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Cochrane Database of Systematic Reviews Protocol - Intervention

Dimebon for Alzheimer's disease

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the efficacy and safety of latrepirdine for the treatment of AD.

Background

Description of the condition

Alzheimer’s disease (AD) is a devastating and progressive neurodegenerative disorder, with a global prevalence estimated at 26 million in 2006, a number expected to quadruple by 2050 (Brookmeyer 2007). Common symptoms include significant memory loss, difficulty completing daily tasks, a decline in problem‐solving ability and changes in mood, behaviour and personality (Alzheimer's Association 2010). There are currently many theories attempting to explain the pathobiology of AD. One major theory posits a dysfunction of the central cholinergic transmission and a loss of cholinergic neurons (Bassil 2009). The formation of toxic amyloid‐β (Aβ) deposits (Hardy 2002), neurotoxic aggregates of the tau protein (Anderton 2001), mitochondrial dysfunction (Bachurin 2003) and neuro‐inflammation (McGreer 2007) are several of the other well‐known hypotheses of AD pathogenesis. Despite massive global efforts to develop a successful treatment, disease‐modifying agents have yet to pass the clinical trial phases required for licensing approval. Four agents are currently available for the treatment of AD: donepezil, galantamine, rivastigmine (cholinesterase inhibitors) and memantine (an N‐methyl‐D‐aspartate (NMDA) antagonist) (Mangialasche 2010). These medications provide symptomatic relief, but with modest effect sizes (Birks 2006; McShane 2006). Furthermore, they do not prevent or reverse the progression of the disease (Rafii 2009). Thus, there is an urgent need for more effective symptomatic and disease‐modifying interventions worldwide.

Description of the intervention

Latrepirdine (sold as Dimebon), an orally available non‐selective anti‐histamine developed in Russia and available since 1983, has recently been suggested as a possible treatment of AD and related dementias (Bachurin 2001).

How the intervention might work

At this time, the underlying mechanisms of action of latrepirdine are poorly understood (Wu 2008). Pharmacologic effects reported thus far include weak inhibition of butyrylcholinesterase, acetylcholinesterase and the NMDA receptor signalling pathway (Bachurin 2001). Unlike some other antihistamines (e.g. diphenhydramine) which are highly anticholinergic and have potentially negative cognitive effects (Kanamaru 2007), dimebon has been shown in vitro to weakly inhibit acetylcholinesterase and butyrylcholinesterase, thus potentially possessing pro‐cholinergic activity. In addition, latrepirdine has been shown to prevent lipid peroxidation and inhibit opening of the mitochondrial permeability transition pore, as well as voltage‐gated Ca2+ channels in neurons (Bachurin 2003; Wu 2008). Importantly, while in vitro work showed protective actions against Aβ‐induced neurotoxicity, an in vivo study showed no effect on  markers of Aβ‐induced neurotoxicity (Wang 2011). 

Why it is important to do this review

Latrepirdine showed clinical benefits in an eight‐week, open‐label, pilot study with 14 Alzheimer’s disease (AD) patients in Russia 12. A subsequent phase II trial of latrepirdine, published in the Lancet in 2008, reported significant improvements in cognitive, functional, behavioural and global outcomes over a period of six months in a sample of 155 patients with mild‐to‐moderate AD (Doody 2008).  However, the CONNECTION trial, a six‐month phase III confirmatory trial launched in 2008, demonstrated no significant effects of latrepirdine as a monotherapy compared with placebo in its co‐primary and secondary outcomes (Jones 2010). Currently, one more phase III trial, testing latrepirdine in conjunction with approved anti‐dementia drugs, is underway with results to be expected in December 2011 (study NCT00829374 on clinicaltrials.gov).

Given these contradictory findings, a systematic review is required to determine the clinical efficacy and safety of latrepirdine in patients with AD.

Objectives

To evaluate the efficacy and safety of latrepirdine for the treatment of AD.

Methods

Criteria for considering studies for this review

Types of studies

We will consider all randomized, controlled and double‐blind safety and efficacy trials of latrepirdine for patients with AD. For cross‐over trials, we will consider only the first treatment phase.  

We will also include randomized controlled trials where latrepirdine in combination with another treatment is compared to the other treatment alone.

Types of participants

We will include patients with a clinical diagnosis of AD with mild, moderate or severe dementia as determined by standardized diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA) (McKhann 1984).

Types of interventions

Latrepirdine at any dosage with a placebo control arm.

Types of outcome measures

Primary outcomes

  1. Clinical global impression of change

  2. Cognitive function

Secondary outcomes

  1. Behavioural symptoms including agitation and night‐time motor activity

  2. Mood including biological symptoms (e.g. sleep, appetite)

  3. Functional performance

  4. Activities of daily living

  5. Changes in global disease severity

  6. Quality of life

  7. Caregiver burden and caregiver quality of life

  8. Safety and Tolerability

  9. Drop outs, and drop outs due to adverse events

  10. Institutionalization

  11. Dependency

  12. Mortality

  13. Direct and indirect costs of health and social care

Search methods for identification of studies

Electronic searches

See Cochrane Dementia and Cognitive Improvement Group methods used in reviews.

We will search the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group using the terms: latrepirdine OR dimebon OR dimebolin OR 2,3,4,5‐tetrahydro‐2,8‐dimethyl‐5‐(2‐(6‐methyl‐3‐pyridyl)ethyl)‐1H‐pyrido(4,3‐b)indole. This register contains reports of trials from bibliographic databases such as MEDLINE, EMBASE, PsycINFO and Web of Science, as well as references from searches performed in many trial registers and grey literature sources. The Specialized Register is updated regularly and search strategies used for the retrieval of studies can be seen on the Group's module in The Cochrane Library. We will perform additional searches in other sources to ensure that as many relevant and up‐to‐date reports of trials are retrieved as possible. The search strategy that has been created for the retrieval of references to studies in MEDLINE (via the Ovid SP platform) is available in Table 1.

