Design and Analysis of Studies to Assess the Effect of Inhaled Corticosteroids on Growth
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Drug Information Journal. Vol. 34, pp. 397-409,Zoo0 F’rinted in the USA. All rights reserved.
DESIGN AND ANALYSIS OF STUDIES TO ASSESS THE EFFECT OF INHALED CORTICOSTEROIDS ON GROWTH SUSANP. DUKE,MS Senior Statistician, U S Clinical Statistics, Glaxo Wellcome Inc., Research Triangle Park, North Carolina
SARAH. HUGHES,MSc Principal Statistician, UK Clinical Statistics, Glaxo Wellcome plc, Uxbridge, United Kingdom
PATRICK F. DARKEN, PHD Statistician, US Clinical Statistics, Glaxo Wellcome Inc., Research Triangle Park, North Carolina
COLINREISNER,MD, FCCP, FACAAI Senior Clinical Program Head, US Respiratory Clinical Development, Glaxo Wellcome Inc., Research Triangle Park, North Carolina
Assessment of child growth is problematic: growth is nonlinear in the long-term, and unpredictable in the short-term; growth is subject to a number of environmental as well as genetic influences; and growth is diflcult to measure reliably. The potential for growth delay as an effect of asthma is established, although it has proved difficult to quantify how great an impact this has on height, growth velociv, orfinal attained height. I n the treatment of asthmatic children, there remain uncertainties as to the effect of inhaled corticosteroids on growth, given the great number of factors affecting growth. I n this paper we present recommendations for the design and analysis of trials to assess the effect of regular treatment with inhaled corticosteroids on growth in asthmatic children. Design recommendations are articulated for study duration, entry criteria, other factors that may affect growth, measuring height, measuring growth, study objectives, and considerations relating to confounding between treatment allocation and the effect of the disease on growth. Special attention is given to analyses that address both the intra-subject correlation arising from multiple measurements in longitudinal studies of growth and the potential bias in treatment comparisons due to dropouts, especially those due to treatment failure. Key Words: Growth; Study design; Statistical analysis; Mixed model; Inhaled corticosteroids; Asthma
INTRODUCTION IN is a complex process and is influenced by a number of factors (1-5). Corticosteroids are
Reprint address: Susan P. Duke, Glaxo Wellcome Inc., MALB256, Five Moore Drive, PO BOX 13398, Research Triangle Park, NC 27709-3398.
an effective means of treating asthma. It has long been known, however, that oral corticosteroids have a systemic effect (1,6,7) and can reduce growth when used for short periods or over prolonged periods of time. Inhaled corticosteroids treat the airways topically in the lungs and are the recommended therapy for long-term control of asthma in children with moderate and severe disease,
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Susan P. Duke, Sara H. Hughes, Patrick F. Darken, and Colin Reisner
as well as one of the therapeutic options for It is essential to have a well-designed trial children with mild persistent disease (8). in which a
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