Randomized controlled study of the histamine H3 inverse agonist MK-0249 in adult attention-deficit/hyperactivity disorder.

BACKGROUND: It has been suggested that the histamine subtype 3 receptor inverse agonists such as MK-0249 might be effective in treating attention-deficit/hyperactivity disorder (ADHD). We evaluated the effects of MK-0249 in adults with ADHD. METHOD: A randomized, double-blind, placebo-controlled, incomplete block, 2-period crossover study of MK-0249 5-10 mg/d and osmotic-release oral system (OROS) methylphenidate 54-72 mg/d (active comparator) was performed in 72 men and women aged ≥ 18 to ≤ 55 years who met DSM-IV criteria for ADHD of either inattentive or combined subtype and who had a chronic course of behavior disorder. The study was conducted from August 2007 through April 2008 at 6 US sites. Primary efficacy was assessed by the mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score after 4 weeks of treatment. RESULTS: Change from baseline in AISRS at week 4 for MK-0249 was not different from placebo (P = .341), whereas a significant benefit was seen for OROS methylphenidate versus placebo (P < .001). Analysis of secondary end points, including the Conners Adult ADHD Rating Scales, showed results consistent with the AISRS. A similar percentage of patients reported adverse events for MK-0249 compared with placebo (73% versus 69%, respectively). However, a greater percentage of patients reported insomnia as an adverse event with MK-0249 treatment compared with placebo (32% versus 11%, respectively). CONCLUSIONS: MK-0249 10 mg/d is not effective for the treatment of adult ADHD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00475735.

Randomized, controlled trial of telcagepant over four migraine attacks.

METHODS: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as ≥ 3 successes, and lack of consistent efficacy was defined as ≥ 2 failures, in treatment response. A total of 1677 patients treated ≥ 1 attack and 1263 treated all four attacks. RESULTS: Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2-24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence ≥ 2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%). CONCLUSION: Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704).

Comparison of the efficacy and tolerability of preservative-free and preservative-containing formulations of the dorzolamide/timolol fixed combination (COSOPT™) in patients with elevated intraocular pressure in a randomized clinical trial.

BACKGROUND: The aim of this study was to compare the efficacy and tolerability of preservative-free (PF) and preservative-containing (PC) formulations of the dorzolamide/timolol fixed combination (COSOPT™) in patients with elevated intraocular pressure (IOP). METHODS: A parallel, randomized, double-masked study was conducted. After a 3-week run-in on timolol, patients with ocular hypertension, as confirmed by an IOP ≥22 mmHg, were randomized 1:1 to receive PF or PC dorzolamide/timolol twice daily for 12 weeks. IOP was measured at hour 0 (drug trough) and hour 2 (drug peak) at baseline (last day of 3-week timolol run-in), and weeks 2, 6 and 12. RESULTS: A total of 261 patients were randomized. Mean baseline IOPs were 23.7 mmHg for both treatments at hour 0 and 21.2 mmHg for PF dorzolamide/timolol and 21.4 mmHg for PC dorzolamide/timolol at hour 2. At all study time points (trough and peak at weeks 2, 6, and 12), the difference between treatments in mean change from baseline IOP was <0.5 mmHg. The 95% confidence intervals for the estimated treatment difference (PF minus PC) in mean change from baseline IOP at week 12 was -0.86 to 0.23 mmHg for trough (primary endpoint) and -0.39 to 0.67 mmHg for peak (secondary endpoint). The most common adverse events were ocular burning/stinging, reported by 16.0% and 21.5% of patients receiving PF and PC dorzolamide/timolol respectively, and taste perversion, reported by 3.1% and 5.4% of patients receiving PF and PC dorzolamide/timolol respectively. CONCLUSIONS: In patients with elevated IOP, PF and PC dorzolamide/timolol were equivalent in efficacy for change in trough and peak IOP, and had generally similar tolerability.

Randomized, controlled, double-blind trial of taranabant for smoking cessation.

