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Bronchodilating effects of a new beclometasone dipropionate plus formoterol fumarate formulation via pressurized metered-dose inhaler in asthmatic children: a double-blind, randomized, cross-over clinical study

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Abstract

A new pediatric fixed combination of beclometasone dipropionate (BDP) 50 μg and formoterol fumarate (FF) 6 μg via pressurized metered-dose inhaler (pMDI) (CHF1535, Chiesi, Italy) was investigated. In a double-blind, randomized, placebo-controlled, cross-over study, a single CHF1535 administration using AeroChamber Plus™ spacer device (2 actuations, total dose BDP 100 μg/FF 12 μg) was compared to the same pMDI free combination in 56 asthmatic children aged ≥ 5 and < 12 years. Primary efficacy variable was forced expiratory volume during the first second (FEV1) area under the curve corrected by time over 12 h following morning dose (AUC0-12h). Further CHF1535 doses (50 μg/6 μg, 100 μg/12 μg, and 200 μg/24 μg) were also explored. Adverse events, electrocardiogram, and vital signs were monitored for safety. CHF1535 was non-inferior to free combination [adjusted mean difference (95% CI) 0.004 L (− 0.050, 0.041] with lower confidence limit greater than the limit set at 0.1 L. FEV1 AUC0-12h of each CHF1535 dose vs placebo were 0.037 L (p = 0.160), 0.119 L (p < 0.001), and 0.094 (p < 0.001) for 50/6, 100/12, and 200/24, respectively. No safety signals were found.

Conclusion: CHF1535 was as effective as free combination BDP/FF, with a trend towards a dose-related response. All treatments were safe.

Trial registration: ClinicalTrials.gov ID: NCT01584492

What is Known:

•Inhaled pressurized metered-dose solutions (pMDI) are the preferred treatment for pediatric asthma.

•Combination therapy of inhaled corticosteroids and long-acting β2- agonists is a well-established approach to control airway inflammation and airway obstruction also in pediatric patients.

What is New:

•A novel pediatric pMDI fixed combination of beclomethasone dipropionate 50 μg and formoterol fumarate 6 μg (CHF 1535) was non-inferior to the free combination at the same dose in pulmonary function over the 12-h post-dose period in asthmatic children, with trend towards a dose-related response.

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Data availability

Study data are available at the archives of the Sponsor Chiesi Farmaceutici S.p.A. (Parma, Italy) and in the Investigator Files at the participating sites according to ICH/GCP Guidelines.

Abbreviations

AEs:

Adverse events

ANCOVA:

Analysis of covariance

AUC:

Area under curve

BDP:

Beclometasone dipropionate

ECG:

Electro-cardiogram

FEV1 :

Forced expiratory volume in 1 s

FF:

Fluticasone furoate

GINA:

Global initiative for asthma

HFA:

Hydro-fluoro-alkane

ICS:

Inhaled corticosteroid

ISMB:

Independent safety monitoring board

ITT:

Intention-to-treat

LABA:

Long-acting beta-2 agonist

pMDI:

Pressurized metered-dose inhaler

PP:

Per population

SAEs:

Serious adverse events

SD:

Standard deviation

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Acknowledgments

The authors would like to thank the patients and their families for their participation in the study as well as Chiesi Farmaceutici S.p.A. (Parma, Italy) for support in conducting this study; CROMSOURCE srl, Via Giorgio De Sandre 3, 37135 Verona (Italy) for the management and periodic monitoring of the clinical sites; BIOMEDICAL SYSTEMS, Waversesteenweg 1945 chaussée de Wavre/B, 1160 Brussels (Belgium), for centralized spirometry and ECG services; and CROS NT srl, Via Germania 2, 37135 Verona (Italy) for data management and statistical analysis. In addition to the authors, the following investigators participated in this clinical trial: Malgorzata Zuronska-Gebala, Specialistic Medical Centre, Tarnow (Poland) and Olga Yablon, Vinnytsya Regional Children Clinical Hospital, Department of Pulmonology, Department of Pediatry No. 1, Vinnytsya 21029 (Ukraine).

Funding

This study was funded funded by the Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43122 Parma (Italy).

