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Pharmacological Treatment of Dementia

Summary

Evidence Report/Technology Assessment: Number 97

Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.

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Introduction / Methods / Results / Discussion / Availability of Full Report / References

Introduction

The focus of this review is the pharmacological treatment of dementia. Pharmacotherapy is often the central intervention used to improve symptoms or delay the progression of dementia syndromes. The available agents vary with respect to their therapeutic actions, and are supported by varying levels of evidence for efficacy. This report is a systematic evaluation of the evidence for pharmacological interventions for the treatment of dementia in the domains of cognition, global function, behavior/mood, quality of life/activities of daily living (ADL) and caregiver burden.

Many medications have been studied in dementia patients. These agents can be classified into three broad categories:

Cholinergic neurotransmitter modifying agents, such as acetylcholinesterase inhibitors.
Non-cholinergic neurotransmitters/neuropeptide modifying agents.
Other pharmacological agents.

Although only five agents have been approved by the Food and Drug Administration (FDA) for the treatment of dementia, many other pharmacological agents have been evaluated in trials and may be prescribed in off-label use.

Given the range of pharmacological agents that have been tested in dementia, a systematic review of these interventions (using a consistent methodology) provides a meaningful contribution in this area. The key questions addressed in this systematic review are as follows:

Does pharmacotherapy for dementia syndromes improve cognitive symptoms and outcomes?
Does pharmacotherapy delay cognitive deterioration or delay disease onset of dementia syndromes?
Are certain drugs, including alternative medicines (non-pharmaceutical), more effective than others?
Do certain patient populations benefit more from pharmacotherapy than others?
What is the evidence base for the treatment of ischemic vascular dementia (VaD)?

This review considers different types of dementia populations (not just Alzheimer's Disease [AD]) in subjects from both community and institutional settings. The studies eligible in this systematic review were restricted to parallel RCTs of high methodological quality.

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Methods

A team of content specialists was assembled from both international and local experts. The purpose of the expert panel was to assist in the topic assessment and refinement process. In addition, complex methodological issues were evaluated by this expert panel.

Search Strategy

Search strategies were developed and undertaken in the electronic databases including Cochrane Central, MEDLINE®, PreMEDLINE®, EMBASE, AMED, CINAHL®, AgeLine, and PsycINFO. In addition to the electronic databases, the bibliographies of retrieved papers were reviewed.

Eligibility Criteria

Studies were included that met the following criteria:

Populations included dementia patients who were 18 years or older in age.
Diagnosis of dementia using criteria of International Classification of Diseases (ICD) 9 or 10, Diagnostic and Statistical Manual of Mental Disorders (DSM) III, III-R or IV, National Institute of Neurological and Communication Disorders and Stroke (NINCDS), Neurological and Communication Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA), or Neurological and Communication Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINCDS-AIREN).
Potential populations at high risk of dementia conversion in order to address the issue of delay in onset. These populations included: Mild Cognitive Impairment (MCI), Cognitive Impairment not Dementia (CIND), Cognitive Loss No Dementia (CLoND).
Interventions were restricted to pharmacological agents, including food supplements (as defined by the FDA) administered for at least 1 day.
Parallel design randomized control trials (RCT) in the English language of any sample size.
Score of 3 or greater on the modified Jadad quality scale.

All types of instruments were considered for this review within the outcome domains.

Populations of dementias caused by toxic agents (e.g., alcohol) and temporary dementia (e.g., side effect of anesthesia) were excluded.

Data Collection and Reliability of Study Selection

All studies meeting eligibility criteria were reviewed to assess quality and data abstracted according to predetermined criteria. The articles were grouped according to the pharmacological agent used in the intervention. A team of study assistants were trained in the criteria for eligibility and quality for the purposes of this systematic review. Standardized forms and a guide explaining the criteria were developed from previous templates.

Study outcomes were classified into the following domains:

General cognitive function.
Specific cognitive function.
Global clinical assessment.
Behavior/mood.
Quality of life/ADL.
Effects on primary caregiver (also referred to as caregiver burden).
Safety as measured by the incidence of adverse effects (particularly serious events).
Acceptability of treatment as measured by withdrawal rate from trial due to side effects of the medication.