RATIONALE: It has been proposed that cannabinoid-1 receptor inverse agonists might be effective for smoking cessation. We evaluated this hypothesis with the cannabinoid-1 receptor inverse agonist taranabant. METHODS: Adults who smoked > or =10 cigarettes a day for >1 year and had an expired CO level of > or =10 ppm participated in a randomized, double-blind, 8-week, study of taranabant (N = 159) or placebo (N = 158). Taranabant was titrated from 2 mg once daily to 8 mg once daily. Patients received smoking cessation counseling. The primary efficacy endpoint was continuous abstinence, defined as no cigarettes assessed by daily patient self-report and verified by breath CO level (<10 ppm) and plasma cotinine test (<10 ng/ml), during the last 4 weeks of the 8-week treatment period. RESULTS: The percentage of patients achieving continuous abstinence was 7.5% for taranabant 2-8 mg and 6.3% for placebo (odds ratio = 1.2 [90% confidence interval (CI), 0.6, 2.5], P = 0.678). Change from baseline in body weight in the taranabant 2-8-mg group was -1.5 (90% CI, -1.8, -1.3) versus 0.6 kg (90% CI, 0.4, 0.9) in the placebo group. Compared to placebo, taranabant 2-8 mg was associated with an increased incidence of psychiatric-related adverse events (e.g., depression, 8.2% versus 2.5%, P = 0.048), gastrointestinal-related adverse events (e.g., nausea, 49.7% versus 19.0%, P < 0.001), and flushing/hot flash adverse events (10.7% versus 1.9%, P = 0.002). CONCLUSIONS: Taranabant 2-8 mg did not improve smoking cessation and was associated with increased incidences of psychiatric-related, gastrointestinal-related, and flushing adverse events (ClinicalTrials.gov NCT00109135).

Item analysis of ADAS-Cog: effect of baseline cognitive impairment in a clinical AD trial.

We explored the association of Alzheimer's disease (AD) Assessment Scale (ADAS-Cog) item scores with AD severity using cross-sectional and longitudinal data from the same study. Post hoc analyses were performed using placebo data from a 12-month trial of patients with mild-to-moderate AD (N =281 randomized, N =209 completed). Baseline distributions of ADAS-Cog item scores by Mini-Mental State Examination (MMSE) score and Clinical Dementia Rating (CDR) sum of boxes score (measures of dementia severity) were estimated using local and nonparametric regressions. Mixed-effect models were used to characterize ADAS-Cog item score changes over time by dementia severity (MMSE: mild =21-26, moderate =14-20; global CDR: mild =0.5-1, moderate =2). In the cross-sectional analysis of baseline ADAS-Cog item scores, orientation was the most sensitive item to differentiate patients across levels of cognitive impairment. Several items showed a ceiling effect, particularly in milder AD. In the longitudinal analysis of change scores over 12 months, orientation was the only item with noticeable decline (8%-10%) in mild AD. Most items showed modest declines (5%-20%) in moderate AD.

Effect of gaboxadol on sleep in adult and elderly patients with primary insomnia: results from two randomized, placebo-controlled, 30-night polysomnography studies.

STUDY OBJECTIVES: To evaluate the efficacy and tolerability of gaboxadol in the treatment of adult and elderly patients with primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled, multicenter, 30-night, polysomnography studies. SETTING: Sleep laboratory. PATIENTS: Primary insomnia, 18-64 y (adult study), or > or =65 y (elderly study). INTERVENTIONS: Adult study: gaboxadol 15 mg (GBX15; N = 148), 10 mg (GBX10; N = 154), or placebo (N = 156); elderly study: GBX10 (N = 157), gaboxadol 5 mg (GBX5; N = 153), or placebo (N=176). MEASUREMENTS AND RESULTS: Primary endpoints were wake after sleep onset (WASO) and latency to persistent sleep (LPS). Slow wave sleep (SWS) was a secondary endpoint. Analyses were based on the change from baseline for the average of nights 1/2, and nights 29/30, and compared gaboxadol versus placebo. Exploratory endpoints included patient's subjective assessment of total sleep time (sTST), WASO (sWASO), time to sleep onset (sTSO), and number of awakenings (sNAW); these analyses were based on weekly means. 1) Adult study. GBX15 significantly (P < or = 0.05) improved WASO through nights 29/30 but had no significant effects on LPS. No significant differences were seen for GBX10 versus placebo on WASO or LPS. GBX15 and GBX10 enhanced SWS. GBX15 significantly improved sTST, sWASO, sTSO, and sNAW at weeks 1 and 4. 2) Elderly study. GBX10 significantly improved WASO through nights 29/30; a significant improvement was also seen for GBX5 at nights 1/2 but this was not maintained through nights 29/30. GBX10 significantly improved LPS at nights 1/2 but the improvement was not maintained through nights 29/30; no significant differences were seen for GBX5 versus placebo on LPS. GBX10 and GBX5 enhanced SWS. GBX10 significantly improved sTST at week 1, and sTST, sWASO, and sNAW at week 4. Gaboxadol was generally well tolerated in both studies. CONCLUSIONS: The maximum studied doses of gaboxadol (GBX15 in adult patients and GBX10 in elderly patients) were effective at enhancing objective polysomnography measures of sleep maintenance and SWS, and also some subjective sleep measures, over 30 nights but had little or no effects on sleep onset. The clinical relevance of the enhancement of SWS by gaboxadol is unclear.

