Efficacy of an Anti-TSLP Monoclonal Antibody in the Management of Chronic Bronchial Disease Induced by Bronchiolitis Obliterans Syndrome in Allogeneic Hematopoietic Stem Cells Transplantation Recipients

Phase 2RecruitingNCT07771855

Hopital Foch36 enrolled

Overview

Allogeneic hematopoietic stem cell transplantation (HSCT) is burdened with a high morbidity and mortality rates. Graft versus host disease (GVHD) is the clinical manifestation of an immune conflict. The expression of GVHD in the bronchioles is responsible for bronchiolitis obliterans syndrome (BOS), defined by the appearance of an obstructive ventilatory disorder. BOS may affect up to 10% of allogeneic transplant recipients. Repeated aggression-repair phenomena of the bronchial epithelium lead to an irreversible fibrous remodeling. The management of BOS remains a therapeutic challenge. A number of patients worsen their ventilatory disorder despite the available treatments and progress to obstructive respiratory failure complicated by repeated bronchial exacerbations. When the patient is far from the allograft and in the absence of any sign of active extrathoracic GVHD, the mechanisms of aggravation of the ventilatory disorder are equivocal. It seems more likely that the bronchial disease evolves on its own due to a persistent local inflammation without any immunological conflict. In this case, it would be reasonable to model the management on that of severe bronchial diseases for which the logic of cortisone sparing is now permitted by the arrival of targeted biotherapies. Since 2006, the therapeutic arsenal of bronchial inflammatory pathologies, mainly asthma, has been enriched with the class of targeted biotherapies. These therapies, targeting IgE (omalizumab), Th2 cytokines IL-5, IL-4, IL-13 (mepolizumab, benralizumab, dupilumab) and more recently the cytokine derived from the bronchial epithelium TSLP (tezepelumab), have shown effectiveness in reducing bronchial exacerbations, improving quality of life and reducing dependence on corticosteroids. TSLP is an alarmin that reflects bronchial epithelial involvement. The objective of this study is to test the performance of an anti-TSLP biotherapy (tezepelumab) in the reduction of bronchial exacerbations in alloHSCT recipients suffering from obstructive bronchial disorders not supposed to be still related to an active GVHD.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

Interventions

TezepelumabDRUG

Participants will receive tezepelumab (TEZSPIRE®) 210 mg by subcutaneous injection once every 4 weeks for 12 months, starting with one injection on the day of enrollment. The investigational product is supplied as a pre-filled syringe containing 210 mg of tezepelumab in 1.91 mL (110 mg/mL). A total of 13 subcutaneous injections are planned during the study. The first injection at enrollment and injections at Visits 4, 7, 10 and 13 will be administered at the investigation center. Injections at Visits 2, 3, 5, 6, 8, 9, 11 and 12 will be administered at the participant's home by a nurse from the Libhéros network.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult recipients, minimum age 18 2. Recipient of an allogeneic bone marrow or haematopoietic stem cell transplant 3. At more than 3 years after the date of the transplantation 4. BOS defined by the occurrence of a new fixed obstructive ventilatory disorder after the allograft (accepted criteria: FEV1/FVC ≤70% and FEV1 \< 75% pred value and decline of more than 10% over less than 2 years OR FEV1/FVC \> 70% and FEV1 \< 75% pred value and decline of FEV1 more than 10% over less than 2 years and Normal TLC \> 80% OR decline of FEV1 more than 10% over less than 2 years and TLC \> 120% and/or RV/TLC \> 40%) 5. Presenting an exacerbation profile: 2 or more moderate to severe bronchial exacerbations in the previous 12 months 6. On optimal inhaled therapy comprising at least one long-acting bronchodilator and one inhaled corticosteroid for at least three months. 7. Stable dose of systemic immunosuppressive regimen for the last 4 weeks 8. Being covered by a national health insurance 9. Signed consent form Exclusion Criteria: 1. Patients with an indication to increase their immunosuppressive treatment, in particular due to active GVH 2. FEV1\< 20% theorical value 3. Being deprived of liberty or under guardianship 4. Absence of signed consent 5. Hypersensitivity (allergy) to tezelumab or to any of the excipients of TEZPIRE 6. A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy 7. Respiratory infection in the course of treatement (including acute bacterial and viral infection, long term treatment for fungal or non-tuberculosis mycobacteria) 8. History of documented immune complex disease (Type III hypersensitivity reactions) following any biologic therapy 9. Severe GVHD scleroderma-like manifestations of skin making subcutaneous injections of the investigational treatment impossible or overly difficult 10. Pregnant, breastfeeding or lactating women

Locations (6)

CHU de Besançon

Besançon, France

NOT_YET_RECRUITING

Hôpital Haut-Lévêque - CHU Bordeaux

Bordeaux, France

NOT_YET_RECRUITING

CHU Caen Normandie

Caen, France

NOT_YET_RECRUITING

CHRU de Lille

Lille, France

NOT_YET_RECRUITING

Hôpital Saint-Louis APHP

Paris, France

NOT_YET_RECRUITING

Foch Hospital

Suresnes, France

RECRUITING

Outcomes

Primary Outcomes

Change in the annualized number of bronchial exacerbations

Within-patient change in the annualized number of bronchial exacerbations between the 12-month period prior to treatment initiation and the 12-month treatment period

Time frame: 13 months

Secondary Outcomes

Number of days alive and without bronchial exacerbation

Number of days during the study period during which the participant is alive and without bronchial exacerbation. Unit of measure: days.