Measurement of Benefits and Harms

Evaluation of efficacy is based upon reported changes for outcomes in the principal domains of interest. Evaluation of the potential for harm is considered within three main areas:

The most frequently reported adverse events across studies for a specific drug.
The overall withdrawal rate due to adverse events for both the control and treatment groups.
The range of frequencies reported for a subset of specific symptoms (nausea, diarrhea, dizziness, agitation, eating disorder) selected a priori and evaluated for all pharmacological interventions.

Measure of Effect Size and Meta-analysis

Effect sizes (ES) for trials were conducted for those pharmacological interventions with the same outcomes. In studies with multiple dosage groups and where sufficient data were provided, each dose level had an ES estimated separately relative to placebo. Before calculating a pooled effect size measure, the reasonableness of pooling was assessed on clinical and biological grounds, in terms of clinical homogeneity and therefore statistical meta-analysis was not appropriate for all outcomes or interventions.

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Results

Question 1: Does Pharmacotherapy for Dementia Syndromes Improve Cognitive Symptoms and Outcomes?

Seventy-two studies examined cholinergic neurotransmitter modifying agents, 61 studies examined non-cholinergic neurotransmitter/neuropeptide modifying agents and 76 trials evaluated other agents used to treat dementia. Table 1 lists all the pharmacological agents and the number of trials (in brackets) eligible for review in this study. Twenty of these agents are detailed in this summary. All drug agents are detailed in the full report.

Summary of Cholinergic Neurotransmitter Modifying Agents

Carnitine. Six trials^1-6 evaluated carnitine in 925 subjects with mild to moderate severity, recruited predominately from the community. A dose of 2-to-3 g was compared to placebo for either 24 or 52 weeks.

Evidence of benefit is conflicting for the domains of general or specific cognition. Results were not statistically significant in any study but the lack of sufficient power may have influenced these results. Similarly, no statistically significant differences were found in the domains of global assessment, behavior/mood, and quality of life/ADL. Statistical power could not be evaluated for the most of these outcomes.

Four of the six studies scored 3 for quality on reporting adverse events. Withdrawal rates due to adverse events varied from 0-3 percent (excluding results from one outlier trial⁷), and gastrointestinal symptoms were the most frequently reported types of adverse events.

Donepezil. Ten trials^8-17 in 3239 subjects evaluated the efficacy of donepezil compared to placebo, and one trial18 compared donepezil with vitamin E. Eight of the studies evaluated AD patients, for which at least half were recruited from the community (other studies did not specify). The subjects had predominately mild to moderate disease and doses of 5 or 10 mg were used with study duration from 12 to 56 weeks.

There is consistent evidence of benefit in the domains of general cognitive function and global assessment; the combined effect sizes for the Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-cog) and the Clinician's Interview-Based Impression of Change (CIBIC) were estimated. Based on the three studies that evaluated two different doses (5 and 10 mg), there was no consistent dose response relationship as the benefit was of similar magnitude for global assessment outcomes. Two of the three studies that evaluated behavior/mood outcomes, using the Neuropsychiatric Inventory (NPI), showed no statistically significant changes relative to placebo but these trials lacked sufficient power to detect a difference. There is evidence of benefit in ADL outcomes, although this outcome was evaluated by a variety of instruments. Caregiver burden outcomes were measured in a single study that did not report the findings for this domain.

Adverse events quality scores were 3 or greater for the majority of studies (n=7). Four trials provided evidence of a dose response for adverse events. One study showed a statistical difference for balance-related problems and asthenia (neurological fatigue) between placebo and treatment groups. Withdrawal due to adverse events ranged from 0-18 percent for treatment groups and 0-11 percent for placebo. Four out of 6 studies testing for differences between groups were statistically significant for diarrhea, nausea and vomiting.

Galantamine. Six trials^19-24 in 3530 subjects compared the efficacy of galantamine with placebo. Doses of 24 and 32 mg were evaluated in half of these studies. Five studies evaluated only AD patients and there was limited information regarding the subjects' residence (community or institutional settings). All studies recruited subjects with mild to moderate disease and the drug was administered from 3 to 6 months duration.