Rofecoxib in patients with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial.

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis -- a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive side-effects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

Is bigger better for depression trials?

OBJECTIVE: A key assumption underlying the principle that power increases with sample size is that the standardized effect size is fixed over time. In therapeutic areas where it may be difficult to continually recruit from a homogeneous population, this assumption may not be valid; patients randomized toward the end of enrollment may derive from a more heterogeneous population and negatively impact the power of a study. Post hoc analyses were performed on clinical data from four phase III depression trials with paroxetine to evaluate this possibility. METHODS: Each study used a randomized, double-blind, placebo-controlled design and enrolled approximately 150 patients per treatment arm. Plots of observed p-values for the treatment difference between paroxetine and placebo (on the HAM-D17 change from baseline score at week 8) by cumulative enrollment were made for each study. RESULTS: As previously reported, three of the four studies showed an overall significant treatment effect and one did not. In each study, a significant treatment effect was observed before approximately 100 patients had been enrolled per treatment arm. Continuing to enroll additional patients did not maintain the achieved level of significance in most instances, and in one case appeared to alter a potentially positive study into a failed study. Plots of p-values versus cumulative enrollment by patient quarters using combined data from all four studies suggested that late-enrolling patients were more likely to be placebo responders than early-enrolling patients. Hypothesized explanations for this finding include a depleted pool of depressed patients and the rush for patient recruitment at the end of a study in order to meet completion timelines. However, no corroborative evidence could be found to support either possibility. CONCLUSIONS: This analysis demonstrates that bigger is not necessarily better for depression trials.

Efficacy of the dorzolamide/timolol fixed combination versus latanoprost in the treatment of ocular hypertension or glaucoma: combined analysis of pooled data from two large randomized observer and patient-masked studies.

In previous analyses of primary efficacy data from two randomized clinical trials, standard dosing regimens of the dorzolamide/timolol fixed combination (COSOPT) and latanoprost (XALATAN) were shown to have equivalent efficacy with regard to reduction in mean daytime diurnal intraocular pressure (IOP). We performed additional post hoc analyses of pooled data from these studies to compare further the efficacy of the two treatments. The studies used identical 3-month, parallel group, randomized, observer-masked and patient-masked, multicenter designs. Patients with a baseline IOP > or = 24 mm Hg were randomized to either the 2% dorzolamide/0.5% timolol combination eye drops twice daily (n = 273) or 0.005% latanoprost eye drops once daily (n = 271). The IOP measurements were made at 8 AM, 10 AM, 2 PM, and 4 PM at the baseline visit and then on each of the 3 monthly assessment days. The following measures were analyzed on a post hoc basis: 1) percentages of patients meeting target levels of IOP reduction; 2) mean IOP reduction in those patients with high IOP (> or =30 mmHg) at baseline; 3) mean IOP at each of the assessment time points during a day. A total of 259 patients in the dorzolamide/timolol group and 268 patients in the latanoprost group were included in the efficacy analysis. At 3 months, both treatments showed similar efficacy with regard to the percentages of patients who achieved target levels of IOP reduction (e.g., 40% IOP reduction in 15% of dorzolamide/timolol combination patients and 13% of latanoprost patients), mean IOP reduction in those patients with high IOP at baseline (dorzolamide/ timolol combination, 12.5 mmHg, latanoprost, 12.6 mmHg), and mean IOP at each time point during the day. By the measures used in this analysis, the dorzolamide/timolol combination and latanoprost were equally effective at lowering IOP in patients with ocular hypertension or glaucoma.

A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment.

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients > or =65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine. BACKGROUND: A previous small open-label study in migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used in the treatment of asthma. We sought to confirm these findings in a randomized controlled trial. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-groups study enrolled adult migraine outpatients who experienced > or =3 and < or =8 migraine attacks per month for the last 6 months. Patients were entered into a 2-month, single-blind, placebo run-in phase. Only patients who experienced > or =3 migraine attacks in the second month were eligible to enter the subsequent 3-month, double-blind treatment phase of the study. The primary efficacy endpoint was the percentage of patients reporting at least a 50% decrease in migraine attack frequency per month during the double-blind treatment period (months 3-5) compared to baseline (run-in month 2). RESULTS: A total of 93 patients were randomized to montelukast 20 mg and 84 patients to placebo at the end of the placebo run-in month 2; 76 patients on montelukast and 72 patients on placebo completed the double-blind treatment period. Over 3 months of treatment, there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (P= .304). In addition, montelukast 20 mg was not significantly superior to placebo on any of the secondary endpoints. There were no differences between treatment groups for adverse events. CONCLUSION: Montelukast 20 mg was well tolerated in migraine patients but was not an effective prophylactic for prevention of migraine.

