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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.72 no.6 São Paulo June 2014

http://dx.doi.org/10.1590/0004-282X20140055 

Articles

Effects of galantamine and galantamine combined with nimodipine on cognitive speed and quality of life in mixed dementia: a 24-week, randomized, placebo-controlled exploratory trial (the REMIX study)

Efeitos da galantamina e da galantamina combinada à nimodipina sobre a velocidade de processamento cognitivo e qualidade de vida na demência mista: ensaio clínico exploratório, randomizado e controlado com placebo (estudo REMIX)

Paulo Caramelli 1  

Jerson Laks 2  

André Luis Fernandes Palmini 3  

Ricardo Nitrini 4  

Márcia Lorena Fagundes Chaves 5  

Orestes Vicente Forlenza 6  

Francisco de Assis Carvalho do Vale 7  

Maira Tonidandel Barbosa 1   8  

Cássio Machado de Campos Bottino 9  

João Carlos Machado 8  

Helenice Charchat-Fichman 10  

Fabio Lorea Lawson 11  

1Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte MG, Brazil;

2Centro de Doença de Alzheimer e outras Desordens Mentais na Velhice, Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ, Brazil;

3Serviço de Neurologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre RS, Brazil;

4Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo SP, Brazil;

5Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil;

6Laboratório de Neurociências LIM-27, Departamento e Instituto de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo SP, Brazil;

7Liga de Neurologia Cognitiva e Comportamental, Universidade Federal de São Carlos, Sao Carlos SP, Brazil;

8Instituto de Ensino e Pesquisa do Envelhecimento, Departamento de Medicina Geriátrica, Hospital Mater Dei; Faculdade de Ciências Médicas de Minas Gerais, Belo Horizonte MG, Brazil;

9Programa Terceira Idade, Departamento e Instituto de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo SP, Brazil;

10Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro RJ, Brazil;

11Janssen-Cilag Farmacêutica Ltda., Sao Paulo SP, Brazil.


ABSTRACT

The effects of galantamine (GAL) on quality of life (QoL) and cognitive speed, as well its effects combined with nimodipine (NIM) in Alzheimer disease (AD) with cerebrovascular disease (mixed dementia), have not been explored.

Method

: Double-blind, placebo-controlled, multicenter Brazilian trial, studying the effects of GAL/NIM vs. GAL/placebo (PLA) in mild to moderate mixed dementia. Patients were randomized to receive GAL/NIM or GAL/PLA for 24 weeks. Primary efficacy measures were changes on a computerized neuropsychological battery (CNTB) and QoL Scale in Alzheimer's Disease (QoL-AD) from baseline to week 24.

Results

: Twenty-one patients received at least one drug dose (9 GAL/NIM and 12 GAL/PLA). Groups were matched for age, sex, education, cognitive and QoL scores at baseline. No significant differences were observed between groups on primary or secondary measures. QoL and cognitive performance showed significant improvement (p<0.05) from baseline when all GAL-treated patients were analyzed. Adverse events were predominantly mild to moderate.

Conclusion

: GAL treatment improved QoL in mixed dementia, in addition to its previously known cognitive benefits. The combination GAL/NIM was not advantageous. However, the small sample size precludes any definitive conclusions. Trial registered at ClinicalTrials.gov: NCT00814658

Key words: Alzheimer disease; cerebrovascular disorders; galantamine; nimodipine

RESUMO

Os efeitos da galantamina (GAL) sobre qualidade de vida (QdV) e velocidade de processamento cognitivo, bem como da combinação com nimodipina (NIM) no tratamento da doença de Alzheimer (DA) com doença cerebrovascular (demência mista) ainda não foram investigados.

Método

: Estudo multicêntrico brasileiro, duplo-cego, controlado com placebo, avaliando os efeitos de GAL/NIM x GAL/placebo (PLA) na demência mista leve a moderada. Pacientes receberam tratamento com GAL/NIM ou GAL/PLA por 24 semanas. Medidas de eficácia primária foram as variações no desempenho em bateria de testes neuropsicológicos computadorizados e na escala QdV-DA ao final do estudo.

