Analysis of genotype 2 and 3 hepatitis C virus variants in patients treated with telaprevir demonstrates a consistent resistance profile across genotypes.

Study C209 evaluated the activity of telaprevir in treatment-naïve patients with genotypes 2 or 3 (G2, G3) hepatitis C virus (HCV) infection. Telaprevir monotherapy showed potent activity against HCV G2, but limited activity against G3. This analysis was performed to characterize HCV viral variants emerging during telaprevir-based treatment of G2/G3 HCV-infected patients. Patients were randomized to receive 2 weeks of treatment with telaprevir (telaprevir monotherapy), telaprevir plus peginterferon alfa-2a and ribavirin (triple therapy), or placebo plus peginterferon alfa-2a and ribavirin (control), followed by 22-24 weeks of peginterferon/ribavirin alone. Viral breakthrough was defined as an increase >1 log10 in HCV RNA from nadir, or HCV RNA >100 IU/mL in patients previously reaching <25 IU/mL. Twenty-three patients (47%) had G2 and 26 (53%) had G3 HCV. Viral breakthrough occurred during the initial 2-week treatment phase in six G2 patients (66.7%; subtypes 2, 2a and 2b) and three G3 patients (37.5%; all subtype 3a), all in the telaprevir monotherapy arm. Four breakthrough patients (three G2, one G3) subsequently achieved sustained virologic response (SVR). In all patients with breakthrough and available sequence data, mutations associated with reduced susceptibility to telaprevir in genotype 1 (G1) HCV were observed. No novel G2/G3-specific mutations were associated with telaprevir resistance. The telaprevir resistance profile appeared consistent across HCV genotypes 1, 2 and 3. Although viral breakthrough with resistance occurred in patients receiving telaprevir monotherapy, half of these patients achieved an SVR upon addition of peginterferon/ribavirin highlighting the importance of combination therapy.

Effects of galantamine in Alzheimer's disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment.

To evaluate the effects of galantamine withdrawal, and compare this with uninterrupted therapy, two 6-week double-blind withdrawal studies (Studies 1 and 2) were performed. These enrolled individuals who had completed one of two 3- or 5-month randomized clinical trials (parent trials) involving patients with mild to moderate Alzheimer's disease (AD). In Study 1 (GAL-USA-11; n'723), patients continuously treated with galantamine 16 mg/day exhibited a mean (± standard error [SE]) improvement in 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale score of 1.8 (± 0.46) points at Week 6 compared with the parent trial baseline, (p < 0.001 vs placebo; observed cases analysis). Over the same period, patients switched from galantamine to placebo and those who had received continuous placebo, exhibited mean (± SE) deteriorations of 0.7 (± 0.49) and 1.2 (± 0.49) points, respectively. Similar trends were apparent in Study 2 (GAL-USA-5; n=118). In Study 1, subgroup analyses demonstrated cognitive benefits with continuing galantamine treatment and deterioration associated with galantamine withdrawal in patients with advanced moderate AD (baseline Mini-Mental State Examination score ≤14) and in individuals deemed non-responsive in terms of Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus) evaluation at the end of the parent trial (CIBIC-plus score > 4). No safety issues were identified. In patients with mild to moderate AD who have exhibited cognitive benefits from up to 5 months' galantamine treatment, continuing therapy reinforces previously achieved benefit, whereas in patients in whom galantamine is discontinued, although no safety concerns arise, the natural progression of AD is apparent.

Galantamine and behavior in Alzheimer disease: analysis of four trials.

OBJECTIVES: Many individuals with Alzheimer's disease (AD) experience behavioral and neuropsychiatric symptoms, which may cause caregiver distress and lead to the institutionalization of the patient. This analysis characterized behavioral symptoms and caregiver distress in trials of galantamine and their response to treatment. MATERIALS AND METHODS: Data were pooled from four randomized, placebo-controlled clinical trials of galantamine in patients with mild to moderate AD (three studies) or AD plus cerebrovascular disease (one study) (n = 2177). Behavior and associated caregiver distress were assessed in each study using the Neuropsychiatric Inventory (NPI) and NPI distress (NPI-D), respectively. RESULTS: After 5/6 months, but not after 3 months, NPI score was significantly improved with galantamine vs placebo (P = 0.013). The benefit was particularly pronounced in patients categorized as having advanced moderate AD. At 5/6 months, there was a numerical benefit of galantamine over placebo in terms of caregiver distress; the difference was statistically significant in patients with moderate or advanced moderate AD. CONCLUSIONS: Galantamine reduces behavioral symptoms in patients with mild to moderate AD, leading to reduced caregiver burden. The reductions were greatest in patients with moderate or advanced moderate disease.