Efficacy and tolerability of the dorzolamide 2%/timolol 0.5% combination (COSOPT) versus 0.005% (XALATAN) in the treatment of ocular hypertension or glaucoma: results from two randomized clinical trials.

PURPOSE: To compare the efficacy of the fixed dorzolamide 2%/timolol 0.5% combination (COSOPT) versus latanoprost 0.005% (XALATAN). METHODS: Two 3-month, parallel group, randomized, observer-masked and patient-masked, multicentre, clinical trials were performed in patients with ocular hypertension or open-angle glaucoma. Study 1 (n=256) was conducted in the United States and Study 2 (n=288) was conducted in Europe/Israel. Patients could be included whether or not they were currently taking ocular hypotensive therapy, and regardless of the effectiveness of any previous therapy. Patients were washed out from their usual ocular hypotensive medications and then those with a baseline intraocular pressure (IOP) >/= 24 mmHg were randomized to either the dorzolamide/timolol combination eye drops twice daily or latanoprost eye drops once daily in both eyes. Efficacy was assessed by daytime diurnal IOP (the mean of measurements made at 0800, 1000, 1400 and 1600 h). RESULTS: At baseline, the mean daytime diurnal IOP was 26.1 mmHg in the dorzolamide/timolol combination group versus 25.6 mmHg in the latanoprost group in Study 1, and 25.3 mmHg in the dorzolamide/timolol combination group versus 24.7 mmHg in the latanoprost group in Study 2. After 3 months, the mean daytime diurnal IOP was 18.9 mmHg for the dorzolamide/timolol combination versus 18.4 mmHg for latanoprost in Study 1, and 17.4 mmHg for the dorzolamide/timolol combination versus 17.5 for latanoprost in Study 2. The difference between treatments in mean IOP change at 3 months was -0.04 mmHg [95% confidence interval (CI) -0.85, 0.77] in Study 1, and -0.57 mmHg (95% CI -1.31, 0.16) in Study 2. The probability that the true difference lay between -1.5 and 1.5 mmHg, the predefined bounds for equivalence, was >0.950 in both studies. Both treatments were well tolerated over 3 months, although ocular stinging occurred more frequently with the dorzolamide/timolol combination. CONCLUSIONS: The dorzolamide/timolol combination and latanoprost were equally effective at lowering IOP.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that enhances prevention of chemotherapy-induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5-hydroxytryptamine(3) (5-HT(3)) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study. METHODS: In this open-label, randomized, single-period study, 16 healthy male subjects were enrolled. Subjects received one of two oral aprepitant regimens for 5 days (8 subjects per regimen): (1) 125 mg aprepitant on day 1 and then 80 mg/d on days 2 to 5 or (2) 40 mg aprepitant on day 1 and then 25 mg/d on days 2 to 5. All subjects also received a single oral dose of midazolam, 2 mg, at prestudy (3 to 7 days before aprepitant treatment) and on days 1 and 5 (1 hour after aprepitant administration). RESULTS: Coadministration of midazolam and 125/80 mg aprepitant increased the midazolam area under the plasma concentration-time curve by 2.3-fold on day 1 (P <.01) and by 3.3-fold on day 5 (P <.01), as compared with midazolam alone (prestudy). The 125/80-mg regimen of aprepitant also increased the midazolam maximum observed concentration by 1.5-fold on day 1 (P <.05) and by 1.9-fold on day 5 (P <.01). The midazolam half-life values increased from 1.7 hours (prestudy) to 3.3 hours on both day 1 and day 5. Coadministration of 40/25 mg aprepitant and midazolam did not result in significant changes in the midazolam area under the plasma concentration-time curve, maximum observed concentration, and half-life at either day 1 or day 5. CONCLUSIONS: The 5-day 125/80-mg regimen of aprepitant produced moderate inhibition of CYP3A4 activity in humans, as measured with the use of midazolam as a probe drug.

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated. METHODS: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen. RESULTS: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P <.010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P <.010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P <.010). CONCLUSIONS: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.

Telephone screening for amnestic mild cognitive impairment.