Evidence of benefit is consistent in the domains of general cognitive function, global assessment and quality of life/ADL. Two of the three studies that evaluated behavior/mood found statistically significant differences in favor of galantamine. A dose effect was evident in the ADL domain when comparing the pooled estimates of the Disability Assessment for Dementia (DAD); no dose effect was observed for outcomes in the global assessment domain, and this could not be evaluated for the general cognition domain. Caregiver burden was not evaluated in any trial.

Five of the six trials scored 3 out of 5 on our quality scale for rating adverse events. Withdrawal rates due to adverse events ranged from 4-9 percent for placebo and 8-27 percent for the treatment group. One study showed a dose response for adverse events. Although four trials did not report significance testing for differences between groups, two trials did report a statistically significant difference in weight loss between the placebo and treatment group. The most common adverse events were gastrointestinal symptoms (nausea and vomiting, diarrhea), eating disorders/weight loss, and dizziness.

Metrifonate. Nine studies^25-33 compared metrifonate to placebo in 2759 subjects with mild to moderate AD (the majority of studies did not specify community settings). Metrifonate doses from 50 to 80 mg were given for 21 days to 26 weeks duration.

All but one study showed metrifonate to have a consistent positive effect on measures of general cognitive function; none of the studies evaluated specific cognitive function measures. Effects on global assessment were less consistent but suggested a positive effect in four of the eight studies. Evidence for effect in the domains of behavior/mood and quality of life/ADL were not statistically significant in the majority of studies that evaluated these domains; however these were primarily evaluated as secondary outcomes and likely lacked sufficient power.

With the exception of a single study, quality scores for reporting adverse events were greater than 3. However, only one trial tested for differences between groups and found nausea and vomiting, diarrhea, and muscle and joint disorder to have statistically significantly differences. Withdrawal due to adverse events varied from 0-9 percent for placebo and 0-12 percent for the treatment group. It was difficult to determine which types of reported adverse events had the potential to cause serious harm. This is noteworthy as metrifonate has been withdrawn from use in North America, and Bayer has suspended Phase III trials,³⁴ because some patients in clinical trials have experienced serious muscle weakness. This decision was based on the results of an experimental study showing risk of respiratory paralysis with the use of metrifonate. Other adverse events of concern included severe leg cramps, dyspepsia, and bradycardia. None of the studies that we reviewed indicated that if present, these events differed with statistical significance between groups. It is not clear if this inconsistency is a function of the methods used to collect and report adverse events, or a limitation of RCTs as a source of detecting serious adverse events when the incidence is low.

Nicergoline. Four trials^35-38 in 705 subjects compared nicergoline to placebo and one trial³⁹ compared it to a second drug (antagonic-stress) in mixed populations that included AD, Multi-Infarct Dementia (MID), Progressive Degenerative Dementia (PDD), Vascular Dementia (VaD), mixed dementia, and Senile Dementia of the Alzheimer's Type (SDAT), which were classified as mild to moderate in severity.

All placebo-controlled trials found a positive effect for general cognitive outcomes, but half the results were based on observed case (OC) analyses. The evidence for benefit was mixed in the domain of global assessments. No statistically significant differences were found for behavior/mood, nor quality of life/ADL outcomes but these were evaluated in few studies and as secondary outcomes (suggesting that sufficient power was an issue).

Quality scores for reporting adverse events varied from 2 to 5 for these four trials, and none tested for differences between groups. Withdrawal due to adverse events varied from 0-8 percent for placebo and 0-9 percent for the treatment group. With the exception of headache, which was reported in all four trials, it was difficult to determine which types of adverse events most characterized exposure to this pharmacological agent.

Physostigmine. Four studies^40-43 in 1198 subjects with mild to moderate AD evaluated physostigmine administered in patch and oral form (30-to-60 mg dose) from 6 to 24 weeks duration. All subjects were recruited from the community.

There is evidence that physostigmine has a statistically significant positive effect on general cognitive function, as three of the four studies showed improvement. Evidence for an effect on global function was mixed with no consistent effect. Similarly, for quality of life/ADL outcomes, all three studies that evaluated this domain showed no statistically significant difference but these were secondary outcomes and may reflect a lack of power. Behavior/mood and caregiver burden outcomes were not tested.

