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Cochrane Database of Systematic Reviews Protocol - Intervention

Posatirelin (l‐pyro‐2‐aminoadipyl‐l‐leucyl‐l‐prolinamide) treatment for persons with dementia

Authors' declarations of interest

Version published: 08 October 2008 Version history

https://doi.org/10.1002/14651858.CD007347

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view the current version 03 August 2018
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Abstract

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

Primary:

  • To assess the efficacy of posatirelin treatment in improving function, cognition, mood, behaviour, quality of life, and mortality in older persons with dementia.

Secondary:

  • To assess the efficacy of posatirelin treatment in decreasing medication use for the purpose of minimizing negative drug interactions (for example, ChEIs, whose effectiveness can decrease when paired with incontinence medication) and number of adverse drug reactions.

  • To make recommendations for consumers, healthcare professionals, decision‐makers, and researchers regarding the efficacy of posatirelin treatment for dementia.

Background

There has been a steady increase in global life expectancy, from 46.5 years in 1950 to 1955 to 65.2 years in 2002 (WHO 2003). This trend will continue, according to the United Nations Population Division, and there is an increasing proportion of individuals aged 65 years and above and 85 years and above (UN 2006). Chronic diseases such as dementia are the leading cause of mortality among the aging and the aged (Wilkins 2006). According to Statistics Canada (Hill 1996), one in three seniors over the age of 85 has dementia, and 64% of those with dementia are diagnosed with Alzheimer's disease (CSHA 1994). The incidence of Alzheimer's disease is estimated to continue rising, and an effective treatment and/or cure is still not evident (Cummings 2004). The need to effectively treat Alzheimer's disease as well as other forms of dementia is even more pressing, with the majority of baby‐boomers fast approaching 65 years of age. Treatment of these conditions is costly, and many healthcare systems are not prepared to deal with this potential crisis. There exists a gap between recommended care and received care globally, and both Canada and the United States do not fare well compared to other solvent nations (Morgan 2007).

Posatirelin (l‐pyro‐2‐aminoadipyl‐l‐leucyl‐prolinamide, RGH‐2202) is a synthetic tripeptide with neurotrophic (Casabona 1992), cholinergic (Ferrari 1998), and catecholaminergic properties (Oka 1989). Posatirelin is a synthetic analogue to thyrotropin‐releasing hormone (TRH), which has been implicated in benefiting treatment of stroke; posatirelin differs from TRH because its central nervous system effects are greater than its hormonal effects (Noda 1995). Animal studies have suggested its efficacy in improving cognitive and behavioural function in both healthy and post‐focal‐ischemia rats (Noda 1995; Oka 1989). Several human studies have also suggested beneficial effects on human subjects with various forms of cognitive impairments (Cucinotta 1994; Ferrari 1998; Gasbarrini 1997; Parnetti 1995; Parnetti 1996). Posatirelin is not currently available for treatment outside clinical trials.

While there are some treatments for dementia and Alzheimer's disease (e.g. cholinesterase inhibitors [ChEIs]) that slow down disease progression, they are effective mainly in patients with mild to moderate stages of the disease and lose their efficacy as the disease progresses (Herrmann 2007; Hogan 2007). In addition, such therapies are not without side effects and are countered by other pharmacological agents frequently prescribed to the population in question (e.g. incontinence medication) (Hogan 2007). Therefore, a novel effective treatment with fewer adverse effects could potentially relieve some of the burden healthcare systems face with the aging global population. Posatirelin may be a more effective treatment for dementia (compared to current methods), therefore a systematic review will be conducted (incorporating meta‐analysis, if applicable) to determine the effects of posatirelin treatment on function, cognition, mood, behaviour, decreased medication use, adverse drug reactions, and mortality in older adults with dementia.

Objectives

Primary:

  • To assess the efficacy of posatirelin treatment in improving function, cognition, mood, behaviour, quality of life, and mortality in older persons with dementia.

Secondary:

  • To assess the efficacy of posatirelin treatment in decreasing medication use for the purpose of minimizing negative drug interactions (for example, ChEIs, whose effectiveness can decrease when paired with incontinence medication) and number of adverse drug reactions.

  • To make recommendations for consumers, healthcare professionals, decision‐makers, and researchers regarding the efficacy of posatirelin treatment for dementia.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) in which older adults (aged 65+) with dementia were allocated to an experimental posatirelin group or a placebo control group. Parallel group trials are preferred, but randomized cross‐over trials will also be considered for inclusion (in which only the data obtained prior to cross‐over will be considered for inclusion in the review). Since this is a review of pharmacological trials, non‐blinded studies will not be considered for the purposes of this review. Only placebo‐controlled, double‐blinded studies will be considered for inclusion in this review.

Types of participants

The participants will be older adults (65+) living with dementia (of any type and stage) who reside either in long‐term care facilities or in the community. Dementia will be diagnosed using accepted criteria such as the International Classification of Diseases (ICD‐9 or ICD‐10) (WHO 1992), Diagnostic and Statistical Manual of Mental Disorders (DSM‐III, DSM‐III‐TR, or DSM‐IV) (APA 1995), and/or corresponding scores on the Mini‐Mental State Examination (Folstein 1975) and/or other accepted neuropsychological tests for dementia. There are no restrictions on gender, geographic location, or socioeconomic status. There is no restriction on language of publication.

