A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer's disease and Parkinson's disease

David J. M. McGhee; Craig W. Ritchie; John P. Zajicek; Carl E. Counsell

doi:10.1186/s12883-016-0606-3

A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer's disease and Parkinson's disease

David J. M. McGhee, Craig W. Ritchie, John P. Zajicek, Carl E. Counsell

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Abstract

Background
Disease-modification clinical trials in neurodegenerative disorders have struggled to separate symptomatic effects of putative agents from disease-modification. In response, a variety of clinical trial designs have been developed. A systematic review was undertaken to examine which trial designs have been used in Alzheimer’s disease (AD) and Parkinson’s disease (PD) to detect disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed to identify novel clinical trial designs used in the past or planned for use in the future. We aimed to critique whether the methods used would have identified true disease-modification.

Methods
MEDLINE, Embase and CENTRAL (1980–2015) were searched to identify papers meriting review in full. ClinicalTrials.gov was searched to identify unpublished or planned randomised controlled trials (RCTs). We included RCTs in PD or AD which aimed to demonstrate the disease-modifying properties of drug therapy and differentiate that benefit from any symptomatic effect.

Results
128 RCTs were finally included: 84 in AD (59 published, 25 unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial designs were applied including long-term follow-up, wash-in and wash-out analyses, randomised delayed-start, the use of time-to-event outcome measures and surrogate disease progression biomarkers. Deficiencies in each of these design strategies, the quantity of missing data in included RCTs and the methods used to deal with missing data, meant that none of the included studies convincingly demonstrated disease-modification. No truly novel clinical trial designs were identified.

Conclusion
We currently believe that the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.

Original language	English
Article number	92
Pages (from-to)	1-13
Number of pages	13
Journal	BMC Neurology
Volume	16
DOIs	https://doi.org/10.1186/s12883-016-0606-3
Publication status	Published - 16 Jun 2016

Bibliographical note

Acknowledgements

This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0707-10124). The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report or for the decision to submit for publication.

Keywords

Alzheimer's disease
Parkinson's disease
disease progression
biomarkers
clinical trials
neuroprotective agents

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10.1186/s12883-016-0606-3Licence: CC BY

A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer’s disease and Parkinson’s disease
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Final published version, 549 KBLicence: CC BY

Cite this

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abstract = "BackgroundDisease-modification clinical trials in neurodegenerative disorders have struggled to separate symptomatic effects of putative agents from disease-modification. In response, a variety of clinical trial designs have been developed. A systematic review was undertaken to examine which trial designs have been used in Alzheimer{\textquoteright}s disease (AD) and Parkinson{\textquoteright}s disease (PD) to detect disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed to identify novel clinical trial designs used in the past or planned for use in the future. We aimed to critique whether the methods used would have identified true disease-modification.MethodsMEDLINE, Embase and CENTRAL (1980–2015) were searched to identify papers meriting review in full. ClinicalTrials.gov was searched to identify unpublished or planned randomised controlled trials (RCTs). We included RCTs in PD or AD which aimed to demonstrate the disease-modifying properties of drug therapy and differentiate that benefit from any symptomatic effect.Results128 RCTs were finally included: 84 in AD (59 published, 25 unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial designs were applied including long-term follow-up, wash-in and wash-out analyses, randomised delayed-start, the use of time-to-event outcome measures and surrogate disease progression biomarkers. Deficiencies in each of these design strategies, the quantity of missing data in included RCTs and the methods used to deal with missing data, meant that none of the included studies convincingly demonstrated disease-modification. No truly novel clinical trial designs were identified.ConclusionWe currently believe that the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.",

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note = "Acknowledgements This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0707-10124). The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report or for the decision to submit for publication.",

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AU - McGhee, David J. M.

AU - Ritchie, Craig W.

AU - Zajicek, John P.

AU - Counsell, Carl E.

N1 - Acknowledgements This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0707-10124). The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report or for the decision to submit for publication.

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N2 - BackgroundDisease-modification clinical trials in neurodegenerative disorders have struggled to separate symptomatic effects of putative agents from disease-modification. In response, a variety of clinical trial designs have been developed. A systematic review was undertaken to examine which trial designs have been used in Alzheimer’s disease (AD) and Parkinson’s disease (PD) to detect disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed to identify novel clinical trial designs used in the past or planned for use in the future. We aimed to critique whether the methods used would have identified true disease-modification.MethodsMEDLINE, Embase and CENTRAL (1980–2015) were searched to identify papers meriting review in full. ClinicalTrials.gov was searched to identify unpublished or planned randomised controlled trials (RCTs). We included RCTs in PD or AD which aimed to demonstrate the disease-modifying properties of drug therapy and differentiate that benefit from any symptomatic effect.Results128 RCTs were finally included: 84 in AD (59 published, 25 unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial designs were applied including long-term follow-up, wash-in and wash-out analyses, randomised delayed-start, the use of time-to-event outcome measures and surrogate disease progression biomarkers. Deficiencies in each of these design strategies, the quantity of missing data in included RCTs and the methods used to deal with missing data, meant that none of the included studies convincingly demonstrated disease-modification. No truly novel clinical trial designs were identified.ConclusionWe currently believe that the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.

AB - BackgroundDisease-modification clinical trials in neurodegenerative disorders have struggled to separate symptomatic effects of putative agents from disease-modification. In response, a variety of clinical trial designs have been developed. A systematic review was undertaken to examine which trial designs have been used in Alzheimer’s disease (AD) and Parkinson’s disease (PD) to detect disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed to identify novel clinical trial designs used in the past or planned for use in the future. We aimed to critique whether the methods used would have identified true disease-modification.MethodsMEDLINE, Embase and CENTRAL (1980–2015) were searched to identify papers meriting review in full. ClinicalTrials.gov was searched to identify unpublished or planned randomised controlled trials (RCTs). We included RCTs in PD or AD which aimed to demonstrate the disease-modifying properties of drug therapy and differentiate that benefit from any symptomatic effect.Results128 RCTs were finally included: 84 in AD (59 published, 25 unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial designs were applied including long-term follow-up, wash-in and wash-out analyses, randomised delayed-start, the use of time-to-event outcome measures and surrogate disease progression biomarkers. Deficiencies in each of these design strategies, the quantity of missing data in included RCTs and the methods used to deal with missing data, meant that none of the included studies convincingly demonstrated disease-modification. No truly novel clinical trial designs were identified.ConclusionWe currently believe that the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.

KW - Alzheimer's disease

KW - Parkinson's disease

KW - disease progression

KW - biomarkers

KW - clinical trials

KW - neuroprotective agents

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DO - 10.1186/s12883-016-0606-3

M3 - Article

SN - 1471-2377

VL - 16

SP - 1

EP - 13

JO - BMC Neurology

JF - BMC Neurology

M1 - 92

ER -

A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer's disease and Parkinson's disease

Abstract

Bibliographical note

Keywords

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Cite this