Resultados

: Vinte um pacientes receberam pelo menos uma dose da droga (9 GAL/NIM e 12 GAL/PLA). Os grupos foram emparelhados por idade, sexo, escolaridade, escores cognitivos e de QdV na linha de base. Não foram observadas diferenças significativas entre os dois grupos nas medidas de eficácia primária e secundária. Na avaliação de todos os pacientes que receberam GAL, houve melhora significativa (p<0,05) em QdV-DA e desempenho cognitivo. Os eventos adversos foram predominantemente leves a moderados.

Conclusão

: O tratamento com GAL proporcionou melhora da QdV na demência mista, além dos benefícios cognitivos previamente conhecidos. A combinação GAL/NIM não foi vantajosa. O reduzido tamanho amostral impede conclusões definitivas.

Palavras-Chave: doença de Alzheimer; desordens cerebrovasculares; galantamina; nimodipina

Mixed dementia (defined as an association of both Alzheimer disease – AD – and cerebrovascular disease – CVD) is a common cause of dementia worldwide1. It is usually underdiagnosed and, according to a Brazilian study, mixed dementia is the second most frequent cause of dementia among people aged ≥65 years in the country, being responsible for circa 14% of all cases2.

There is still a lack of well-established therapeutic options for patients with this condition based on high quality evidence. Most studies have investigated the efficacy and safety of different agents on each condition separately (AD or CVD)3,4,5, even though the association of AD and CVD is well documented in the medical literature6.

Ischemic lesions seem to play a prominent role in cognitive decline, even in the presence of AD pathology. Cholinesterase inhibitors (ChEIs), especially galantamine (GAL), proved to be effective in the treatment of AD5 and also in the treatment of patients with mixed dementia (AD with CVD)7. In a study with rivastigmine, patients with AD and concurrent vascular risk factors had more benefits on cognition and functional performance than patients without concurrent vascular risk factors8.

GAL has demonstrated beneficial effects on both cognitive and non-cognitive outcomes in patients with VaD and in AD with CVD9,10. GAL is the only ChEI approved for treatment of patients with AD with CVD in Brazil and in some other countries. However, its effects on quality of life (QoL) and cognitive speed in patients with mixed dementia have not been investigated so far. Moreover, the efficacy of GAL treatment combined with nimodipine (NIM), a calcium channel antagonist with putative neuroprotective effects in patients with subcortical vascular dementia, has not been explored. NIM improves cerebral blood flow via its vasodilatory effects, and, by restricting the influx of calcium ions into neurons, may prevent neuronal apoptosis11. A few studies have found evidence that NIM provides some short-term benefits, mainly in measures of cognitive function and global impression3.

The aim of the present exploratory study was to compare GAL plus NIM vs. GAL alone on cognitive speed and QoL measures in patients with mixed dementia.

Method

Study design

This was a double-blind, placebo-controlled, exploratory, parallel study involving 11 centers in four Brazilian states (Minas Gerais, Rio de Janeiro, Rio Grande do Sul, and São Paulo), conducted from May, 2008 to October, 2009. Patients were randomized (1:1) to one of two treatment arms: GAL (16-24 mg/day) plus NIM (90 mg/day) or GAL (16-24 mg/day) plus placebo (PLA). Both groups were followed for 24 weeks. GAL dose was started at 8 mg QD, with monthly increments up to 24 mg QD if well-tolerated, for both arms. NIM dose was 30 mg three times a day (TID) throughout the study and PLA was also given TID. Patients were submitted to six clinical evaluations throughout the study: enrollment visit, baseline, and follow-up visits at 4, 8, 16 and 24 weeks after baseline.