Time frame: 13 months

Number of days alive and without hospitalization

Number of days during the study period during which the participant is alive and without hospitalization.

Time frame: 13 months

Change in corticosteroid regimen

Change in corticosteroid regimen, including inhaled and/or systemic corticosteroid therapy.

Time frame: 13 months

Change in Asthma Control Questionnaire 6 (ACQ-6) score

Change in the Asthma Control Questionnaire 6 (ACQ-6) score during the study period. Unit of measure: score, ranging from 0 to 6.

Time frame: 13 months

Change in Breathlessness, Cough and Sputum Scale (BCSS) score

Change in the Breathlessness, Cough and Sputum Scale (BCSS) total score during the study period. Unit of measure: score, ranging from 0 to 4.

Time frame: 13 months

Change in St George's Respiratory Questionnaire (SGRQ) score

Change in the St George's Respiratory Questionnaire (SGRQ) total score during the study period. Unit of measure: score, ranging from 0 to 100.

Time frame: 13 months

Change in forced expiratory volume in 1 second (FEV1)

Change in forced expiratory volume in 1 second (FEV1), measured by spirometry before and after bronchodilator administration. Unit of measure: liters (L).

Time frame: 13 months

Change in forced expiratory volume in 1 second (FEV1) percent predicted

Change in forced expiratory volume in 1 second (FEV1), expressed as a percentage of the predicted value and measured by spirometry before and after bronchodilator administration. Unit of measure: percent (%).

Time frame: 13 months

Change in forced vital capacity (FVC)

Change in forced vital capacity (FVC), measured by spirometry before and after bronchodilator administration. Unit of measure: liters (L).

Time frame: 13 months

Change in forced vital capacity (FVC) percent predicted

Change in forced vital capacity (FVC), expressed as a percentage of the predicted value and measured by spirometry before and after bronchodilator administration. Unit of measure: percent (%).

Time frame: 13 months

Change in FEV1/FVC ratio

Change in the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), measured by spirometry before and after bronchodilator administration. Unit of measure: ratio (L/L).

Time frame: 13 months

Change in FEV1/FVC ratio expressed as a percentage

Change in the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), measured by spirometry before and after bronchodilator administration. Unit of measure: percent (%).

Time frame: 13 months

Change in total lung capacity (TLC)

Change in total lung capacity (TLC), measured by plethysmography before bronchodilator administration. Unit of measure: liters (L).

Time frame: 13 months

Change in total lung capacity (TLC) percent predicted

Change in total lung capacity (TLC), expressed as a percentage of the predicted value and measured by plethysmography before bronchodilator administration. Unit of measure: percent (%).

Time frame: 13 months

Change in residual volume (RV)

Change in residual volume (RV), measured by plethysmography before bronchodilator administration. Unit of measure: liters (L).

Time frame: 13 months

Change in residual volume (RV) percent predicted

Change in residual volume (RV), expressed as a percentage of the predicted value and measured by plethysmography before bronchodilator administration. Unit of measure: percent (%).

Time frame: 13 months

Change in TLC/RV ratio

Change in the ratio of total lung capacity (TLC) to residual volume (RV), measured by plethysmography before bronchodilator administration. Unit of measure: ratio (L/L).

Time frame: 13 months

Change in respiratory resistance at 5 Hz (R5)

Change in respiratory resistance at 5 Hz (R5), measured by inspiratory and expiratory oscillometry. Unit of measure: not specified in the protocol.

Time frame: 13 months

Change in respiratory resistance at 20 Hz (R20)

Change in respiratory resistance at 20 Hz (R20), measured by inspiratory and expiratory oscillometry. Unit of measure: not specified in the protocol.

Time frame: 13 months

Change in respiratory resistance difference between 20 Hz and 5 Hz (R20-R5)

Change in the difference between respiratory resistance at 20 Hz and 5 Hz (R20-R5), measured by inspiratory and expiratory oscillometry. Unit of measure: not specified in the protocol.

Time frame: 13 months

Change in respiratory reactance at 5 Hz (X5)

Change in respiratory reactance at 5 Hz (X5), measured by inspiratory and expiratory oscillometry. Unit of measure: not specified in the protocol.

Time frame: 13 months

Change in frequency of resonance (Fr)

Change in frequency of resonance (Fr), measured by inspiratory and expiratory oscillometry. Unit of measure: hertz (Hz).

Time frame: 13 months

Change in blood eosinophil count

Change in blood eosinophil count during the study period. Unit of measure: G/L.

Time frame: 13 months

Change in eosinophil count in induced sputum

Change in eosinophil count in induced sputum during the study period. Unit of measure: percent (%).

Time frame: 13 months

Change in blood total IgE level

Change in blood total IgE level during the study period. Unit of measure: kUI/L.

Time frame: 13 months

Annualized hospitalization rate per patient-year

Number of hospitalization events occurring during the study period, standardized per patient-year. Unit of measure: hospitalizations per patient-year.

Time frame: 13 months

Efficacy of an Anti-TSLP Monoclonal Antibody in the Management of Chronic Bronchial Disease Induced by Bronchiolitis Obliterans Syndrome in Allogeneic Hematopoietic Stem Cells Transplantation Recipients

Overview

Conditions

Interventions

Eligibility

Locations (6)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts