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Efficacy of Fluticasone Propionate Associated With Salmeterol Using Inhalation Chamber Versus Placebo to Improve the Respiratory Function in Children Over Six Years of Age Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation With a Decline of FEV1 ≥10% From Pre Transplantation (RESPPEDOBS)

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ClinicalTrials.gov Identifier: NCT04655508
Recruitment Status : Recruiting
First Posted : December 7, 2020
Last Update Posted : June 8, 2021
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Bronchiolitis Obliterative Syndrome (BOS) is the primary noninfectious pulmonary complication after hematopoietic stem cell transplantation (HSCT) and usually carries a poor prognosis. It occurs in about 10% of children underwent HSCT. The National Institutes of Health (NIH) published guidelines and criteria for the diagnosis of BOS. BOS defined by spirometric criteria according to modified NIH consensus guidelines: FEV1 < 75% predicted and a greater than 10% decline from pretransplant baseline, and FEV1/FVC <0.7 (FCV: Forced Vital Capacity). Nevertheless Cheng and al. indicate that the magnitude of FEV1 decline before diagnosis exceeded the diagnostic requirement of a greater than 10% decline compared with baseline FEV. Moreover, the decline in FEV1 prior to BOS diagnosis appeared to occur within 6 months for those patients. Recent studies suggest that any intervention should be targeted during the FEV1 decline, and before the diagnosis of BOS. For this, inhalated treatment are used: Bergeron et al. reported improvements in symptoms as well in FEV1 one month followed treatment including formoterol and budesonide in a prospective trial including adults (12% increase of FEV1 for 62% adults). Williams and al. in another prospective adult's cohort, showed that the association between fluticasone, montelukast and azythromycin was associated with stable lung function, reduced systemic corticosteroids, and improved quality of life at 3 months for adults with BOS.

In our national French prospective cohort which include 300 children with HSCT from 2014 to 2017 (RESPPEDHEM Programme Hospitalier de Recherche Clinique 2012), 35% of children presented a decline of FEV1≥ 10% without BOS criteria (FEV1 < 75% and FEV1/FVC <0.7). Among them, some received combination of corticoids and long acting beta agonists for 6 months. Children with this type of inhalated treatment improved their FEV1 to 88.1% predicted while children without any treatment have a FEV1 at 80.7% predicted. Our hypothesis is that association of Fluticasone Propionate and Salmeterol can be used as a treatment of the decline of FEV1 for children and so prevent BOS.


Condition or disease Intervention/treatment Phase
Stem Cell Transplant Complications Respiratory Disease Bronchiolitis Obliterans Drug: Seretide Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 243 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Efficacy of Fluticasone Propionate Associated With Salmeterol Using Inhalation Chamber Versus Placebo to Improve the Respiratory Function in Children Over Six Years of Age Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation With a Decline of FEV1 ≥10% From Pre Transplantation
Actual Study Start Date : May 21, 2021
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2024


Arm Intervention/treatment
Experimental: Seretide

For children between 6 to 11 years (< 12 years): 50 μg inhaled fluticasone propionate and 25 μg salmeterol (SERETIDE® 50/25) :two puffs twice a day from randomisation during 6 months using inhalation chamber

- For children between 12 to 17 years (> or = 12 years) : 125 μg inhaled fluticasone propionate and 25 μg salmeterol (SERETIDE® 125/25): two puffs twice a day from randomisation during 6 months using inhalation chamber

Drug: Seretide

For children between 6 to 11 years (< 12 years): 50 μg inhaled fluticasone propionate and 25 μg salmeterol (SERETIDE® 50/25) :two puffs twice a day from randomisation during 6 months using inhalation chamber

- For children between 12 to 17 years (> or = 12 years) : 125 μg inhaled fluticasone propionate and 25 μg salmeterol (SERETIDE® 125/25): two puffs twice a day from randomisation during 6 months using inhalation chamber


Placebo Comparator: placebo
For children between 6 to 11 years (< 12 years): placebo of SERETIDE® 50/25 :two puffs twice a day from randomisation during 6 months using inhalation chamber For children between 12 to 17 years (> or = 12 years) : placebo of SERETIDE® 125/25: two puffs twice a day from randomisation during 6 months using inhalation chamber
Drug: Placebo
For children between 6 to 11 years (< 12 years): placebo of SERETIDE® 50/25 :two puffs twice a day from randomisation during 6 months using inhalation chamber For children between 12 to 17 years (> or = 12 years) : placebo of SERETIDE® 125/25: two puffs twice a day from randomisation during 6 months using inhalation chamber




Primary Outcome Measures :
  1. FEV: Forced Expiratory Volume in 1 second [ Time Frame: The primary criterion will be measured at months 0, 1, 3, 6, 9 and 12. ]
    The primary criterion will be the change in the FEV1% predicted value from inclusion to 6 months following the initiation of treatment


Secondary Outcome Measures :
  1. Graft Versus Host Disease [ Time Frame: The criterion will be measured at months 0, 1, 3, 6, 9 and 12. ]
    GVHD occurrence (Acute and Chronic GVHD manifestations defined on NIH consensus with scoring), First line of treatment: cumulative dose of corticosteroid systemic exposure and cumulative dose of calcineurins inhibitors and Second line of GVHD treatment exposure will be assessed using the other type of treatment

  2. Dyspnea [ Time Frame: The criterion will be measured at months 0, 1, 3, 6, 9 and 12. ]
    dyspnea will be evaluate at the NYHA scoring from I to IV (I: none, IV: symptomatic at rest)

  3. Step Test [ Time Frame: The criterion will be measured at months 0, 1, 3, 6, 9 and 12. ]
    step test: Respiratory rate, dyspnea Heart rate, SaO2 during the exercise.