Long-term response to galantamine in relation to short-term efficacy data: pooled analysis in patients with mild to moderate Alzheimer's disease.

BACKGROUND: This analysis aimed to identify an operational, clinically relevant definition of response achieved in short-term clinical trials to support the identification of patients with Alzheimer's disease (AD) who would benefit most from long-term galantamine therapy. METHODS: Data were analyzed from 6 randomized placebo-controlled trials of up to 6 months' duration, which included patients with mild to moderate AD receiving maintenance doses of galantamine 16-24 mg/day, and from 12 open-label extensions (galantamine 24 mg/day maintenance therapy). Assessments included changes from baseline in the 11-item AD Assessment Scale-Cognitive subscale (ADAS-Cog 11). RESULTS: Pooled analysis of the 5-6 month trial data showed that at the trial endpoint (2-5 months after reaching maintenance doses), the proportions of galantamine- (n=1,173) versus placebo-treated patients (n=801) with probable AD categorized according to "improved", "stable" or "non-rapid decline" criteria, were 45.8% versus 27.2%, 59.5% versus 37.1%, and 87.6% versus 69.7%, respectively (observed cases analysis), whilst changes in ADAS-Cog 11 scores versus baseline were -4.9, -4.7 and -2.9 points, respectively, for "improved", "stable" and "non-rapid decline" galantamine-treated patients (-1.5 points for galantamine recipients overall). "Improved" or "stable" galantamine-treated patients displayed mean improvement in ADAS-Cog 11 scores over baseline until 18 months after starting treatment, and attenuated deterioration thereafter; for galantamine-treated patients exhibiting "non-rapid decline", mean ADAS-Cog 11 score returned to baseline after approximately 12 months. CONCLUSIONS: Patients who demonstrate improvement, stability, or limited cognitive decline 2-5 months after reaching maintenance doses of galantamine are more likely to experience continued benefit from long-term galantamine therapy.

Effects of ritonavir-boosted darunavir vs. ritonavir-boosted atazanavir on lipid and glucose parameters in HIV-negative, healthy volunteers.

BACKGROUND: Darunavir (TMC114) is a new HIV protease inhibitor (PI). DESIGN: This Phase I, randomized, open-label trial compared the effects of darunavir plus low-dose ritonavir (RTV) (darunavir/RTV) with those of atazanavir/RTV on lipid and glucose parameters. METHODS: Forty-nine HIV-negative, healthy male volunteers received RTV 100 mg once a day (qd) for 7 days, followed by either darunavir/RTV 800/100 mg qd (n=25) or atazanavir/RTV 300/100 mg qd (n=24) for 21 days. Mean changes in fasting lipid and glucose parameters at day 28 were calculated using post-RTV alone (day 7) and baseline (day -1) values as references. Short-term safety, tolerability and RTV pharmacokinetic parameters were evaluated. RESULTS: After 7 days of RTV treatment, the mean triglyceride concentration increased by approximately 30 mg/dL in both groups, changes in other lipid and glucose parameters were relatively small. Mean concentrations of lipids and glucose over the treatment period were mostly similar between the treatment groups. Mean changes from day 7 to day 28 for the darunavir/RTV and atazanavir/RTV groups, respectively, were -3.6 and -0.5 mg/dL for high-density lipoprotein cholesterol; 5.0 and 5.3 mg/dL for low-density lipoprotein cholesterol; 4.9 and 1.2 mg/dL for total cholesterol; 6.4 and 14.0 mg/dL for triglycerides; -1.7 and -2.4 mg/dL for glucose; and -1.4 and 0.3 mg/dL for insulin. No grade 3 or 4 lipid or glucose laboratory abnormalities were reported. Treatment-emergent hyperbilirubinaemia was reported for all volunteers (including five grade 4 cases) during atazanavir/RTV treatment. CONCLUSIONS: Co-administration of darunavir or atazanavir with low-dose RTV resulted in minor and similar changes in lipid and glucose parameters in HIV-negative healthy volunteers.

Analyses of mortality risk in patients with dementia treated with galantamine.

OBJECTIVE: To analyze mortality data from patients with Alzheimer's disease (AD), Alzheimer's plus cerebrovascular disease (AD + CVD) or vascular dementia (VaD). METHODS: (1) Meta-analysis of mortality data from double-blind, placebo-controlled, randomized trials; and (2) recontact study to collect additional longer term mortality data from previous galantamine trial participants. RESULTS (META-ANALYSIS): Across 12 trials (< or =6 months duration), there was no increased risk of mortality associated with the use of galantamine (n = 4116) compared with that of placebo (n = 2386) (OR galantamine/placebo: 0.67, 95% CI 0.41-1.10). RESULTS (RECONTACT STUDY): Median survival was 79 months for patients with AD (n = 478) and 59 months for patients with AD + CVD (n = 180) or VaD (n = 145). Prolonged galantamine treatment (> vs < or =6 months) was not associated with decreased survival time (75 vs 61 months respectively; P = 0.02). Cox regression analyses were consistent with the Kaplan-Meier analyses. CONCLUSIONS: We found no short-term or longer term evidence of increased risk of mortality associated with the use of galantamine in patients with AD, AD + CVD or VaD.

