A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma

Omar S Usmani; Anu Kemppinen; Elizabeth Gardener; Vicky Thomas; Priyanka Raju Konduru; Christina Callan; Andrew McLoughlin; Vanessa Woodhead; Adam Brady; Elizabeth F Juniper; Peter J Barnes; David Price

doi:10.1016/j.jaip.2017.02.006

A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma

Omar S Usmani, Anu Kemppinen, Elizabeth Gardener, Vicky Thomas, Priyanka Raju Konduru, Christina Callan, Andrew McLoughlin, Vanessa Woodhead, Adam Brady, Elizabeth F Juniper, Peter J Barnes, David Price

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Abstract

BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice.

OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients.

METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score.

RESULTS: In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007).

CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

Original language	English
Pages (from-to)	1378-1387.e5
Number of pages	10
Journal	The journal of allergy and clinical immunology. In practice
Volume	5
Issue number	5
Early online date	25 Mar 2017
DOIs	https://doi.org/10.1016/j.jaip.2017.02.006
Publication status	Published - Sept 2017

Bibliographical note

Acknowledgements
We thank the study participants and the principal investigators and staff at the study sites for their contributions (listed in Table E7 in this article's Online Repository at www.jaci-inpractice.org). We are grateful to Optimum Patient Care Ltd research nurses Latife Hardaker, Miriam Cottle, Susanne Skinner, and Amanda Rosenberg and to Interface Clinical Services for site and patient recruitment and conduct of study clinics. We thank the Research in Real Life Ltd study team members Marjan Bojarnejad, Elwira Fidziukiewicz, Clare Fraser, Tahreem Sarwar, Cate Savage, and Natalie Tett for their support in the setup and conduct of the study and Clinical Studies lead Sandra Kreuzaler for study oversight. We also thank Alessandra Cifra for support with medical writing. MedDRA is owned by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) on behalf of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

Keywords

ACQ7
Biomarkers
Combination therapy
Fluticasone
Formoterol
Fractional exhaled nitric oxide
Inhaled corticosteroids
Pragmatic trials
Salmeterol
Step-down
Antiasthmatic agents

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© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
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Cite this

Usmani, O. S., Kemppinen, A., Gardener, E., Thomas, V., Konduru, P. R., Callan, C., McLoughlin, A., Woodhead, V., Brady, A., Juniper, E. F., Barnes, P. J., & Price, D. (2017). A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma. The journal of allergy and clinical immunology. In practice, 5(5), 1378-1387.e5. https://doi.org/10.1016/j.jaip.2017.02.006

Usmani, OS, Kemppinen, A, Gardener, E, Thomas, V, Konduru, PR, Callan, C, McLoughlin, A, Woodhead, V, Brady, A, Juniper, EF, Barnes, PJ & Price, D 2017, 'A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma', The journal of allergy and clinical immunology. In practice, vol. 5, no. 5, pp. 1378-1387.e5. https://doi.org/10.1016/j.jaip.2017.02.006

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title = "A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma",

abstract = "BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice.OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients.METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score.RESULTS: In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007).CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.",

keywords = "ACQ7, Biomarkers, Combination therapy, Fluticasone, Formoterol, Fractional exhaled nitric oxide, Inhaled corticosteroids, Pragmatic trials, Salmeterol, Step-down, Antiasthmatic agents",

author = "Usmani, {Omar S} and Anu Kemppinen and Elizabeth Gardener and Vicky Thomas and Konduru, {Priyanka Raju} and Christina Callan and Andrew McLoughlin and Vanessa Woodhead and Adam Brady and Juniper, {Elizabeth F} and Barnes, {Peter J} and David Price",

note = "Acknowledgements We thank the study participants and the principal investigators and staff at the study sites for their contributions (listed in Table E7 in this article's Online Repository at www.jaci-inpractice.org). We are grateful to Optimum Patient Care Ltd research nurses Latife Hardaker, Miriam Cottle, Susanne Skinner, and Amanda Rosenberg and to Interface Clinical Services for site and patient recruitment and conduct of study clinics. We thank the Research in Real Life Ltd study team members Marjan Bojarnejad, Elwira Fidziukiewicz, Clare Fraser, Tahreem Sarwar, Cate Savage, and Natalie Tett for their support in the setup and conduct of the study and Clinical Studies lead Sandra Kreuzaler for study oversight. We also thank Alessandra Cifra for support with medical writing. MedDRA is owned by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) on behalf of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).",

year = "2017",

month = sep,

doi = "10.1016/j.jaip.2017.02.006",

language = "English",

volume = "5",

pages = "1378--1387.e5",

journal = "The journal of allergy and clinical immunology. In practice",

issn = "2213-2201",

publisher = "Elsevier",

number = "5",

}

TY - JOUR

T1 - A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma

AU - Usmani, Omar S

AU - Kemppinen, Anu

AU - Gardener, Elizabeth

AU - Thomas, Vicky

AU - Konduru, Priyanka Raju

AU - Callan, Christina

AU - McLoughlin, Andrew

AU - Woodhead, Vanessa

AU - Brady, Adam

AU - Juniper, Elizabeth F

AU - Barnes, Peter J

AU - Price, David

N1 - Acknowledgements We thank the study participants and the principal investigators and staff at the study sites for their contributions (listed in Table E7 in this article's Online Repository at www.jaci-inpractice.org). We are grateful to Optimum Patient Care Ltd research nurses Latife Hardaker, Miriam Cottle, Susanne Skinner, and Amanda Rosenberg and to Interface Clinical Services for site and patient recruitment and conduct of study clinics. We thank the Research in Real Life Ltd study team members Marjan Bojarnejad, Elwira Fidziukiewicz, Clare Fraser, Tahreem Sarwar, Cate Savage, and Natalie Tett for their support in the setup and conduct of the study and Clinical Studies lead Sandra Kreuzaler for study oversight. We also thank Alessandra Cifra for support with medical writing. MedDRA is owned by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) on behalf of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

PY - 2017/9

Y1 - 2017/9

N2 - BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice.OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients.METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score.RESULTS: In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007).CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

AB - BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice.OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients.METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score.RESULTS: In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007).CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

KW - ACQ7

KW - Biomarkers

KW - Combination therapy

KW - Fluticasone

KW - Formoterol

KW - Fractional exhaled nitric oxide

KW - Inhaled corticosteroids

KW - Pragmatic trials

KW - Salmeterol

KW - Step-down

KW - Antiasthmatic agents

U2 - 10.1016/j.jaip.2017.02.006

DO - 10.1016/j.jaip.2017.02.006

M3 - Article

C2 - 28351782

SN - 2213-2201

VL - 5

SP - 1378-1387.e5

JO - The journal of allergy and clinical immunology. In practice

JF - The journal of allergy and clinical immunology. In practice

IS - 5

ER -

A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma

Abstract

Bibliographical note

Keywords

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