The quality scores for reporting adverse events were generally low, scoring 1 or 2 out of 5. Withdrawal rates due to adverse events varied from 1-5 percent for placebo and 12-55 percent in the treatment group, with one study not reporting rates. The high withdrawal rates were in studies with sample sizes that varied from 181 to 475 subjects. A single study tested for differences between groups, and found that dizziness, tremor, weight loss, asthenia, confusion, delirium, and respiratory problems (not detailed) were significantly different statistically. The cluster of reported types of adverse events suggests that gastrointestinal problems (abdominal pain, diarrhea, nausea and vomiting and eating disorder) were most frequently reported.

Posatirelin. Four trials^44-47 evaluated posatirelin in 931 subjects in a variety of mild to moderate dementia populations (AD, PDD, VaD) using 10 mg per day dose for 3 months duration.

Three of the four trials showed statistically significant improvement in general cognitive function and quality of life/ADL (as measured by Gottfries-Brane-Steen (GBS) subscales for these domains). The evidence remains inconsistent for benefit in global assessment (evaluated in only one trial) and behavior/mood (mixed results). Caregiver burden and specific cognitive function were not evaluated.

Quality scores for reporting adverse events varied from 2 to 4. Withdrawal rates due to adverse events ranged from 0-3 percent in placebo and 0-4 percent in the treatment group. None of the studies tested for statistically significant differences between groups for adverse events. At least three studies reported arrhythmia, nausea/vomiting, headache, rash/skin disorder, and sleep disorder.

Rivastigmine. Six studies^48-53 evaluated 2071 subjects with three of these studies limited to AD patients. Doses of rivastigmine varied from 1 to 12 mg, given for 14 to 26 weeks and only one study specified a community sample.

Evidence shows that general cognitive function improves with rivastigmine at dose of 12 mg but there are mixed results for efficacy at lower doses. Two trials evaluated specific cognitive function but the results were not consistent within studies (between general and specific measures). Similarly, the results were not consistent for general and specific cognition between studies. There is consistent evidence of benefit for global function but the dosage at which this occurs has statistically significant variation among studies. In the domains of behavior/mood, quality of life/ADL, the findings were neither statistically significant nor consistent; most of these analyses were not based on intention to treat analysis and lack of sufficient power cannot be ruled out. Caregiver burden outcomes were not evaluated.

Quality scores for reporting adverse events varied from 2 to 5. Withdrawal rates due to adverse events ranged from 4-11 percent in the placebo and 11-27 percent in the treatment group. Two trials demonstrated a dose response; however, one of these trials showed statistically significant differences for nausea and vomiting only, and the other trial showed statistically significant differences for all the adverse events reported. The majority of studies reported dizziness, nausea and vomiting, eating disorder/weight loss, and headache. It should be noted that one study allowed intentional prescribed anti-emetic drugs to increase the tolerance of subjects taking rivastigmine.

Tacrine. Six studies^54-59 evaluated tacrine in 994 subjects predominately with mild to moderate AD at doses of 80 to 160 mg lasting from either 12/13 or 30/36 weeks in duration. Two other studies^60,61 involving 425 patients were non-placebo controlled studies. The majority of studies recruited community-based subjects.

A single trial showed benefit for general cognitive function. The small effect size was based on a series of related publications. The five trials showing no benefit for general cognitive function comprised small sample sizes and much shorter study duration. Thus, the evidence for benefit in general cognitive function is limited to a single trial. There is evidence for benefit in global function in two of the three trials. Changes in behavior/mood, quality of life/ADL domains, specific cognitive function, and caregiver burden were all not statistically significant, but lack of sufficient power cannot be ruled out.

The quality scores for reporting adverse events varied from 1 to 3. The proportion of subjects withdrawing due to adverse events ranged from 0-12 percent for placebo and 0-55 percent in the treatment group. The higher rates of withdrawal were associated with higher doses. Elevated alanine transaminase (ALT) or hepatic abnormality (placebo = 4-13 percent; all doses tacrine = 7-67 percent) was reported in six studies, raising concerns for the potential for serious liver damage. None of these trials tested for differences between treatment and placebo with respect to adverse events. Five studies reported nausea and vomiting, gastrointestinal problems, and dizziness. There is evidence for potentially serious adverse events associated with liver dysfunction in six trials.

