Safety and Efficacy of Low-dose IL-2 in Birch Pollen Allergy (Rhinil-2)

• ClinicalTrials.gov Identifier: NCT03776643
• Recruitment Status: Completed
• First Posted: December 17, 2018
• Last Update Posted: December 14, 2022
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborator: Iltoo Pharma
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

Brief Summary:

Several studies have reported a deficit and/or a defect in regulatory T cells in allergic subjects, which can be correlated with the allergic responses, especially for respiratory allergies. Low-dose IL-2 (ld-IL2) specifically targets and activates regulatory T cells (Tregs), which are cells that regulate immune responses. Thus by stimulating Tregs, ld-IL2 would control allergic responses.

This study is designed to evaluate the efficacy of ILT-101 (ld-IL-2), compared to placebo, on the nasal response assessed by Total Nasal Symptom Score (TNSS) during a controlled birch allergen exposure.

Condition or disease	Intervention/treatment	Phase
Allergic Rhinoconjunctivitis to Birch Pollen; With a Positive Skin Prick Test to Birch Pollen	Drug: ILT-101 ld-(IL2)	Phase 2

Detailed Description:

Primary objective To evaluate the efficacy of ILT-101 (ld-IL-2), compared to placebo, on nasal response on day 40

Secondary objectives To evaluate the efficacy of ILT-101 on rhino-conjunctivitis symptoms, on inflammatory mediators, allergic specific immune responses and safety.

Experimental design This is a monocentric, randomized, placebo controlled, double-blind trial in parallel-groups, evaluating a treatment by ILT-101/placebo, 1 MIU daily for 5 days and 1 MIU every week, until day 36.

Population involved Male or female, aged between 18 and 55 years, with allergic rhinitis to birch pollen.

Number of subjects: 24

Duration of patient participation: 3 months (treatment period: 36 days months, follow-up period: 34 days)

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Safety/Efficacy
• Masking: Double (Participant, Investigator)
• Masking Description: Double Blind
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of Low-dose IL-2 in Birch Pollen Allergy
• Actual Study Start Date: February 1, 2019
• Actual Primary Completion Date: August 16, 2022
• Actual Study Completion Date: August 16, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: ILT-101 (ld-IL2); Subcutaneous injections of ILT-101	Drug: ILT-101 ld-(IL2); Subcutaneous injections of ILT-101 or Placebo starting with once-daily administration for 5 consecutive days followed by once every two weeks administration during five months; Other Name: Placebo
Placebo Comparator: placebo; Subcutaneous injections of placebo	Drug: ILT-101 ld-(IL2); Subcutaneous injections of ILT-101 or Placebo starting with once-daily administration for 5 consecutive days followed by once every two weeks administration during five months; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change in nasal congestion expressed as area under the curve (AUC), during birch allergen exposure in ALYATEC's Environmental Exposure Chamber (EEC) [ Time Frame: on day 40 ]
   Change in nasal congestion expressed as area under the curve (AUC), during birch allergen exposure in ALYATEC's Environmental Exposure Chamber (EEC)

Secondary Outcome Measures :

