A novel metric for treatment durability in clinical trials of minimally invasive treatments for benign prostatic hyperplasia.

Introduction: Clinical trial manuscripts commonly report results of individual endpoints. However, durability of a medical treatment may be difficult to determine when evaluating endpoint outcomes individually. We reviewed pivotal trial manuscripts of two minimally invasive benign prostatic hyperplasia (BPH) treatments and estimated the rate of treatment durability using a composite, symptom-centric metric.Methods: Data were derived from published pivotal trial reports of two minimally invasive BPH treatments - water vapor thermal therapy (WVTT) and prostatic urethral lift (PUL). We estimated the risk of medical or surgical retreatment using life-table methods, and the number of patients achieving the minimal clinically important difference (MCID) for the International Prostate Symptom Score (IPSS) using z-score methods. Treatment durability was defined as a MCID on the IPSS at the 4-year follow-up visit while free from medical or surgical retreatment.Results: Comparing WVTT to PUL, the rate of medical or surgical retreatment was 10.6% vs. 31.8%, the IPSS MCID was achieved in 82.2% vs. 79.5%, and treatment durability rates were 71.8% vs. 51.7%.Conclusions: Utilization of a composite treatment durability metric derived from endpoints commonly reported in the BPH literature may allow patients and their providers to make better informed treatment decisions.

Cerebrospinal shunt infection in patients receiving antibiotic-impregnated versus standard shunts.

OBJECT: Cerebrospinal fluid shunt infections are associated with significant morbidity and mortality in the treatment of adult and pediatric hydrocephalus. Antibiotic-impregnated shunt (AIS) catheters have been used with the aim of reducing shunt infection. While many studies have demonstrated a reduction in shunt infection with AIS, this reported efficacy has varied within the literature. METHODS: The authors performed a systematic literature review to identify all published articles comparing the incidence of CSF shunt infection in AIS versus non-AIS catheters. The incidence of infection for AIS versus non-AIS catheters was calculated using the Mantel-Haenszel common odds ratio, and baseline demographics were compared between AIS and non-AIS cohorts. RESULTS: Twelve AIS versus non-AIS cohort comparisons were identified in the literature (5 pediatric hydrocephalus, 3 adult hydrocephalus, and 4 mixed populations). In a total of 5613 reported shunt procedures (2664 AISs vs 2949 non-AISs), AISs were associated with a reduction in shunt infection (3.3% vs 7.2%; OR 0.439, p < 0.0001). In 787 shunt procedures for adult hydrocephalus (427 AIS vs 360 non-AIS), AISs were associated with reduction in shunt infection (0.9% vs 5.8%; OR 0.153, p < 0.0001). In 1649 shunt procedures for pediatric hydrocephalus (854 AIS vs 795 non-AIS), AISs were associated with reduction in shunt infection (5.0% vs 11.2%; OR 0.421, p < 0.0001). CONCLUSIONS: The authors' systematic review of the literature demonstrates that AIS catheters are associated with a significant reduction over non-AIS catheters in the reported incidence of CSF shunt infection in adult and pediatric populations. The AIS catheters do not appear to be associated with an increased incidence of antibiotic-resistant microorganisms. Prospective, randomized trials are needed to firmly assess and confirm this apparent difference in infection incidence.

A nonradiographic system for assessing pressure for the Codman-Hakim Programmable Valve.

BACKGROUND: The Codman-Hakim Programmable Valve is widely used in shunting hydrocephalus and other conditions. OBJECT: To establish an accurate valve verification system for the Codman-Hakim programmable valve that does not require radiographic exposure. METHODS: Prospective clinical trial tested a new valve verification system at 9 research sites. RESULTS: The Valve Programming and Verification System allowed us to establish the valve setting in 62% of subjects with a programmable valve. CONCLUSION: The Valve Programming and Verification System avoids radiation exposure, is cost-effective, and time efficient for the patient and provider. In approximately one third of subjects, those in whom "adjustment complete" is not achieved, cranial radiographs are still needed.

The use of implanted programmable infusion pumps in the management of nonmalignant, chronic low-back pain.

Objectives. To assess the mode-of-use of implanted programmable infusion pumps in patients with nonmalignant, chronic low-back pain. Materials and Methods. Charts from 101 consecutive eligible patients were analyzed retrospectively. Data were extracted relating to patient demographics, pump mode of infusion and flow rate, and medications used. Results. Morphine was the agent most frequently used and most patients received one medication at each visit. At the last visit, 94.1% of patients were receiving constant-flow treatment; 90.1% had received such treatment for ≥ six months and 68.3% throughout the entire analysis period. For patients attaining constant-flow treatment, mean time from implantation to start of such treatment was 2.7 months. Discussion. The results suggest that many patients with nonmalignant low-back pain could be implanted with a constant-flow pump when their programmable device needs replacing or, in some cases, at the start of intrathecal treatment. This would reduce costs and the requirement for surgery.