Velnacrine. Three studies^62-64 evaluated the effects of velnacrine in 774 AD patients with a probable severity classification. Doses between 75 mg twice daily and 225 mg were given for 15 to 24 weeks duration. Location of recruitment was not specified.

Statistically significant positive effects were observed for general cognitive function, and global assessment in the two studies with sample sizes over 300 subjects. Behavior/mood and caregiver burden showed some benefit in one trial⁶² at the highest dose only. Quality of life/ADL was tested as a secondary outcome and showed mixed findings.

Quality scores for reporting adverse events were 3 for all studies. Withdrawal rates varied from 0-22 percent for the placebo group and 5-33 percent for the treatment group. None of the studies reported a dose response. None of the studies tested for statistical differences between the placebo and treatment groups. Two studies reported aberrant hematology and hepatic abnormality^62,64; for these two studies the rates of occurrence were 2-21 percent for placebo, and 32-40 percent for all doses. The potential for serious effects is not well specified in these trials. All studies reported diarrhea and nausea and vomiting.

Summary of Non-cholinergic Neurotransmitter/Neuropeptide Modifying Agents

Haloperidol. Five studies^65-69 evaluated the effect of haloperidol relative to placebo in a total of 622 subjects with mild to moderate disease that included AD patients and mixed populations (MID/VaD/ PDD). One trial had only 15 patients, and one trial⁶⁵ lasted only 3 weeks. Two studies recruited subjects from institutions; one from the community; and, two did not specify.

Mixed results were observed for improvement in global assessment. In three of the trials there was benefit in the domain of behavior/mood which reached statistical significance. Two trials evaluated caregiver burden and found no statistically significant differences but lack of sufficient power cannot be ruled out. Few studies evaluated outcomes in quality of life/ADL. Haloperidol did not affect general cognitive function in two trials and was not evaluated in the other studies.

The quality scores for reporting adverse events varied from 1 to 5 and only three of five studies reported withdrawal rates; the proportion of subjects withdrawing due to adverse events ranged from 5-17 percent for placebo and 17-33 percent in the treatment group. One trial showed a dose-response effect but the study lasted only 3 weeks. Three trials tested for differences between treatment and placebo with respect to extra-pyramidal symptoms (placebo = 17-32 percent; all doses = 34-97 percent), and two found statistically significant differences.^65,66 One study⁶⁶ found statistically significant differences between groups for balance-related problems.

Memantine. Three trials^70-72 evaluated memantine in 1066 patients, primarily with VaD, with 10- or 20-mg doses for durations of 12 or 28 weeks. Disease severity was moderate to severe in a single study⁷⁰ and mild to moderate in the remaining two studies.^71,72 One study included patients that were institutionalized; one study included community subjects; and the other study did not report the source of patients.

Consistent evidence of benefit in general cognitive function was demonstrated in the two studies that evaluated this domain. Findings for global assessment are mixed. The only trial that evaluated mixed dementia populations (including some VaD) with moderate to severe dementia found statistically significant improvements in global function, behavior/mood, and quality of life/ADL outcomes, but did not evaluate general cognitive function. It should be noted that this trial with mixed populations used half the dose of memantine for half the study duration in patients with greater disease severity, and had approximately half the sample size of the other two trials evaluated in this systematic review. Despite a lower dose, a smaller number of more severely affected patients and a shorter duration, a statistically significant difference was found.

The quality scores for reporting adverse events varied from 3 to 4. Only two of three studies reported withdrawal rates; the proportion of subjects withdrawing due to adverse events ranged from 3-7 percent for placebo and 9-12 percent in the treatment group. A single trial tested for differences between treatment and placebo, and none of the comparisons were significantly different statistically.

Selegiline. Six trials^73-78 evaluated selegiline in 733 patients with AD, PDD, and dementia Alzheimer's type (DA) with 10 mg per day and study duration of 60 days or 2 years.

All but one trial that evaluated general cognition showed no statistically significant changes. A single trial found statistical improvements in specific cognitive tests (Sternberg Memory tests); this trial also showed statistically significant improvements in global assessment and behavior/mood. Only this trial, which had the highest quality score (7), showed consistently positive findings across all domains tested. Three of the five trials that evaluated part or all of these domains had very small sample sizes and were likely underpowered, possibly accounting for the inconsistent findings. Based on a single trial there is evidence that selegiline and selegiline combined with vitamin E, delays the time to important functional decline milestones.