1. Change in nasal congestion expressed as area under the curve (AUC), assessed during 4 hours of exposure [ Time Frame: at Day 8 ]
   TNSS, expressed as area under the curve (AUC), assessed during 4 hours of exposure: TOTAL NASAL SYMPTOM SCORE Definition of response choices (drop down menu for each of the 4 questions below) 0 = None 1 = Mild (symptom clearly present but easily tolerated) 2 = Moderate (annoying but tolerable symptom) 3 = Severe (difficult to tolerate symptom, disrupts activities)
2. Change in nasal response intensity [ Time Frame: at Day 8 ]
   determined by Visual Analogue Scale (VAS) ranged from 0 to 10 cm where higher values correspond to more intense symptoms
3. Changes in Tregs expressed in percentag (%) [ Time Frame: at day 8 ]
   Changes in Tregs in percentag compared to baseline
4. Changes in Tregs expressed in percentag (%) [ Time Frame: at day 40 ]
   Changes in Tregs in percentag compared to baseline
5. Changes in Tregs expressed in percentag (%) [ Time Frame: at day 70 ]
   Changes in Tregs in percentag compared to baseline
6. Changes in absolute count in Tregs [ Time Frame: at day 8 ]
   Changes in absolute count in Tregs compared to baseline
7. Changes in absolute count in Tregs [ Time Frame: at day 40 ]
   Changes in absolute count in Tregs compared to baseline
8. Changes in absolute count in Tregs [ Time Frame: at day 70 ]
   Changes in absolute count in Tregs compared to baseline
9. Changes in eosinophils expressed in percentag (%) [ Time Frame: at day 8 ]
   Changes in eosinophils in percentag compared to baseline
10. Changes in eosinophils expressed in percentag (%) [ Time Frame: at day 40 ]
    Changes in eosinophils in percentag compared to baseline
11. Changes in eosinophils expressed in percentag (%) [ Time Frame: at day 70 ]
    Changes in eosinophils in percentag compared to baseline
12. Changes in absolute count in eosinophils [ Time Frame: at day 8 ]
    Changes in absolute count in eosinophils compared to baseline
13. Changes in absolute count in eosinophils [ Time Frame: at day 40 ]
    Changes in absolute count in eosinophils compared to baseline
14. Changes in absolute count in eosinophils [ Time Frame: at day 70 ]
    Changes in absolute count in eosinophils compared to baseline
15. Changes in Inate Lymphoid Cell type 2(ILC2) expressed in percentag (%) [ Time Frame: at day 8 ]
    Changes in Inate Lymphoid Cell type 2 in percentag compared to baseline
16. Changes in Inate Lymphoid Cell type 2(ILC2) expressed in percentag (%) [ Time Frame: at day 40 ]
    Changes in Inate Lymphoid Cell type 2 in percentag compared to baseline
17. Changes in Inate Lymphoid Cell type 2(ILC2) expressed in percentag (%) [ Time Frame: at day 70 ]
    Changes in Inate Lymphoid Cell type 2 in percentag compared to baseline
18. Changes in absolute count in Inate Lymphoid Cell type 2(ILC2) [ Time Frame: at day 8 ]
    Changes (in absolute count in Inate Lymphoid Cell type 2 compared to baseline
19. Changes in absolute count in Inate Lymphoid Cell type 2(ILC2) [ Time Frame: at day 40 ]
    Changes (in absolute count in Inate Lymphoid Cell type 2 compared to baseline
20. Changes in absolute count in Inate Lymphoid Cell type 2(ILC2) [ Time Frame: at day 70 ]
    Changes (in absolute count in Inate Lymphoid Cell type 2 compared to baseline
21. Changes of antigen-specific T-cell immune responses (cytokine IL-4 ) [ Time Frame: at day 40 ]
    cytokine IL-4 at day 40
22. Changes of antigen-specific T-cell immune responses (cytokine IL-4 ) [ Time Frame: at day 70 ]
    cytokine IL-4 at day 70
23. Changes of antigen-specific T-cell immune responses (cytokine IL-5) [ Time Frame: at day 40 ]
    cytokine IL-5 at day 40
24. Changes of antigen-specific T-cell immune responses (cytokine IL-5) [ Time Frame: at day 70 ]
    cytokine IL-5 at day 70
25. Changes of antigen-specific T-cell immune responses [ Time Frame: at day 40 ]
    IL-13 secretion after antigen restimulation at day 40
26. Changes of antigen-specific T-cell immune responses [ Time Frame: at day 70 ]
    IL-13 secretion after antigen restimulation at day 70
27. Changes in allergen-specific IgE dosages basophil activation test with pollen allergen [ Time Frame: at day 40 ]
    allergen-specific IgE dosages at day 40
28. Incidence of adverse events at day 8 [ Time Frame: up to Day 8 ]
    Adverse events throughout the study (according to NCI-CTC AE classification)
29. Incidence of adverse events at day 40 [ Time Frame: up to Day 40 ]
    Adverse events throughout the study (according to NCI-CTC AE classification)
30. Incidence of adverse events at 70 [ Time Frame: up to Day 70 ]
    Adverse events throughout the study (according to NCI-CTC AE classification)