Management of patients with Alzheimer's disease plus cerebrovascular disease: 12-month treatment with galantamine.

UNLABELLED: We evaluated the long-term cognitive effects and safety of galantamine 24 mg/day in patients with Alzheimer's disease plus cerebrovascular disease (AD + CVD or mixed dementia). Subgroup analysis was performed of patients with AD + CVD who participated in a 6-month, multicenter, randomized, double-blind, parallel-group study and a 6-month, open-label, active-treatment extension. METHOD: Two hundred and eighty-five patients with AD + CVD were randomized to receive either placebo (n = 97) or galantamine 24 mg/day (n = 188) for 6 months. Two hundred and thirty-eight (84%) patients continued with the open-label phase of the study (86 from the placebo group, 152 from the galantamine group) and were treated with galantamine 24 mg/day. The primary efficacy measure was cognitive performance as assessed using the eleven-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog/11). Standard safety evaluations and adverse-event monitoring were performed throughout the 12-month study period. Patients with AD + CVD treated with galantamine experienced statistically and clinically significant improvement in cognition at month 6 (mean change in ADAS-cog/11 score -1.1; p < or = 0.05 vs. baseline) and maintained their cognitive function for the entire 12-month study (mean change in ADAS-cog/11 score +0.1). In contrast, the cognitive function deteriorated among those in the placebo group (mean change in ADAS-cog/11 at month 6 +2.0; p < or = 0.001 vs. baseline). Patients with AD + CVD who were switched from placebo to galantamine for the open-label phase of the trial did show improvement in cognitive function; however, they never attained the same cognitive level as patients who had been treated with galantamine for the entire 12 months [mean (+/- SE) ADAS-cog/11 scores in the placebo/galantamine group 25.7 +/- 1.32 and 24.2 +/- 1.57 at months 6 and 12, respectively, and in the galantamine/galantamine group 21.5 +/- 0.87 and 22.2 +/- 1.06 at months 6 and 12, respectively]. The results of this subgroup analysis indicate that galantamine is effective for long-term maintenance of the cognitive function in patients with AD + CVD and is safe and well tolerated in this patient population.

Galantamine in the treatment of cognitive decline in patients with vascular dementia or Alzheimer's disease with cerebrovascular disease.

INTRODUCTION: Alzheimer's disease and vascular dementia are the two most common types of dementia, with significant overlap of clinical symptoms and pathology. Previous results from a 6-month, double-blind, placebo-controlled, international, multicentre study of the cholinomimetic galantamine in patients with probable vascular dementia or mixed dementia (Alzheimer's disease with cerebrovascular disease) showed significant cognitive, behavioural and functional benefits in these patients. Furthermore, results of a 6-month, open-label extension of this study confirmed that patients with vascular dementia or Alzheimer's disease with cerebrovascular disease may benefit from galantamine therapy for at least 1 year. The objective of the current analysis was to determine if the long-term cognitive benefits of galantamine seen in the above-mentioned study are influenced by dementia type (probable vascular dementia vs Alzheimer's disease with cerebrovascular disease). STUDY DESIGN: A post hoc sub-analysis of a 6-month, multicentre, randomised, double-blind, placebo-controlled study and a subsequent 6-month, open-label extension. PATIENTS AND METHODS: Patients diagnosed with probable vascular dementia or Alzheimer's disease with cerebrovascular disease were treated with galantamine (Reminyl) 24 mg/day for 12 months (6 months double-blind and 6 months open-label) or placebo for 6 months (double-blind) followed by galantamine 24 mg/day for 6 months (open-label). Changes in scores on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog/11) were assessed at months 6, 7.5 and 12. Mean changes from baseline were analysed. RESULTS: Patients with probable vascular dementia treated with galantamine for 6 or 12 months showed significant improvements in ADAS-cog/11 scores versus baseline, which were maintained at the end of the 12-month study. Patients who had Alzheimer's disease with cerebrovascular disease continuously treated with galantamine maintained the cognitive abilities seen at baseline for at least 12 months. Additionally, patients who had Alzheimer's disease with cerebrovascular disease who were switched from placebo to open-label galantamine therapy for 6 months demonstrated cognitive benefits, but these benefits were significantly less than those observed in patients treated with galantamine continuously for the 12-month period. Galantamine was well tolerated throughout the entire 12-month study. CONCLUSIONS: These findings suggest that the drug is efficacious for such common forms of dementia as vascular dementia and Alzheimer's disease with cerebrovascular disease. Moreover, some patients benefit from galantamine therapy that is initiated early, soon after diagnosis, and continued for at least 1 year.

Sleep-related outcomes in persons with mild to moderate Alzheimer disease in a placebo-controlled trial of galantamine.

