Analysis of outcome in retrieved dropout patients in a Rivastigmine vs Placebo, 26-week, Alzheimer disease trial

Martin Farlow, Steven Potkin, Barbara Koumaras, Jeffrey Veach, Dario Mirski

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Background: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. Objective: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine. Design and Methods: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Results: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called "off drug") for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n=17) compared with the rivastigmine 6- to 12-mg/d group (n=33) at week 26 (MMSE score, -8.2 vs -3.0; P=.009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n=38) compared with the rivastigmine 6- to 12-mg/d group (n=88) at week 26 (MMSE score, -5.69 vs -2.5; P=.004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P=.007, P=.009) and the pooled studies (P=.002, P=.017). Conclusions: After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.

Original languageEnglish
Pages (from-to)843-848
Number of pages6
JournalArchives of Neurology
Volume60
Issue number6
DOIs
StatePublished - Jun 1 2003

Fingerprint

Rivastigmine
Patient Dropouts
Alzheimer Disease
Placebos
Cognition
Cholinesterase Inhibitors
Therapeutics
Placebo
Alzheimer's Disease
Drop out
Cognitive Therapy

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Analysis of outcome in retrieved dropout patients in a Rivastigmine vs Placebo, 26-week, Alzheimer disease trial. / Farlow, Martin; Potkin, Steven; Koumaras, Barbara; Veach, Jeffrey; Mirski, Dario.

In: Archives of Neurology, Vol. 60, No. 6, 01.06.2003, p. 843-848.

Research output: Contribution to journalArticle

Farlow, Martin ; Potkin, Steven ; Koumaras, Barbara ; Veach, Jeffrey ; Mirski, Dario. / Analysis of outcome in retrieved dropout patients in a Rivastigmine vs Placebo, 26-week, Alzheimer disease trial. In: Archives of Neurology. 2003 ; Vol. 60, No. 6. pp. 843-848.
@article{01d16fa143804df2a0ccf23e9cca2080,
title = "Analysis of outcome in retrieved dropout patients in a Rivastigmine vs Placebo, 26-week, Alzheimer disease trial",
abstract = "Background: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. Objective: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine. Design and Methods: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Results: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called {"}off drug{"}) for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n=17) compared with the rivastigmine 6- to 12-mg/d group (n=33) at week 26 (MMSE score, -8.2 vs -3.0; P=.009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n=38) compared with the rivastigmine 6- to 12-mg/d group (n=88) at week 26 (MMSE score, -5.69 vs -2.5; P=.004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P=.007, P=.009) and the pooled studies (P=.002, P=.017). Conclusions: After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.",
author = "Martin Farlow and Steven Potkin and Barbara Koumaras and Jeffrey Veach and Dario Mirski",
year = "2003",
month = "6",
day = "1",
doi = "10.1001/archneur.60.6.843",
language = "English",
volume = "60",
pages = "843--848",
journal = "Archives of Neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "6",

}

TY - JOUR

T1 - Analysis of outcome in retrieved dropout patients in a Rivastigmine vs Placebo, 26-week, Alzheimer disease trial

AU - Farlow, Martin

AU - Potkin, Steven

AU - Koumaras, Barbara

AU - Veach, Jeffrey

AU - Mirski, Dario

PY - 2003/6/1

Y1 - 2003/6/1

N2 - Background: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. Objective: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine. Design and Methods: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Results: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called "off drug") for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n=17) compared with the rivastigmine 6- to 12-mg/d group (n=33) at week 26 (MMSE score, -8.2 vs -3.0; P=.009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n=38) compared with the rivastigmine 6- to 12-mg/d group (n=88) at week 26 (MMSE score, -5.69 vs -2.5; P=.004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P=.007, P=.009) and the pooled studies (P=.002, P=.017). Conclusions: After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.

AB - Background: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. Objective: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine. Design and Methods: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Results: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called "off drug") for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n=17) compared with the rivastigmine 6- to 12-mg/d group (n=33) at week 26 (MMSE score, -8.2 vs -3.0; P=.009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n=38) compared with the rivastigmine 6- to 12-mg/d group (n=88) at week 26 (MMSE score, -5.69 vs -2.5; P=.004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P=.007, P=.009) and the pooled studies (P=.002, P=.017). Conclusions: After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.

UR - http://www.scopus.com/inward/record.url?scp=0038796988&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038796988&partnerID=8YFLogxK

U2 - 10.1001/archneur.60.6.843

DO - 10.1001/archneur.60.6.843

M3 - Article

C2 - 12810489

AN - SCOPUS:0038796988

VL - 60

SP - 843

EP - 848

JO - Archives of Neurology

JF - Archives of Neurology

SN - 0003-9942

IS - 6

ER -