Eligibility Criteria

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

Criteria

Inclusion criteria

• male or female aged between18-55 years
• Positive clinical history of seasonal allergic rhinitis to birch pollen for at least 2 consecutive pollinic seasons before inclusion and requiring medication intake with or without GINA 1 associated asthma, with documentation of sensitivity within 12 months before enrollment by : *Positive skin prick test (SPT) and validated in vitro tests for specific Immunoglobulin E (IgE); *Positive Skin prick test (SPT): wheal for birch pollen ≥ 5 mm in diameter for histamine wheal ≥ 3 mm (positive control) and NaCl reaction < 2 mm (negative control) *Positive specific IgE to birch pollen >0.75 kUI/L;
• Negative beta-HcG pregnancy test at screening visit for women of childbearing age;
• Normal electrocardiogram without clinically significant abnormalities;
• Ability to stay in the EEC for up to 4 hours, without any conditions or factors which could make this not possible
• Positive nasal response (TNSS≥5) at baseline exposure
• Free, informed and written consent signed by the patient and the investigator, before any specific examination required by the study;
• Affiliation to a social security scheme (beneficiary or assignee)
• Negative SARS-CoV-2 test less than 72 hours prior to screening visit

Exclusion Criteria:

• Asthma: GINA 2 to 5
• Eosinophilia > 0.6x109/mL;
• Any history of anaphylactic reactions;
• Specific immunotherapy treatment at the moment, including Omalizumab;
• Specific immunotherapy for birch-pollens within 3 previous years;
• Use of systemic corticosteroid or others immunosuppressive treatment within previous 6 months;
• Moderate to severe allergic rhinoconjunctivitis with or without asthma due to grass pollen, if the study is performed during grass pollen season (according to ARIA)
• Significant rhinitis, or sinusitis, due to daily contact with other allergen causing symptoms that are expected to coincide with exposures, as assessed by the investigator

• Contraindications known to treatment with IL-2:

  • Hypersensitivity to the active substance or to any of the excipients;
  • Immunosuppressed patient;
  • Psychotropic, hepatotoxic, nephrotoxic, myelotoxic or cardiotoxic drugs;
  • Other chronic diseases not clinically controlled;
  • Signs of active infection requiring treatment;
  • Previous history of organ transplantation.
  • Heart failure (≥ grade II, class. NYHA), kidney failure (Cockroft <60 ml/min/1.73m2), liver failure (transaminase> 3N), pulmonary insufficiency (any grade);
• Leukocytes <3000 / mm3 lymphocytes <800 / mm3, platelets <80 000 / mm3, Hemoglobin < 10.0 g/dL or 6.2 mmol/L, red cell blood < 3.5 T/L;
• Positivity of at least one of the thyroid-specific antibodies (anti-TPO, anti-TG, or anti-TRAKS) associated with an abnormal thyroid workup (TSH, T3, or T4) at inclusion;
• Chronic uncontrolled arterial hypertension (Systolic BP > 140 mmHg and/or Diastolic BP > 90 mmHg);
• Poor venous capital will forbid blood samples;
• Vaccination with attenuated live vaccine in the month before the inclusion or planned during the study;
• Vaccination against COVID-19 during the study period or if the 2nd dose of vaccine is planned during the 15 days preceding Visit 3
• Surgery in the previous three months or anticipated under study;
• Participation in other interventional research with study drug in the previous month and during the study;
• Psychiatric illness or any other concomitant chronic illness or addiction that could interfere with the ability to meet the requirements of the protocol or provide informed consent;
• Presence or history of unhealed cancer for more than five years, presence or history of healed cancer for less than five years, except carcinoma in situ of the cervix or basal cell carcinoma;
• Pregnant or lactating women;
• Men and women of childbearing age without effective contraception during the treatment period;

Contacts and Locations

Locations

France

CIC Paris Est GH Pitié Salpétrière

Paris, France, 75013

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Iltoo Pharma

Investigators

• Study Chair: David Klatzmann, Pr; APHP / CIC BTI / Hopital Pitie Salpétrière, Paris

More Information

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT03776643
• Other Study ID Numbers: P 160936J
• First Posted: December 17, 2018
• Last Update Posted: December 14, 2022
• Last Verified: December 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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