  4. Bronchiolitis Obliterative Syndrome [ Time Frame: The criterion will be measured at months 0, 1, 3, 6, 9 and 12. ]
    The investigators will measure the number of patients presented with Bronchiolitis Obliterative Syndrome

  5. Adverse events [ Time Frame: The criterion will be measured at months 0, 1, 3, 6, 9 and 12. ]
    The investigators will measure the Occurrence of infections

  6. Pulmonary function [ Time Frame: FEV1 will be measured at months 0, 1, 3, 6, 9 and 12 ]
    A plethysmography will be performed to measured pulmonary parameters: FEV1 (Forced Expiratory Volume)

  7. Pulmonary function [ Time Frame: VC will be measured at months 0, 1, 3, 6, 9 and 12 ]
    A plethysmography will be performed to measured pulmonary parameters: VC (Vital Capacity)

  8. Pulmonary function [ Time Frame: TLC will be measured at months 0, 1, 3, 6, 9 and 12 ]
    A plethysmography will be performed to measured pulmonary parameters: TLC (Total Lung Capacity)

  9. Pulmonary function [ Time Frame: RV will be measured at months 0, 1, 3, 6, 9 and 12 ]
    A plethysmography will be performed to measured pulmonary parameters: RV (Residual Volume)

  10. Pulmonary function [ Time Frame: FRC will be measured at months 0, 1, 3, 6, 9 and 12 ]
    A plethysmography will be performed to measured pulmonary parameters: FRC (Functional Residual Capacity)

  11. Pulmonary function [ Time Frame: sRaw will be measured at months 0, 1, 3, 6, 9 and 12 ]
    A plethysmography will be performed to measured pulmonary parameters: sRaw (Specific airway resistance)

  12. Pulmonary function [ Time Frame: DLCO will be measured at months 0, 1, 3, 6, 9 and 12 ]
    A plethysmography will be performed to measured pulmonary parameters: DLCO (Diffusing Capacity of the Lungs)



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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Children and adolescent aged 6 to 17 years
  • Getting an Allo Hematopoietic cell stem transplantation
  • Provide written informed consent from legal guardian
  • Covered by medical insurance (social security ou CMU).

Randomisation criteria:

- Decline of FEV1 ≥ 10% from pre transplantation between M3 and M12 after the transplantation, confirmed over two functional test performed one week apart, without Bronchiolitis Obliterative Syndrome international criteria, neither initiation of inhaled treatment from transplantation to randomization visit.

Exclusion Criteria:

  • Patients with no affiliation to a social security scheme (beneficiary or legal)
  • Pregnancy
  • Asthma defined by reversibility with salbutamol (FEV1 > 12% or FEV1> 200ml) under inhaled corticosteroids or long acting beta agonists during the last three months
  • Patients with hypersensitivity to the active substances: salmeterol, fluticasone propionate, or to the excipients: norflurane.

Non-Randomisation criteria :

  • Viral respiratory infection (fever ≥ 38°C, tachypnea according to age, positive viral PCR (Polymerase Chain Reaction) pharyngeal aspiration) during the last month;
  • Lower respiratory tract infection (fever ≥ 38°C, tachypnea, radiologically or echography confirmed pneumonia, sputum) during the last month;
  • Invasive fungal disease (as defined by European Organisation for Research and Treatment of Cancer/Mycoses Study Group consensus group) during the last month.
  • Potent cytochrome P450 3A4 inhibitors, such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir and nefazodone.
  • Corticosteroids or bronchodilatators inhaled treatment after transplantation
  • Bronchiolitis Obliterative Syndrome

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04655508


Contacts
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Contact: Véronique Houdouin, Doctor 01 40 03 36 78 ext +33 veronique.houdouin@aphp.fr
Contact: Christophe Delclaux, Professor 01 40 03 41 90 ext +33 christophe.delclaux@aphp.fr

Locations
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France
Houdouin véronique Recruiting
Paris, France, 75019
Contact: houdouin véronique, MD PHD    0140033678    veronique.houdouin@rdb.aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
GlaxoSmithKline
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04655508    
Other Study ID Numbers: P180600
First Posted: December 7, 2020    Key Record Dates
Last Update Posted: June 8, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bronchiolitis
Respiration Disorders
Respiratory Tract Diseases
Bronchiolitis Obliterans
Bronchitis
Respiratory Tract Infections
Infections
Bronchial Diseases
Lung Diseases, Obstructive
Lung Diseases
Fluticasone-Salmeterol Drug Combination
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Sympathomimetics