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Table 1. Search strategy for MEDLINE

Source

Search Strategy

Medline (Ovid SP)

1.      latriperdine.mp.

2.      dimebon.mp.

3.      dimebolin.mp.

4.      2,3,4,5‐tetrahydro‐2,8‐dimethyl‐5‐(2‐(6‐methyl‐3‐pyridyl)ethyl)‐1H‐pyrido(4,3‐b)indole.mp.

5.      (1 OR 2 OR 3 OR 4)

6.      (Alzheimer* OR AD).mp.

7.      Alzheimer Disease/

8.      Dement*.mp.

9.      (6 OR 7 OR 8)

10.    (5 AND 9)

11.    randomized controlled trial.pt.

12.    controlled clinical trial.pt.

13.    randomized.ab.

14.    "randomized controlled trial".tw.

15.    placebo.ab.

16.    drug therapy.fs.

17.    randomly.ab.

18.    trial.ab.

19.    groups.ab.

20.    (11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19)

21.    humans.sh.

22.    (20 AND 21)

23. (10 AND 22)

We will also search trials registries, conference proceedings, correspondence, and news releases.

Searching other resources

We will handsearch the reference lists of all relevant studies in order to identify any articles not found through the electronic search. We will contact the corresponding author of relevant studies to identify references and provide unpublished data. We will approach pharmaceutical companies for additional published and unpublished trials.

Data collection and analysis

Selection of studies

Three review authors will independently screen the titles and abstracts of citations obtained from the searches and discard irrelevant articles. The three authors will assess retrieved studies for inclusion based on pre‐determined criteria. We will resolve any disagreements by consulting the co‐reviewers.  

Data extraction and management

Two authors will independently extract data from included studies. We will extract numerical results of primary and secondary outcomes using a data extraction form developed by the reviewers. We will resolve any discrepancies through discussion or by consulting a third reviewer. 

We will obtain missing information from included studies by contacting the authors of the original study.

Assessment of risk of bias in included studies

Two authors will assess the methodological quality of each included study using The Cochrane Collaboration’s tool for assessing risk of bias (Higgins 2009). This tool uses six criteria: sequence generation, allocation concealment, blinding, incomplete data outcomes, free from selective reporting and other bias. Each criterion is assigned a low risk of bias, a high risk of bias, or an unclear risk of bias based on how adequately the study fulfilled each criterion.

Measures of treatment effect

We will treat outcome measures, including cognition, activities of daily living and behaviour that arise from ordinal scales as continuous variables. We will combine change scores from baseline, if possible, and use them to determine mean difference. Where change scores are unavailable, we will extract mean, standard deviation and the number of people in each group at each time point.

For dichotomous outcomes (i.e. clinical impression of change versus no clinical impression of change, tolerability), we will use odds ratio (OR) to measure treatment effect. 

Unit of analysis issues

If we identify any studies employing a cross‐over design for inclusion in this review, we will analyze only data from the first treatment phase when assessing the safety and efficacy of the drug. We will analyze data from any subsequent phase separately.

Dealing with missing data

We will request unreported data from the author of the original study. If we do not receive requested data, we will perform statistical calculations to complete the missing information where possible. 

Assessment of heterogeneity

When pooling trials, we will use I2 to identify heterogeneity across studies, where I2 > 40% indicates significant heterogeneity. If there is minimal heterogeneity, we will use a fixed‐effect analysis. In the case that heterogeneity is substantial, we will undertake a comparison of the fixed‐effect and random‐effects analyses. In addition, we will perform analyses to determine sources of heterogeneity including length of study, severity of AD and dose if possible.   

Assessment of reporting biases

We will perform a comprehensive search, including trial registries, to minimize the risk of reporting biases. In addition, if we include a sufficient number of studies in the review, we will enter data from all included trials into a funnel plot to investigate publication bias. 

Data synthesis

When possible, we will combine study outcomes using a fixed‐effect model to provide a pooled estimated effect from data.

Subgroup analysis and investigation of heterogeneity

Where data are available, we will conduct analysis based on relevant and clinically meaningful subgroups such as dosage, duration of treatment and severity of AD.

Sensitivity analysis

If issues requiring sensitivity analysis arise during the review process, we will undertake these analyses as necessary.

Table 1. Search strategy for MEDLINE

Source

Search Strategy

Medline (Ovid SP)

1.      latriperdine.mp.

2.      dimebon.mp.

3.      dimebolin.mp.

4.      2,3,4,5‐tetrahydro‐2,8‐dimethyl‐5‐(2‐(6‐methyl‐3‐pyridyl)ethyl)‐1H‐pyrido(4,3‐b)indole.mp.

5.      (1 OR 2 OR 3 OR 4)

6.      (Alzheimer* OR AD).mp.

7.      Alzheimer Disease/

8.      Dement*.mp.

9.      (6 OR 7 OR 8)

10.    (5 AND 9)

11.    randomized controlled trial.pt.

12.    controlled clinical trial.pt.

13.    randomized.ab.

14.    "randomized controlled trial".tw.

15.    placebo.ab.

16.    drug therapy.fs.

17.    randomly.ab.

18.    trial.ab.

19.    groups.ab.

20.    (11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19)

21.    humans.sh.

22.    (20 AND 21)

23. (10 AND 22)

Figures and Tables -
Table 1. Search strategy for MEDLINE