The simple random allocation sequence was performed using the PLAN procedure of SAS software, Version 9.1.3 (SAS Institute Inc., Cary, NC, USA). Each patient, at the enrollment, received a randomization number and the corresponding numbered medication. To ensure the blinding was maintained (for both patients and study team), the medication was provided into recipients as tablets (8mg, 16mg, 24mg of GAL and 30mg of NIM or PLA) that were similar in size and appearance. The study was performed under the Good Clinical Practice regulations and according to the Declaration of Helsinki. The protocol and the informed consent for patients and caregivers were approved by the Institutional Review Board of each site. Written informed consent from patients and their responsible relatives was required prior to enrollment.

The key co-primary efficacy measures were change from baseline to week 24 in cognitive speed and on QoL. The secondary endpoints were: (1) global cognitive performance; (2) global clinical impression; and (3) neuropsychiatric symptoms. Two separate analyses were performed considering the pilot study nature of this trial: between treatment groups’ comparison (GAL/NIM vs. GAL/PLA) and changes in efficacy measures from baseline to end of follow-up (within group comparison).

Study patients

Patients were eligible to be included in the trial if they met the following criteria: (1) men or women outpatients; (2) age ≥65 years; (3) fulfilling DSM-IV diagnostic criteria for dementia12; (4) fulfilling NINDS-AIREN diagnostic criteria for AD with CVD (mixed dementia)13; (5) mild to moderate dementia, with Mini-Mental State Examination (MMSE)14 scores ranging from 10 to 26, inclusive; (6) presence of a caregiver; (7) signed informed consent provided by patients and/or their legally-accepted representatives. Patients had to present significant CVD on magnetic resonance imaging, namely the presence of cortical lesions and/or subcortical lesions (periventricular and deep white matter changes) affecting at least 25% of the subcortical area.

The following exclusion criteria were adopted: (1) illiteracy; (2) any other neurodegenerative disorder, such as Parkinson’s disease, frontotemporal dementia, Huntington’s disease, Down syndrome, or Creutzfeldt-Jakob disease; (3) current or past (last six months) clinical history of hepatic or renal failure, history of significant cardiac, pulmonary, gastrointestinal, endocrine, metabolic, neurologic or psychiatric disturbances; or of urinary flow obstruction; (4) cognitive impairment resulting from acute cerebral trauma, hypoxic cerebral damage, vitamin deficiency states, infections, primary or metastatic brain tumor, endocrine or metabolic disease, mental retardation or oligophrenia; (5) use of benzodiazepines or antiepileptic drugs in the last three months; (6) use of any experimental treatment (for dementia or any other condition) in the last 12 months; (7) history of drug or alcohol abuse; (8) participation in previous studies with GAL; and (9) history of known allergy or hypersensitivity to ChEIs. Patients who had taken ChEIs or memantine in the past could participate in the trial if the drug was discontinued at least 30 days before the first evaluation.

Outcome measures

Primary efficacy measures were performed using a computerized neuropsychological battery (CNTB)15,16 and the scores on a QoL measure (the QOL Scale in Alzheimer's Disease, QoL-AD)17,18 at the end of the 24th week of treatment. The CNTB included tasks assessing attention and memory (simple and double-choice reaction tasks, face recognition and word-list learning tasks) assessed as reaction times expressed in milliseconds. QoL-AD includes three versions: two caregiver’s versions (about patients’ and their own perceived QoL) and a patient’s version. The scale is composed of 13 items that measure the domains of physical condition, mood, memory, functional abilities, interpersonal relationships, ability to participate in meaningful activities, financial situation, and global assessments of self as a whole and QOL as a whole. Each item is assessed on a 4-point scale (1=poor, 4= excellent). Scale scores range from 13 to 52, with higher scores indicating greater QOL.

Secondary efficacy measures were: Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog)19,20, Clinician Global Impression Improvement Scale (CGI-I)21, Neuropsychiatric Inventory (NPI)22,23 and Mini-Mental State Examination (MMSE)14,24. Tolerability was assessed based on the rate and severity of investigator-recorded adverse events.

