Analysing time to event data in dementia prevention trials: The example of the guidage study of EGB761®

Autor: P.H. Robert, François Piette, Jacques Touchon, Pierre-Jean Ousset, Hélène Mathiex-Fortunet, B. Scherrer, Gilles Berrut, Florence Pasquier, Bruno Dubois, Jean-François Dartigues, Pierre Garnier, Bruno Vellas, Sandrine Andrieu
Přispěvatelé: CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Bordeaux Ségalen [Bordeaux 2], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Cognition Behaviour Technology (CobTek), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice)-Université Côte d'Azur (UCA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ipsen [Boulogne Billancourt] (Ipsen), IPSEN, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Male
medicine.medical_specialty
Medicine (miscellaneous)
Subgroup analysis
01 natural sciences
law.invention
010104 statistics & probability
03 medical and health sciences
0302 clinical medicine
Physical medicine and rehabilitation
Randomized controlled trial
Alzheimer Disease
Memory
law
Outcome Assessment
Health Care
Post-hoc analysis
Statistics
Humans
Medicine
030212 general & internal medicine
0101 mathematics
Aged
Proportional Hazards Models
Memory Disorders
Nutrition and Dietetics
Plant Extracts
business.industry
Proportional hazards model
[SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology
Hazard ratio
Late effect
Ginkgo biloba
Clinical trial
Log-rank test
Research Design
Dementia
Female
Geriatrics and Gerontology
medicine.symptom
business
[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Zdroj: Journal of Nutrition, Health and Aging
Journal of Nutrition, Health and Aging, Springer Verlag (Germany), 2015, pp.1009-11. ⟨10.1007/s12603-015-0582-0⟩
ISSN: 1279-7707
1760-4788
DOI: 10.1007/s12603-015-0582-0⟩
Popis: International audience; Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761 can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer's type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761 treatment group (p = 0.0054), suggesting a late effect of EGb761. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761 explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time.
Databáze: OpenAIRE
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