Types of interventions

Interventions will include any therapeutic intake of posatirelin (l‐pyro‐2‐aminoadipyl‐l‐leucyl‐prolinamide, RGH‐2202) that was maintained over a sustained period of time (three months or longer) with the aim of improving function, cognition, mood, behaviour, quality of life, mortality, or any combination thereof, in older adults with dementia. We intend to measure the effect of posatirelin, therefore trials in which the posatirelin therapy is the only difference (between groups) will be included. The control group must receive a placebo. Trials in which other therapies (combined with posatirelin therapy) will also be considered for inclusion, but only data relevant to posatirelin treatment versus placebo will be extracted.

Types of outcome measures

Outcome measures will be relevant to the person with dementia, and will include at least one of the following: function (e.g., Katz Index of Activities of Daily Living [ADLs] (Katz 1963)), cognition (e.g., Mini‐Mental State Examination [MMSE] (Folstein 1975)), mood (e.g., the Montgomery‐Åsberg Depression Rating Scale [MADRS], the Cornell Scale for Depression in Dementia (Müller‐Thomsen 2005)), behaviour (e.g., the Neuropsychiatric Inventory [NPI] (Cummings 1994)), quality of life (e.g. the European Organization for Research and Treatment of Cancer QLQ‐C30 [EORTS QLQ‐C30] (EORTS 1993)), adverse drug reactions, and mortality. Measures of clinical global impression (e.g., Clinical Global Impressions [CGI] (Rush Jr. 2000)) will also be examined, if available. Adverse drug reactions from all trials will be reported and discussed, but only data from double‐blind, placebo‐controlled, RCTs will be considered for meta‐analysis. Measures from both dichotomous and continuous scales will be acceptable.

Search methods for identification of studies

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

The Cochrane Dementia Group's Specialized Register will be searched using a combination of terms ("posatirelin*", "l‐pyro‐2‐aminoadipyl‐l‐leucyl‐prolinamide*", "RGH‐2202*", "thyrotropin‐releasing hormone*" in combination with dementia (MeSH), Alzheimer's disease (MeSH), vascular dementia (MeSH), and "cognitive impairment*"). This Register contains records from MEDLINE, EMBASE, CINAHL, PsycINFO and many trials databases and is updated regularly. Reference lists of retrieved articles will be examined for additional trials. Ongoing trials will be tracked and assessed for inclusion when completed.

Data collection and analysis

Selection of trials

Titles and abstracts of citations retrieved will be examined and obviously irrelevant articles will be discarded. This stage of selection will be overly inclusive and any article suggesting a randomized controlled trial or a cross‐over trial will be considered for inclusion. The trials included at this stage will be subsequently assessed by two independent assessors, and trials approved for inclusion by both authors will be included. Any disagreement regarding inclusion will be resolved through discussion, or by referral to a third assessor if necessary.

Assessment of methodological quality

The methodological criteria are based on The Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.0 (Higgins 2008). As with initial inclusion assessment, two assessors will independently assess the studies regarding randomization, allocation concealment, blinding, and attrition (Juni 2001). If descriptions of allocation concealment and/or blinding strategies are not evident, the primary author of the study in question will be contacted in an attempt to retrieve the required information. Each assessed article will be categorized into one of the following categories:

A ‐ Adequate:

  • Measures taken to ensure that allocation to treatment or control group is conducted by a third party (any system in which allocation could not be known in advance)

  • Clear description of randomization procedure that includes concealment of allocation

  • Blinding: outcome assessor is unaware of allocation

B ‐ Unclear:

  • Randomization stated, not described

  • Blinding not reported

C ‐ Inadequate:

  • Use of birthdays, record numbers, date, and similar methods used to assign subjects to treatment or control groups

  • Use of any system in which allocation is not concealed (e.g. random number list)

  • Outcome assessor not blind to allocation treatment

D ‐ Allocation concealment not used

Empirical research suggests that inadequate allocation concealment is associated with bias (Higgins 2008; Moher 1998). Therefore, only studies categorized as A or B will be included in the review. Research has suggested that attrition rates are not consistently related to bias (Schulz 1995). Attrition will therefore not be used as exclusion criteria.

Data extraction and analysis

Data will be extracted from published reports or requested from the corresponding author when necessary. Summary statistics will be required for each trial and each outcome. For continuous data, the weighted mean difference (WMD) will be used when the pooled trials used the same rating scale to assess an outcome. Should the pooled trials use different rating scales for the same outcome measure, the standardized difference in means (SMD) will be used. The change in mean from baseline, the standard deviation of the mean change, and the number of participants in each group at the final assessment will be extracted. Where changes from baseline are not reported, the mean, standard deviation and the number of participants for each group at each time point will be extracted and the necessary data will be calculated. The primary author of any study with missing data will be contacted. For dichotomous data, the effect measure will be relative risk (RR). Binary analyses will be conducted on the reported adverse drug effects.

Only studies that demonstrate clinical homogeneity will be considered appropriate for meta‐analysis. A test for statistical heterogeneity (a consequence of clinical and/or methodological diversity among studies) will be performed using the I2 statistic (a statistic for quantifying inconsistency (I2 = [(Q ‐ df)/Q] x 100%, where Q is the chi‐squared statistic and df is its degrees of freedom; Higgins 2003)). The I2 describes the percentage of variability in effect estimates that is due to heterogeneity, and not sampling error. A value greater than 50% will be considered substantial heterogeneity and a random‐effects model will be used. If there is no substantial heterogeneity, a fixed‐effect model will be used. The confidence intervals in a random‐effects model are broader than those of a fixed‐effect model.

Depending on available data, the following subgroup analyses will be performed:

  • Dementia type

  • Dementia severity

  • Treatment duration

  • Treatment dosage

  • Influence of co‐morbidities

Sensitivity analyses will be performed in order to assess whether methodological quality differences (if present) influence the outcomes in the included trials.