Statistical analysis

The intention-to-treat population for efficacy and safety included all patients who received at least one dose of the study medication and had at least one safety evaluation after the first visit. An exploratory approach was adopted since similar studies with both drugs and assessing the same outcomes were not available to our knowledge. Thus, expected effect size to use in sample size calculation could not be obtained from the literature and the investigators assumed that 40 patients enrolled in each arm should be sufficient to derive robust estimations of clinical benefit in this pilot study. Efficacy was analyzed as the difference in mean change from baseline to endpoint between treatment groups and within groups for the CNTB, QoL-AD, ADAS-Cog, CGI-I, NPI, and MMSE scores. Repeated Measures Analyses of Variance were employed to both between-group and within-group comparisons. All statistical tests assumed a 5% level of significance.

Results

Twenty-one patients were enrolled and randomized and received at least one dose of the proposed drug regimen: 9 in the GAL/NIM group and 12 in the GAL/PLA group. The study did not reach the expected sample size mainly due to the strict eligibility criteria established to ensure that only mixed dementia patients would be enrolled. No differences between the two groups were observed in terms of age (p=0.172), gender distribution (p=0.331) and educational level (p=0.464) (Table 1). Baseline MMSE scores, CNTB measures, QoL, ADAS-Cog and NPI scores were also similar between the two groups (Table 2). Five patients (55.6%) in the GAL/NIM and 8 (66.7%) in the GAL/PLA group completed the study. Reasons for dropout were: 4 due to adverse events (in visit 3); 2 due to adverse event and 1 medical criteria (in visit 4); 1 due to lost to follow up (visit 6) (Figure 1).

Table 1. Baseline sociodemographic and clinical characteristics of the study participants. 

Variable (mean±SD) GAL/NIM GAL/PLA Total sample p-value
(n=9) (n=12)
Age 78.1±5.3 74.3±6.5 76.0±6.2 0.172
Sex 5F:4M 10F:2M 15F:6M 0.331
Years of education 5.0±3.3 4.0±2.7 4.4±2.9 0.464
Disease duration (months) 29.8±33.0 5.6±10.8 14.5±24.1 0.0078
Subcortical vascular disease - n (%) 8 (88.9%) 12 (100%) 20 (95.2%) 0.429
MMSE 15.4±5.6 17.9±3.8 16.9±4.7 0.243

Table 2 . Results for the computerized neuropsychological battery test components, reaction times (milliseconds). 

Outcome measure GAL/NIM GAL/PLA Total sample p-value
Simple-choice reaction time Test (n=12) Baseline 1,208.7±1,670.0 646.7±314.8 880.9±1,073.3 0.337*
24-weeks 467.6±336.7 618.7±329.8 555.7±326.5
Within-group change -325.2 0.303**
Two-choice reaction time Test (n=12) Baseline 1,785.5±1,793.7 1,279.5±696.7 1,490.3±1,225.8 0.274*
24-weeks 727.6±375.0 1,197.9±528.3 1,001.9±511.9
Within-group change -488.4 0.207**
Face Recognition Test (n=11) Baseline 2,890.2±1,432.1 3,168.8±943.0 3,067.5±1,081.0 0.256*
24-weeks 1,730.7±1,514.1 3,148.1±1,964.3 2,632.7±1,874.6
Within-group change -434.8 0.240**
Word Recognition and Learning Test (n=12) Baseline 2,166.1±715.4 3,387.3±2,214.0 2,878.4±1,804.2 0.859*
24-weeks 1,722.0±1,174.2 3,104.6±1,328.3 2,528.5±1,403.8
Within-group change -349.9 0.432**

Figure . CONSORT 2010 Study Flow Diagram. 

Efficacy

For the between-group comparison (GAL/NIM vs. GAL/PLA), no significant differences on primary efficacy measure were found on the CNTB (Table 2) and QoL-AD (Table 3). The secondary efficacy endpoint findings were also similar between GAL/NIM and GAL/PLA, with no statistical significance in between-group comparisons for the ADAS-Cog, CGI-I, MMSE or NPI, suggesting that adjunctive NIM did not contribute to additional benefits (Table 4). Thus, further analyses were developed for efficacy measures using the total sample (both GAL/NIM and GAL/PLA patients), assessing if 24-week therapy with GAL produces significant improvements in cognitive speed, QoL and other dementia clinically-relevant measures.

