Bias due to withdrawal in long-term randomised trials in COPD: Evidence from the TORCH study

Jørgen Vestbo, Julie Anne Anderson, Peter Mark Anthony Calverley, Bartolomé Celli, Gary Thomas Ferguson, Christine Jenkins, Julie Carol Yates, Paul Wyatt Jones

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Introduction: Randomised controlled trials (RCTs) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published. These usually include drugs with symptomatic benefits and have significant withdrawal rates.

Objectives: We aimed at examining bias due to differential withdrawal in the Towards a Revolution in COPD Health (TORCH) trial.

Methods: We did an observational study nested in the TORCH trial, a placebo‐controlled trial of salmeterol/fluticasone propionate combination (SFC) therapy in chronic obstructive pulmonary disease. We included 3057 patients randomly allocated to placebo or SFC in the analyses. We examined rates of withdrawal from the study and analysed change in effect parameters over time and in relation to withdrawal, as well as medication uptake after withdrawal.

Results: There was differential withdrawal with a significantly higher withdrawal rate from the group allocated to placebo than to SFC, 44% compared with 34%. Regardless of treatment group, withdrawal was associated with worse baseline lung function and more frequent exacerbations, leading to selection of a study population in better health than those originally recruited. As a result, annualized exacerbation rates in the first 6 months of the study compared with the last 6 months of the study decreased from 6.8 to 0.9 in the placebo group and from 3.0 to 0.8 in the SFC group. Also, use of medications under test in the study was frequent in patients after withdrawal.

Conclusion: Significant bias may occur in long‐term RCTs of registered medications with symptomatic benefits as a result of differential withdrawal.
OriginalsprogEngelsk
TidsskriftClinical Respiratory Journal
Vol/bind5
Udgave nummer1
Sider (fra-til)44-49
Antal sider6
ISSN1752-6981
DOI
StatusUdgivet - jan. 2011
Udgivet eksterntJa

Fingeraftryk

Chronic Obstructive Pulmonary Disease
Randomized Controlled Trials
Placebos
Health
Pharmaceutical Preparations
Lung
Salmeterol Xinafoate Drug Combination Fluticasone Propionate
Population

Emneord

  • Bias
  • COPD
  • Lung function
  • Randomised controlled trial
  • Withdrawal

Citer dette

Vestbo, J., Anderson, J. A., Calverley, P. M. A., Celli, B., Ferguson, G. T., Jenkins, C., ... Jones, P. W. (2011). Bias due to withdrawal in long-term randomised trials in COPD: Evidence from the TORCH study. Clinical Respiratory Journal, 5(1), 44-49. https://doi.org/10.1111/j.1752-699X.2010.00198.x
Vestbo, Jørgen ; Anderson, Julie Anne ; Calverley, Peter Mark Anthony ; Celli, Bartolomé ; Ferguson, Gary Thomas ; Jenkins, Christine ; Yates, Julie Carol ; Jones, Paul Wyatt. / Bias due to withdrawal in long-term randomised trials in COPD: Evidence from the TORCH study. I: Clinical Respiratory Journal. 2011 ; Bind 5, Nr. 1. s. 44-49.
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Vestbo, J, Anderson, JA, Calverley, PMA, Celli, B, Ferguson, GT, Jenkins, C, Yates, JC & Jones, PW 2011, 'Bias due to withdrawal in long-term randomised trials in COPD: Evidence from the TORCH study', Clinical Respiratory Journal, bind 5, nr. 1, s. 44-49. https://doi.org/10.1111/j.1752-699X.2010.00198.x

Bias due to withdrawal in long-term randomised trials in COPD: Evidence from the TORCH study. / Vestbo, Jørgen; Anderson, Julie Anne; Calverley, Peter Mark Anthony; Celli, Bartolomé; Ferguson, Gary Thomas; Jenkins, Christine; Yates, Julie Carol; Jones, Paul Wyatt.

I: Clinical Respiratory Journal, Bind 5, Nr. 1, 01.2011, s. 44-49.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Bias due to withdrawal in long-term randomised trials in COPD: Evidence from the TORCH study

AU - Vestbo, Jørgen

AU - Anderson, Julie Anne

AU - Calverley, Peter Mark Anthony

AU - Celli, Bartolomé

AU - Ferguson, Gary Thomas

AU - Jenkins, Christine

AU - Yates, Julie Carol

AU - Jones, Paul Wyatt

PY - 2011/1

Y1 - 2011/1

N2 - Introduction: Randomised controlled trials (RCTs) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published. These usually include drugs with symptomatic benefits and have significant withdrawal rates.Objectives: We aimed at examining bias due to differential withdrawal in the Towards a Revolution in COPD Health (TORCH) trial.Methods: We did an observational study nested in the TORCH trial, a placebo‐controlled trial of salmeterol/fluticasone propionate combination (SFC) therapy in chronic obstructive pulmonary disease. We included 3057 patients randomly allocated to placebo or SFC in the analyses. We examined rates of withdrawal from the study and analysed change in effect parameters over time and in relation to withdrawal, as well as medication uptake after withdrawal.Results: There was differential withdrawal with a significantly higher withdrawal rate from the group allocated to placebo than to SFC, 44% compared with 34%. Regardless of treatment group, withdrawal was associated with worse baseline lung function and more frequent exacerbations, leading to selection of a study population in better health than those originally recruited. As a result, annualized exacerbation rates in the first 6 months of the study compared with the last 6 months of the study decreased from 6.8 to 0.9 in the placebo group and from 3.0 to 0.8 in the SFC group. Also, use of medications under test in the study was frequent in patients after withdrawal.Conclusion: Significant bias may occur in long‐term RCTs of registered medications with symptomatic benefits as a result of differential withdrawal.

AB - Introduction: Randomised controlled trials (RCTs) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published. These usually include drugs with symptomatic benefits and have significant withdrawal rates.Objectives: We aimed at examining bias due to differential withdrawal in the Towards a Revolution in COPD Health (TORCH) trial.Methods: We did an observational study nested in the TORCH trial, a placebo‐controlled trial of salmeterol/fluticasone propionate combination (SFC) therapy in chronic obstructive pulmonary disease. We included 3057 patients randomly allocated to placebo or SFC in the analyses. We examined rates of withdrawal from the study and analysed change in effect parameters over time and in relation to withdrawal, as well as medication uptake after withdrawal.Results: There was differential withdrawal with a significantly higher withdrawal rate from the group allocated to placebo than to SFC, 44% compared with 34%. Regardless of treatment group, withdrawal was associated with worse baseline lung function and more frequent exacerbations, leading to selection of a study population in better health than those originally recruited. As a result, annualized exacerbation rates in the first 6 months of the study compared with the last 6 months of the study decreased from 6.8 to 0.9 in the placebo group and from 3.0 to 0.8 in the SFC group. Also, use of medications under test in the study was frequent in patients after withdrawal.Conclusion: Significant bias may occur in long‐term RCTs of registered medications with symptomatic benefits as a result of differential withdrawal.

KW - Bias

KW - COPD

KW - Lung function

KW - Randomised controlled trial

KW - Withdrawal

U2 - 10.1111/j.1752-699X.2010.00198.x

DO - 10.1111/j.1752-699X.2010.00198.x

M3 - Journal article

VL - 5

SP - 44

EP - 49

JO - Clinical Respiratory Journal

JF - Clinical Respiratory Journal

SN - 1752-6981

IS - 1

ER -