STUDY OBJECTIVES: To recognize the potential effect of acetylcholinesterase-inhibiting medications on sleep quality when used for the treatment of mild to moderate Alzheimer disease and describe sleep outcomes for patients treated with galantamine. DESIGN: This study examined sleep quality among individuals with mild to moderate Alzheimer disease using data from a 3-month, double-blind, flexible-dose trial of galantamine. The hypothesis was no difference in sleep quality between galantamine- and placebo-treated subjects. PATIENTS: 136 patients treated with galantamine 24 mg per day and 125 patients treated with placebo. MEASUREMENTS: Based on caregiver reports, the sleep-related outcome measures were the Pittsburgh Sleep Quality Index and the sleep disorders item from the Neuropsychiatric Inventory. Using a P-value of 0.05 (2-tailed), analysis of covariance was used to compare treatments on mean change from baseline to month 3 (Pittsburgh Sleep Quality Index) or mean score at month 3 (Neuropsychiatric Inventory), adjusted for baseline score and investigator. RESULTS: Both patient groups had an average age of 75 years and a mean Mini-Mental Status Examination score of 20. There were no significant differences between groups on the Pittsburgh Sleep Quality Index total (P=0.59) or subscales. For galantamine and placebo, the mean adjusted changes from baseline on the total Pittsburgh Sleep Quality Index were 0.01 and -0.17, respectively. There also was no difference on the Neuropsychiatric Inventory sleep score at month 3 (P=0.51). CONCLUSIONS: Medications to treat Alzheimer disease should maintain sleep quality and have a neutral effect on sleep. These results further confirm the lack of sleep problems associated with galantamine treatment.

An open-label extension trial of galantamine in patients with probable vascular dementia and mixed dementia.

BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are the most common types of dementia worldwide. Galantamine, an acetylcholinesterase inhibitor and allosteric nicotinic modulator, has shown broad clinical benefits in patients with mild to moderate dementia due to AD, probable VaD, or AD with cerebrovascular disease (CVD)-so-called mixed dementia. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profiles of galantamine 24 mg/d in patients with VaD or AD with CVD over the longer term (>6 months). METHODS: This was an open-label extension of a 6-month double-blind study of galantamine. Patients who had been randomized to receive galantamine 24 mg/d or placebo in the double-blind phase were eligible to continue open-label treatment with galantamine 24 mg/d for 6 months. The primary efficacy end point was change in cognition, based on scores on the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11). Secondary measures included changes in functional ability (as measured on the Disability Assessment for Dementia [DAD]) and behavior (as measured on the Neuropsychiatric Inventory [NPI]). Safety and tolerability were also monitored. RESULTS: Four hundred fifty-nine patients (240 men, 219 women; mean [SE] age, 75.2 [0.33] years) entered the open-label phase. Of these patients, 195 (42.5%) had a diagnosis of probable VaD, and 238 (51.9%) had a diagnosis of AD with CVD; the remainder had an inconclusive diagnosis. At month 12 of the study, improvements from baseline (the start of the double-blind phase) in ADAS-cog/11 scores were observed in both the group that received placebo during the double-blind phase (placebo/galantamine group: -0.3 point; 95% CI, -1.64 to 1.06) and the group that received galantamine during the double-blind phase (galantamine/galantamine group: -0.9 point; 95% CI, -1.73 to 0.03). Improvement in functional ability was demonstrated by statistically significant mean (SE) changes from baseline in DAD score in both the placebo/galantamine group (-7.4 [1.68]; P < or = 0.001) and the galantamine/galantamine group (-3.6 [1.33]; P < or = 0.01). There was no significant change in mean (SE) NPI scores in either group (0.2 [0.98] and 0.1 [0.70], respectively). Galantamine treatment was well tolerated. CONCLUSIONS: In these patients with VaD and AD with CVD, galantamine treatment produced similar sustained benefits in terms of maintenance of or improvement in cognition (ADAS-cog/11), functional ability (DAD), and behavior (NPI) after 12 months.

A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease.

OBJECTIVE: To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer's disease. PATIENTS AND STUDY DESIGN: This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer's disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks. MAIN OUTCOME MEASURES: The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed. RESULTS: BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients' scores on the MMSE at week 52 did not differ significantly from baseline (-0.52 +/- 0.39, p < 0.5 vs baseline), whereas donepezil patients' scores deteriorated significantly from baseline (-1.58 +/- 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < or = 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12-18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 +/- 0.80 versus baseline, compared with an increase of 4.08 +/- 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p < or = 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments. Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials. CONCLUSIONS: Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.

Relevant clinical outcomes in probable vascular dementia and Alzheimer's disease with cerebrovascular disease.