Table 3 . Results for the QoL-AD questionnaire, total scores. 

Outcome measure GAL/NIM GAL/PLA Total sample p-value
Caregiver (n=12) Baseline 35.2±9.3 36.0±9.2 35.6±8.8 0.459*
24-weeks 36.6±4.6 34.3±7.2 35.2±6.1
Within-group change -0.4 0.940**
Patient as assessed by caregiver (n=12) Baseline 28.4±10.7 29.7±10.1 29.2±9.9 0.618*
24-weeks 29.8±5.7 28.4±7.2 29.0±6.4
Within-group change -0.2 0.983**
Patient (n=11) Baseline 31.6±6.9 28.3±5.6 29.8±6.2 0.965*
24-weeks 36.6±6.2 33.2±5.4 34.7±5.8
Within-group change 4.9 0.027**

Table 4 . Results for the secondary efficacy measures. 

Outcome measure GAL/NIM GAL/PLA Total sample p-value
ADAS-Cog (n=11) Baseline 26.4±11.2 30.7±11.8 28.7±11.2 0.135*
24-weeks 25.0±9.7 24.6±12.1 24.8±10.5
Within-group change -3.9 0.029**
CGI-I at 24 weeks (n=12) Very much improved 0 (0%) 0 (0%) 0 (0%) 1.000*
Much improved 1 (20%) 2 (25%) 3 (23.1%)
Minimally improved 3 (60%) 4 (50%) 7 (53.8%)
No change 1 (20%) 1 (12.5%) 2 (15.4%)
Minimally worse 0 (0%) 0 (0%) 0 (0%)
Much worse 0 (0%) 0 (0%) 0 (0%)
Very much worse 0 (0%) 0 (0%) 0 (0%)
NPI (n=12) Baseline 23.4±8.1 27.7±17.9 25.9±14.3 0.765*
24-weeks 15±11.5 21.7±16.9 18.9±14.7
Within-group change -7.0 0.096**
MMSE (n=12) Baseline 15.4±3.8 16.6±2.6 16.1±3.1 0.187*
24-weeks 17.6±5.3 17.1±3.7 17.3±4.2
Within-group change 1.2 0.037**

The patient component of the QoL-AD measure (patients’ self-reported QoL) showed significant improvements from baseline to week 24 (difference of means=4.9; p=0.027) when all GAL treated patients were combined in the analysis (regardless initial treatment arm). CNTB individual tests and caregivers versions of the QoL-AD questionnaire did not present significant differences between baseline and the end of follow-up (Tables 2 and 3). Regarding the secondary efficacy measures, GAL treatment led to significant improvements in ADAS-Cog (difference of mean=-3.9; p=0.029) and MMSE (1.2; p=0.037) at 24 weeks as compared to baseline values. Significant changes were not observed for CGI-I and NPI (Table 4).

Adverse events

Six patients discontinued the treatment due to adverse events (three in each group), five mostly because of nausea, vomiting and diarrhea, which were predominantly mild to moderate, and one due to respiratory distress (in the GLA/PLA arm), rated as severe by the investigator.

Discussion

This is the first randomized, double-blind, multicenter clinical trial designed to prospectively evaluate the efficacy and safety of the association between a ChEI and NIM in patients with mixed dementia. The findings of our study showed significant improvement in both QoL-AD, ADAS-Cog and MMSE scores at week 24, compared with baseline, among GAL treated patients (regardless the association with NIM), despite its small sample size. The association of NIM to GAL did not lead to any clinical advantage. We believe that these results may be relevant for current clinical practice and also for future research.

GAL has been tested in several randomized clinical trials for AD3,16,25,26 and has been also evaluated in a systematic review, which examined its efficacy and safety for patients with vascular cognitive impairment, but also included studies enrolling mixed dementia patients4. Two studies were deemed eligible for the systematic review (GAL-INT-26 and GAL-INT-6), the first assessing a population with probable vascular dementia27 and the other, a mixed population of vascular dementia and AD with simultaneous CVD patients9,28.