The quality scores for reporting adverse events varied from 0 to 3. The proportion of subjects withdrawing due to adverse events ranged from 0-4 percent for placebo and 0-9 percent in the treatment group. Only one trial tested for differences between the treatment and placebo groups and showed that balance and falls were statistically significantly different (worse) between groups (particularly the group with selegiline combined with vitamin E [22 percent] versus placebo [5 percent]). However, when adjusted for multiple comparisons, these were no longer statistically significant.

Summary of Other Pharmacological Agents

Cerebrolysin. Six studies^79-84 evaluated the effect of cerebrolysin in a total of 819 subjects All but one of the trials included only AD patients with mild to moderate disease. All of the studies used the same dose of cerebrolysin, 30 ml per day for 5 days per week for 4 to 24 weeks duration. Location of recruitment was not specified.

Cerebrolysin showed a statistically significant improvement in cognition in four of five studies that evaluated this domain. Although a pooled estimate for the ADAS-cog was calculated, the model was positive for heterogeneity and the overall estimate was not statistically significant. The results for specific cognitive tests for the three trials that evaluated this domain were inconsistent. Global assessment measures showed a statistically significant effect in five of the trials. A summary estimate for the Clinical Global Impression (CGI) was presented; this model was also positive for heterogeneity but statistically significant for an overall effect. Two out of three studies showed an effect for behavior/mood, but none of the six studies showed an effect on quality of life/ADL. No study measured caregiver burden.

Two of the six trials scored 5 out of 5 on our quality scale for rating adverse events, but did not report any adverse events. Two studies scored 4, and the other two trials scored 3 and 2. All the studies with scores equal to 4 or less tested for statistical differences in adverse events between placebo and treatment groups. Withdrawals due to adverse events were not reported in one study, and were 1 percent in two studies and none withdrew in three studies. A statistically significant difference between treatment and control group was reported in one study for weight change, anxiety, and headache.

Estrogen. Five studies^85-89 evaluated estrogens for dementia in 247 patients with primarily mild to moderate AD from the community, with the exception of one study that included moderate to severe dementia patients who were all institutionalized. One of the studies with AD patients provided 0.10 mg per day by skin patch for 8 weeks and the others used 1.25 mg per day for 12 to 52 weeks duration. The study including severe subjects used 2.5 mg per day for 4 weeks.

Three trials evaluated general cognitive function and all showed statistically non-significant findings; two trials lacked sufficient power to show changes on the ADAS-cog. Two other trials evaluated specific cognitive function but results were mixed. Most of the outcomes evaluated in the domains of global assessment, behavior/mood, and quality of life/ADL were secondary outcomes and none showed statistically significant differences (but lack of power could be a factor).

One of the five trials scored 5 out of 5 on our quality scale for rating adverse events, but did not report any adverse event. Withdrawal rates due to adverse events ranged from 0-5 percent for placebo and 0-14 percent for the treatment group. The most frequently reported adverse event was vaginal bleeding and a single trial reported a statistically significant difference between placebo and treatment group for this symptom. It was not clear from the descriptions provided in the study if they had ascertained whether vaginal bleeding was present prior to the trial commencement.

Ginkgo biloba. Three trials^90-92 evaluated Ginkgo biloba, 120 to 240 mg per day for 3 to 12 months, in a total of 563 subjects with mixed dementias of mild to moderate severity. All were recruited from the community.

The largest trial had the longest treatment duration but the lowest daily dosage and reported a statistically significant impact for general cognitive function but had mixed findings for global assessment. A second large trial found positive changes for neuropsychological tests, global assessment, and behavior/mood outcomes with double the dosage of the previously described trial and half the treatment interval. In this RCT, clinical efficacy was assessed by using a responder analysis, with therapy response being defined as response in at least two of the three variables: CGI—global function, Syndrome Kurz test (SKT)—special cognitive function, and Nurnberger-Alters-Beobachtungs-Skala (NAB)—ADL. A single trial evaluated behavior/mood and the result was not statistically significant. No trial evaluated caregiver burden or quality of life/ADL.