Two important prerequisites for assessing therapeutic benefits in patients with vascular dementia (VaD), or Alzheimer's disease (AD) with cerebrovascular disease (CVD), are the inclusion of appropriate patients and the use of relevant outcome measures. There is substantial overlap in the clinical symptomatology, risk factors, imaging changes, pathophysiology and neurochemical mechanisms between VaD, AD and AD with CVD. While validated and acceptable clinical criteria suitable for clinical trials have been developed for VaD, there is still debate as to how mixed cases (i.e. AD with CVD) are best conceptualized. As with AD, there is consensus that outcome measures in studies of patients with VaD, or AD with CVD, should include assessments of cognitive and global function, of ability to perform activities of daily living (ADL) and of behavioral symptoms. Other measures, e.g., caregiver burden, would be desirable. Care must be taken in extrapolating AD-specific evaluations to VaD, however, because different specific domains are affected and the disease course is different. In clinical trials, cognitive performance and global function decline steadily in patients with untreated AD compared with smaller changes in patients with untreated VaD, while behavior and ADL deteriorate over 6 months in patients with either untreated AD or untreated VaD. Such differences in untreated outcome need to be considered when interpreting trial results using outcome measures that were largely designed for studies of patients with AD.

Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease.

Galantamine hydrobromide is a tertiary alkaloid drug that has been developed and approved in a number of countries including the USA and several countries in Europe as a treatment for mild-to-moderate Alzheimer's disease (AD). Galantamine has a unique, dual mode of action. It is a reversible, competitive inhibitor of acetylcholinesterase (AChE), and is the only drug actively marketed for the treatment of AD with proven activity as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs). This latter activity is thought to be particularly important since decreases in the expression and activity of nAChRs make a large contribution to the reduction in central cholinergic neurotransmission in patients with AD. Galantamine exhibits favorable pharmacokinetic characteristics including predictable linear elimination kinetics at the recommended maintenance doses (16 and 24 mg/day), a relatively short half-life (approximately 7 h) and high bioavailability. It is extensively metabolized in numerous pathways, mainly in the liver via cytochrome P450 enzymes CYP2D6 and CYP3A4, and has a low potential for clinically significant drug-drug interactions. During four large randomized, double-blind, placebo-controlled trials of up to 6 months duration, galantamine 16 and 24 mg/day significantly benefited cognitive and global function, ability to perform activities of daily living (ADL) and behavior, relative to placebo and baseline, for up to 6 months. Caregiver burden (time spent by caregivers supervising patients or assisting them with ADL), and caregiver distress (related to patients' behavioral symptoms) were also reduced. Cognitive and functional abilities were preserved at or near baseline for at least 12 months in patients who received galantamine 24 mg/day for 12 months in a long-term US study. These benefits were maximized by early and continued galantamine treatment and, again, were associated with significant reductions in caregiver burden. Trials of the efficacy of galantamine in dementia related to cerebrovascular disease have also yielded positive results. There are no safety concerns associated with the use of galantamine. The incidence of adverse events, particularly cholinergically mediated events affecting the gastrointestinal system, is generally low and can be minimized using the recommended slow dose-escalation scheme. Galantamine may, therefore, help to reduce the overall burden and cost involved in caring for dementia patients. Taking all evidence into account, galantamine has the potential to become a first-line therapy for dementia.

Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial.

BACKGROUND: Vascular dementia is the second commonest form of dementia, and vascular factors contribute to the development of dementia in many patients with Alzheimer's disease. Galantamine amplifies the acetylcholine response by inhibiting acetylcholinesterase and modulating nicotinic receptors. It has shown broad, sustained benefits in patients with Alzheimer's disease. We investigated the effects of galantamine in patients with a diagnosis of probable vascular dementia or Alzheimer's disease combined with cerebrovascular disease. METHODS: Eligible patients were randomly assigned galantamine 24 mg/day (n=396) or placebo (n=196) in a multicentre, double-blind, 6-month trial. Primary endpoints were cognition (Alzheimer's disease assessment scale, cognitive subscale [ADAS-cog]) and global functioning (clinician's interview-based impression of change plus caregiver input [CIBIC-plus]). Secondary endpoints included assessments of activities of daily living and behavioural symptoms. Patients were monitored for adverse events. Analyses were on the basis of observed case or last observation carried forward. FINDINGS: Galantamine showed greater efficacy than placebo on ADAS-cog (galantamine change -1.7 [SE 0.4] vs placebo 1.0 [0.5]; treatment effect 2.7 points; p<0.0001) and CIBIC-plus (213 [74%] vs 95 [59%] patients remained stable or improved, p=0.0001). Activities of daily living and behavioural symptoms were also significantly improved compared with placebo (p=0.002 and p=0.016, respectively). Galantamine was well tolerated. INTERPRETATION: Galantamine showed a therapeutic effect on all key areas of cognitive and non-cognitive abilities in this group of dementia patients.