In GAL-INT-6 study, patients with vascular dementia and AD with CVD showed greater clinical benefit over placebo on ADAS-Cog, clinician's interview-based impression of change plus caregiver input (CIBIC-plus), activities of daily living and on behavioral symptoms measures9. The GAL-INT-6 study observed similar benefits on ADAS-Cog among vascular dementia patients, but was not able to verify improvements in other efficacy measures. The GAL-INT-26 trial showed that GAL was superior to placebo for three of the four subtypes of VaD studied (multiple lacunar infarcts, extensive white matter disease and multiple territorial infarcts) in ADAS-cog improvement27. Interestingly, in our study most of the mixed dementia patients had subcortical vascular disease. These and other studies4,7,9,27,28 reported higher rates of nausea and vomiting in GAL treated participants, compared with placebo, consistent with our results and the generally favorable safety profile observed in previous studies in AD disease5,25,26,29.

A systematic review3 of 15 trials evaluating the efficacy of NIM in AD, CVD and mixed dementia found benefits of the NIM therapy on short-term outcomes of global and cognitive function, when results were pooled together, despite dementia specific etiology. Separate analysis of AD and CVD patients showed similar results. Given its mechanism of action, we hypothesized that co-administration with GAL could improve clinical outcomes in comparison to GAL monotherapy in these patients. However, our results did not show any additional efficacy benefits of the association therapy.

The major limitation of our study was the small sample size. This was probably due to the short enrollment period and to the rigorous inclusion criteria that were adopted. The latter aimed to ensure the inclusion of patients truly presenting mixed dementia. An additional limitation is the somewhat large dropout rate, which may be explained by the clinical profile of the population, with several patients presenting comorbidities that impact tolerability and adherence to treatment.

In conclusion, in this exploratory, randomized, 24-week, placebo-controlled trial, GAL was well-tolerated and efficacious in improving QoL in patients with mixed dementia, in addition to its already known cognitive benefits. The combination of GAL to NIM did not demonstrate any apparent advantage, although this aspect should be further explored in larger studies.

Acknowledgments

We thank the investigators Irismar Reis and Vitor Tumas, the patients and their relatives for their participation in the study.

We thank the following colleagues, who contributed to data collection in the different participating centers: Cloyra Almeida, Etelvina Lucas dos Santos, Henrique Cerqueira Guimarães, Irene Moreira, Gilberto Alves, Margarete Borges, Patrícia Paes Araújo Fialho, Rogério Gomes Beato, Viviane Amaral Carvalho.

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Received: February 20, 2014; Revised: March 08, 2014; Accepted: March 31, 2014

Correspondence: Paulo Caramelli; Av. Prof. Alfredo Balena, 190 / Sala 246; 30130-100 Belo Horizonte MG, Brasil; E-mail: caramelli@ufmg.br

Conflict of interest: This study and the present communication were supported by Janssen-Cilag Farmacêutica Ltda., São Paulo, Brazil.

Jerson Laks is a member of the advisory board of Lilly and GSK. He is also a lecturer for APSEN, GSK, Lilly, NOVARTIS, PFIZER, and MOKSHA 8. André L. F. Palmini is on the advisory board of Novartis and Danone and has been on the advisory board of Janssen-Cilag, Abbott and Eli-Lilly. He has also received fees for speaking for Novartis, Janssen-Cilag, Abbott, Eli Lilly, Shire and Danone. Paulo Caramelli, Jerson Laks, André L. F. Palmini, Márcia L. F. Chaves, Orestes V. Forlenza, Cássio M. C. Bottino are funded by CNPq (Bolsistas de Produtividade em Pesquisa). Assistance in manuscript preparation was provided by ANOVA Health Consulting Group (Rio de Janeiro, Brazil), with support from Janssen-Cilag Farmaceutica Ltda, Brazil. Other authors report no conflicts of interest related to the contents of the present manuscript.

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