Author information

Authors and Affiliations

  1. Paediatric Department, University Hospital Motol, V Uvalu 84, 150 06, Praha, Czech Republic

    Petr Pohunek

  2. Global Clinical Development, Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43122, Parma, Italy

    Guido Varoli, Annamaria Muraro, Elena Carzana & Silvia Armani

  3. Pulmonology Department of Community Institution “Zaporizhzhya Regional Clinical Child Hospital” of Zaporizhzhya Regional Council, Zaporizhzhya State Medical University, 70 Lenina str, Zaporizhzhya, 69063, Ukraine

    Yuriy Reznichenko

  4. City Clinical Hospital № 8, 55, 23rd Lyutogo str., Kryvyi Rog, Ukraine

    Svetlana Mokia-Serbina

  5. Poradnia Alergologiczna, ZOZ Debica, ul., Krakowska 91, 39-200, Debica, Poland

    Jerzy Brzostek

  6. Department of Child Pulmonology and Allergology, State Institution “National Institute of Physiatry and Pulmonology n.a. F.G. Yanovskyy of AMS of Ukraine”, 10, Amosova str., Kyiv, 03680, Ukraine

    Viktoriya Kostromina

  7. 1st City Children Clinical Association of Simferopol City, Department of Pulmonology, Simferopol, Department of Pediatry with Physiotherapy Course of Faculty of Postgraduate Education, State Institution “Crimean State Medical University n.a. S.I. Georgiyivskiy”, 31, K. Libknehta, Simferopol, Crimea, Russia

    Mykola Kaladze

  8. Outpatient Clinic of Allergology, Kopcinskiego Str 22, 90-153, Lodz, Poland

    Jadwiga Kaczmarek

Authors
  1. Petr Pohunek
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  2. Guido Varoli
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  3. Yuriy Reznichenko
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  4. Svetlana Mokia-Serbina
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  5. Jerzy Brzostek
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  6. Viktoriya Kostromina
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  7. Mykola Kaladze
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  8. Annamaria Muraro
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  9. Elena Carzana
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  10. Silvia Armani
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  11. Jadwiga Kaczmarek
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Contributions

Petr Pohunek and Guido Varoli contributed to the study design and management and manuscript medical writing; Annamaria Muraro and Elena Carzana generated the random allocation sequence and supported the data management and statistical analysis; Silvia Armani contributed to the design of the study and study drug packaging and distribution. All the other authors acted as investigators and contributed to the management of the study and data collection. All the authors were involved in the review and editing of the draft manuscript and provided their approval of the final version of the manuscript. Petr Pohunek, the corresponding author, warrants that the manuscript is free of bias.

Corresponding author

Correspondence to Petr Pohunek.

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Conflict of interest

Yuriy Reznichenko, Svetlana Mokia-Serbina, Jerzy Brzostek, Viktoriya Kostromina, Mykola Kaladze, and Jadwiga Kaczmarek all received clinical research funds from Chiesi Farmaceutici S.p.A. as site investigators for this study. Petr Pohunek received funds from Chiesi Farmaceutici S.p.A. as Scientific Coordinating Investigator of the study, lecturer fee from Novartis, TEVA, AstraZeneca and travel grant from Novartis and is a member of the advisory boards of Novartis and GlaxoSmithKline. Guido Varoli, Annamaria Muraro, Elena Carzana, and Silvia Armani are full employees of Chiesi Farmaceutici S.p.A., sponsor of the study.

Ethics approval

The regulatory authorities in each participating country and Ethical Review boards for each institution and prior to registration (ClinicalTrials.gov ID: NCT01584492) approved the study.

Consent to participate

Each patient, parents and/or legal guardian provided with the written informed consent prior to study entry.

Consent for publication

All the authors were involved in the review and editing of the draft manuscript and provided their approval of the final version of the manuscript and consent for its publication.

Additional information

Communicated by Peter de Winter

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Pohunek, P., Varoli, G., Reznichenko, Y. et al. Bronchodilating effects of a new beclometasone dipropionate plus formoterol fumarate formulation via pressurized metered-dose inhaler in asthmatic children: a double-blind, randomized, cross-over clinical study. Eur J Pediatr 180, 1467–1475 (2021). https://doi.org/10.1007/s00431-020-03888-x

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  • DOI: https://doi.org/10.1007/s00431-020-03888-x

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