mite allergoids coupled to nonoxidized mannan from Saccharomyces cerevisae efficiently target canine dendritic cells for novel allergy immunotherapy in veterinary medicine. Vet Immunol Immunopathol. 2017 Aug;190:65-72. doi: 10.1016/j.vetimm.2017.07.004. Epub 2017 Jul 23.
• Benito-Villalvilla C, Soria I, Subiza JL, Palomares O. Novel vaccines targeting dendritic cells by coupling allergoids to mannan. Allergo J Int. 2018;27(8):256-262. doi: 10.1007/s40629-018-0069-8. Epub 2018 May 18. Review.
• Manzano AI, Javier Canada F, Cases B, Sirvent S, Soria I, Palomares O, Fernandez-Caldas E, Casanovas M, Jimenez-Barbero J, Subiza JL. Structural studies of novel glycoconjugates from polymerized allergens (allergoids) and mannans as allergy vaccines. Glycoconj J. 2016 Feb;33(1):93-101. doi: 10.1007/s10719-015-9640-4. Epub 2015 Nov 25.
• Soria I, Lopez-Relano J, Vinuela M, Tudela JI, Angelina A, Benito-Villalvilla C, Diez-Rivero CM, Cases B, Manzano AI, Fernandez-Caldas E, Casanovas M, Palomares O, Subiza JL. Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice. Allergy. 2018 Apr;73(4):875-884. doi: 10.1111/all.13396. Epub 2018 Jan 31.
• Gonzalez JL, Zalve V, Fernandez-Caldas E, Cases B, Subiza JL, Casanovas M. A pilot study of immunotherapy in dogs with atopic dermatitis using a mannan-Dermatophagoides farinae allergoid targeting dendritic cells. Vet Dermatol. 2018 Oct;29(5):449-e152. doi: 10.1111/vde.12679.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2022
• Primary Completion (Anticipated): July 1, 2024
• Study Completion (Anticipated): July 1, 2025

Study Registration Dates

• First Submitted: May 27, 2022
• First Submitted That Met QC Criteria: May 27, 2022
• First Posted (Actual): June 2, 2022

Study Record Updates

• Last Update Posted (Actual): November 18, 2022
• Last Update Submitted That Met QC Criteria: November 17, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Allergy; Immunotherapy; Rhinitis/ Rhinoconjunctivitis; Mild to moderate asthma
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Eye Diseases; Bronchial Diseases; Otorhinolaryngologic Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Conjunctival Diseases; Asthma; Rhinitis; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Conjunctivitis
• Other Study ID Numbers: MM09-SIT-040

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No