Effects of galantamine in patients with mild Alzheimer's disease.

BACKGROUND: Galantamine is an acetylcholinesterase inhibitor that modulates nicotinic receptors. It is effective in mild to moderate Alzheimer's disease (AD) but no trial has focused exclusively on mild AD. We performed a post-hoc sub-set analysis using data from four randomised trials to explore the efficacy of galantamine versus placebo in mild AD. METHODS: Participants in all studies met NINCDS-ADRDA criteria for probable AD. We examined data from patients with baseline Mini Mental State Examination (MMSE) 21-24 who received galantamine 24 mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog), Clinician's Interview-Based Impression of Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales were compared. RESULTS: Of the 694 patients (362 GAL, 332 PLAC, mean baseline MMSE 22.4 +/- 1.1, mean age 74 +/- 7.9 years), 65% completed 6 months treatment (223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was -1.5 (95% confidence interval -2.2, -0.8, p < 0.001) for GAL and +0.2 (-0.6, 0.9, p = 0.72) for PLAC. This difference was statistically significant (p = 0.001). Significantly more patients receiving galantamine were classified as 'improved' using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally well tolerated; most common adverse events were nausea, vomiting and diarrhoea. CONCLUSIONS: Pooled data from four randomised trials of patients with mild AD indicate that patients who received galantamine 24 mg/day for 6 months improved cognition more often than those who received placebo and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment.

Ginkgo biloba compared with cholinesterase inhibitors in the treatment of dementia: a review based on meta-analyses by the cochrane collaboration.

Data were derived from the Cochrane Collaboration meta-analyses of the efficacies of ginkgo, donepezil, rivastigmine and galantamine on changes in cognitive function in patients with dementia and, where necessary, were transformed to standardized mean differences. The proportion of patients discontinuing trials was used as a proxy measure of tolerability. Outcomes were assessed after 6 months of treatment. Trial data for cholinesterase inhibitors were more consistent than those for ginkgo, particularly regarding patient populations and outcome measures. Significant benefits on cognition vs. placebo were seen with donepezil, 5 and 10 mg, rivastigmine, 6-12 mg, and galantamine, 16 and 24 mg. Significant benefit vs. placebo with ginkgo was seen only when all doses were pooled. Similar proportions of patients discontinued treatment with ginkgo and placebo. Cholinesterase inhibitors were also well tolerated, although a significantly greater proportion of patients receiving active treatment discontinued vs. placebo with some doses. An evidence-based medicine approach, taking into account the quality of clinical trials, is essential when assessing the safety and efficacy of medications.

Galantamine provides broad benefits in patients with 'advanced moderate' Alzheimer's disease (MMSE < or = 12) for up to six months.

We investigated whether galantamine (Reminyl), a cholinergic agent with a dual mode of action for the treatment of mild to moderate Alzheimer's disease (AD), would benefit patients with more advanced illness. We performed a post hoc analysis on pooled data from four pivotal studies in patients with 'advanced moderate' AD: baseline Mini-Mental State Evaluation (MMSE) scores < or = 12 (range 10-12; mean MMSE score 11) or Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores >30 (range 31-69; mean ADAS-cog score 39). Over 5-6 months, cognitive abilities were improved with galantamine versus placebo (p<0.001; mean treatment difference 6.5 points). At 6 months, galantamine benefited functional abilities (p<0.001 vs placebo). The first quartile of galantamine patients improved over baseline by 10.5 ADAS-cog points. Cognitive and functional abilities were maintained around baseline; behavioural symptoms were delayed. Over 6 months, galantamine provided a broad spectrum of benefits to patients with 'advanced moderate' AD.

A qualitative assessment of the neurological safety of antipsychotic drugs; an analysis of a risperidone database.