All three trials scored 3 or greater on the quality scale for rating adverse events. Two studies had no withdrawals due to adverse events, and one trial had a withdrawal rate of 6 percent for both placebo and treatment groups. Two studies reported no adverse events. One study reported a statistically significant difference between the treatment and the placebo group for skin disorders. The same study reported gastrointestinal and headache adverse effects, but did not test for statistical differences between the placebo and the treatment group.

Idebenone. Four studies^93-96 evaluated the drug idebenone in 1153 subjects of mixed dementia populations of mild to moderate severity; one of these trials evaluated idebenone relative to tacrine. Doses varied from 30 mg per day to 360 mg per day, and the treatment interval ranged from 90 days to 60 weeks.

There was evidence of benefit in general cognitive function and global assessment. Several studies evaluated behavior/mood and quality of life/ADL and these outcomes were found to be statistically different. None of the trials evaluated caregiver burden.

Quality scores for reporting adverse events varied from 1 to 5. Rates of withdrawal due to adverse events varied from 0-5 percent for the placebo group and 0-5 percent in the treatment group; a single trial did not report withdrawal rates. Two trials tested for statistical differences between groups and found none. Although no clear pattern emerges, three studies identified at least one balance-related adverse event.

Oxiracetam. Five studies^97-101 evaluated oxiracetam in 554 subjects with different dementia syndromes of mild to moderate severity. All studies used 1600 mg daily, with one exception where the dose ranged between 1600-2400 mg per day. The treatment interval ranged from 90 days to 26 weeks duration.

All outcomes shown to be positive for this drug were based on Observed Cases (OC) evaluation. The two trials that evaluated general cognitive function showed benefit. The findings for specific cognitive function were mixed. A single trial evaluated global assessment and showed statistically significant change. Behavior/mood and quality of life/ADL outcomes showed mixed results. No study evaluated caregiver burden.

The quality scores for reporting adverse events varied from 2 to 5. The proportion of withdrawals due to adverse events varied from 0-9 percent for the placebo group and 0-6 percent for the treatment group. No clear pattern for adverse events is evident, but three of the five studies reported gastrointestinal related problems, primarily abdominal pain.

Pentoxifylline. Three placebo-controlled studies^102-104 evaluated pentoxifylline and one study compared pentoxifylline to sulodexide, with a total of 482 subjects with predominately MID. The dose administered in all studies was 1200 mg per day but varied between once or three times daily. The treatment intervals ranged from 12 to 36 weeks.

All three placebo trials showed statistically non-significant findings for any primary outcome evaluated on all subjects in the study. Two of these trials had very small sample sizes (n=38, n=28) and employed Observed Cases (OC) analyses; this suggests that the trials lacked sufficient power to evaluate multiple outcomes. The remaining trial had a large sample size (n=289) and employed an Intention to Treat (ITT) analysis; all primary outcomes evaluated were not statistically significant.

The quality scores for reporting adverse events were generally low, varying from 1 to 3. Withdrawal rates due to adverse events varied from 0-25 percent in the placebo group and 0-22 percent in the treatment group. The two studies that reported adverse events indicated the presence of gastrointestinal disturbances, including abdominal pain and nausea and vomiting.

Propentofylline. Four trials^105-108 using propentofylline in 510 patients with AD and VaD were included. A dose of 900 mg per day was consistent across all studies, and the treatment duration ranged from 3 to 12 months.

Two studies with small sample sizes (n=30) showed no statistically significant results for any outcome evaluated but likely lacked power. There were two trials that found benefit in general cognitive function based on the Mini-Mental Status Exam (MMSE). The results for specific cognitive function as measured by the Digit Symbol Substitution Test (DSST) were mixed, as were those for global assessment. Behavior/mood outcomes were evaluated in a single trial and showed no statistically significant difference; this same trial evaluated quality of life/ADL and showed no statistically significant difference. No trial evaluated caregiver burden.

The quality scores for reporting adverse events varied from 1 to 4. The percentage of withdrawals varied from 0-13 percent for the placebo group and 0-12 percent for the treatment group. None of the trials tested for differences between groups. Three of the trials reported gastrointestinal events that included abdominal pain, constipation, and nausea and vomiting.

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