BACKGROUND: Neurological side effects of antipsychotic agents limit the use of these drugs, and development of newer antipsychotic agents has been focused on a reduced risk of extrapyramidal symptoms (EPS) as well as effective symptom control. METHODS: A qualitative analysis of EPS was performed using Extrapyramidal Symptom Rating Scale (ESRS) data from 11 double-blind risperidone trials. An ESRS factor analysis and maximum changes in ESRS scores were compared for the risperidone, haloperidol, and placebo groups. RESULTS: The factor analysis revealed five factors. Between-group comparisons showed no differences between placebo and 1 to 2 mg/day-risperidone groups. Parkinsonism, tremor, akathisia, and sialorrhea were more likely to occur with haloperidol than with placebo or risperidone at 1 to 6 mg/day. Similar results were noted by maximum changes in ESRS scores. At risperidone doses of more than 8 mg/day, acute EPS severity lay between that of the placebo and haloperidol groups. The severity of tardive dyskinesia was greater in patients receiving placebo than in those receiving either active treatment. CONCLUSIONS: As the results described above were derived from a post hoc analysis of an existing database, conclusions must remain tentative. To provide more definitive answers, EPS assessments in future studies should be refined to more accurately predict the type of EPS expected with a given agent in clinical practice.

Effects of risperidone on affective symptoms in patients with schizophrenia.

The effects of risperidone on affective symptoms were determined by an analysis of pooled data from six double-blind trials of risperidone versus haloperidol in 1254 patients with chronic schizophrenia. Symptoms indicating mania were assessed by the Positive and Negative Syndrome Scale (PANSS) excitement and grandiosity items and by the excited cluster (excitement, hostility, uncooperativeness, and poor impulse control); anxious / depressive symptoms were assessed by the PANSS anxious / depressive cluster (somatic concern, anxiety, guilt feelings, and depression). Mean change scores from baseline to endpoint were compared in patients receiving risperidone, haloperidol or placebo by analysis of variance with factors for trial and baseline score included in the model. In all patients, change scores on excitement and grandiosity items and excited and anxious / depressive clusters were significantly greater for risperidone than for haloperidol or placebo. Dropouts due to inefficacy were less frequent with risperidone (5 of 59; 8%) than with haloperidol (7 of 38; 18%) or placebo (8 of 10; 80%). In patients with anxious / depressive symptoms at baseline (anxiety / depression cluster score > or = the median), anxiety / depression scores decreased significantly more with risperidone than with haloperidol, and symptom reduction occurred faster with risperidone. These results are consistent with previous reports and suggest that risperidone is more efficacious than haloperidol for affective symptoms in patients with schizophrenia.

A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms.

Combined data from double-blind risperidone studies were used to analyse the severity of extrapyramidal symptoms (EPS) associated with treatment in patients with chronic schizophrenia. Factors associated with maximum EPS severity were increasing risperidone dose (< or = 8 mg/day was similar to placebo), lower baseline EPS scores, and longer duration of psychotic symptoms, particularly in older patients. EPS severity was significantly greater in patients receiving haloperidol or other antipsychotics than in those receiving risperidone (4 to 8 mg/day) or placebo. Antiparkinsonian medications were required by significantly fewer patients treated with risperidone (4 to 8 mg/day) than by patients treated with haloperidol or other antipsychotics. Combined efficacy data showed that 4 to 8 mg/day was also the most efficacious dose range; there was no increase in efficacy with doses over 4 mg/day. Based on these data and post-marketing experience, 4 mg/day is an appropriate initial target dose for most patients with schizophrenia. Higher doses may be appropriate for patients with chronic illness, and lower doses may be appropriate for patients with a first psychotic episode or for elderly patients.

Prolactin levels and adverse events in patients treated with risperidone.

Hyperprolactinemia is a common clinical disorder that may lead to sexual dysfunction or galactorrhea. It may arise from a variety of etiologies, including the use of antipsychotic agents, presumably because of a dopamine receptor blockade. This analysis was designed to characterize the relationship between risperidone, serum prolactin levels, and possible clinical sequelae. All data from randomized, double-blind studies of risperidone in patients with chronic schizophrenia were analyzed. The two largest studies (the North American and multinational trials) included 841 patients (259 women, 582 men) with paired prolactin level data and 1,884 patients (554 women, 1,330 men) with data on six adverse events possibly associated with increased prolactin levels (amenorrhea, galactorrhea, and decreased libido in women; erectile dysfunction, ejaculatory dysfunction, gynecomastia, and decreased libido in men). Both risperidone and haloperidol produced dose-related increases in plasma prolactin levels in men and women. Among women, the risperidone dose was not correlated with adverse events, nor were the adverse events correlated with endpoint prolactin levels. Among men, the incidence of adverse events was positively correlated with risperidone dose; however, at risperidone doses of 4 to 10 mg/day the incidence of adverse events was not significantly higher than that observed in patients receiving placebo. Furthermore, adverse events in men were unrelated to plasma prolactin levels. Risperidone-associated increase in serum prolactin levels was not significantly correlated to the emergence of possible prolactin-related side effects.