OBJECTIVES: To evaluate the utility of telephone screening for identifying subjects with amnestic mild cognitive impairment (aMCI) for enrollment in a clinical trial and to identify which elements of the modified Telephone Interview for Cognitive Status (TICS-m) best predicted the in-clinic determination of aMCI. METHODS: Subjects aged >/=65 years with memory complaints responded to an advertisement for a clinical trial by calling a central telephone recruiting agency. To determine eligibility, subjects went through a stepwise selection procedure involving a review of major protocol inclusion and exclusion criteria, followed by administration of the Category Fluency Test (CFT) and then the TICS-m. Subjects meeting entry criteria, who obtained a score of /=24 on the Mini-Mental State Examination and a score of

Further evaluation of rizatriptan in menstrual migraine: retrospective analysis of long-term data.

OBJECTIVE: To determine the long-term efficacy of oral rizatriptan 10-mg wafers in the treatment of menstrual migraine attacks. METHODS: Data from an extension study where patients with migraine used rizatriptan 10 mg to treat moderate or severe migraine attacks occurring over periods of up to 6 months were included in a retrospective analysis. Patients used a diary card to record details of each migraine attack and onset of menstruation. Attacks in women were classified as menstrual or nonmenstrual according to 3 time windows relative to onset of menstruation (day 0): -3 to +3 days (7-day window), -2 to + 2 days (5-day window), and 0 to +1 days (2-day window). The analysis looked at the efficacy of rizatriptan 10 mg by menstrual category of attack for each definition on three measures: pain relief at 2 hours (reduction of pain to mild or none), pain free at 2 hours, 24-hours sustained pain free (pain free at 2 hours with no headache recurrence and no use of additional medications from 2 to 24 hours). RESULTS: Ninety-five women used rizatriptan 10 mg to treat a total of 1,839 attacks. The percentage of menstrual attacks was 30% for the -3 to +3 days definition, 23% for the -2 to +2 days definition, and 11% for the 0 to +1 days definition. Rizatriptan 10 mg was equally effective in menstrual and nonmenstrual migraine attacks regardless of the definition used. For example, using the -3 to +3 days definition, 78% of menstrual migraine attacks were relieved at 2 hours after dosing compared with 78% of nonmenstrual attacks. Pain relief rates for the other definitions were as follows: -2 to +2 days, menstrual = 78%, nonmenstrual = 78%; 0 to +1 days, menstrual = 79%, and nonmenstrual = 78%. No differences between menstrual and nonmenstrual attacks were found for the 2-hour pain free and 24-hour sustained pain free measures for any of the three definitions. CONCLUSIONS: Rizatriptan 10-mg wafers were equally effective in the treatment of menstrual and nonmenstrual migraine attacks occurring over 6 months, regardless of the precise definition of menstrual association used and even when the outcome criteria were very stringent. These data provide further evidence that triptans are effective treatments for menstrual migraine.

Restoring migraine sufferers' ability to function normally: a comparison of rizatriptan and other triptans in randomized trials.

BACKGROUND: Many migraine patients are unable to function normally during a migraine attack. Assessments of treatment efficacy have tended to focus on migraine symptoms, rather than looking at functional impact. This study compared the efficacy of different oral triptans for restoring normal function in migraine sufferers. METHODS: Retrospective subgroup analysis of data from five randomized, placebo-controlled, double-blind clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (772 attacks), 50 mg (2,227 attacks), and 25 mg (1,182 attacks), naratriptan 2.5 mg (413 attacks), and zolmitriptan 2.5 mg (578 attacks) for the acute treatment of a moderate or severe migraine attack. Functional disability was evaluated by patients on a 4-grade scale ('normal', 'mild impairment', 'severe impairment', 'requires bedrest') at baseline and at 0.5, 1, 1.5, 2, 3 and 4 h after dosing. This analysis looked at the percentage of patients who had normal functional ability at 2 h, the last time point before escape medications were allowed, in the subgroup of patients who had some level of disability at baseline. RESULTS: Most patients in each trial and treatment group had some level of disability at baseline (range = 94-100%). At 2 h, more patients on rizatriptan 10 mg were able to function normally compared with sumatriptan 100 mg (39 vs. 32%, odds ratio = 1.4, p = 0.021), sumatriptan 50 mg (47 vs. 42%, odds ratio = 1.2, p = 0.033), sumatriptan 25 mg (48 vs. 36%, odds ratio = 1.7, p < 0.001), naratriptan 2.5 mg (39 vs. 22%, odds ratio = 2.5, p < 0.001), and zolmitriptan 2.5 mg (45 vs. 36%, odds ratio = 1.6, p = 0.008). CONCLUSION: In direct head-to-head comparative clinical trials, oral rizatriptan 10 mg enabled more migraine sufferers to function normally at 2 h after dosing than oral sumatriptan, naratriptan, and zolmitriptan.

A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and tolerability of the highly selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib for the treatment of rheumatoid arthritis (RA). METHODS: A double blind, randomized, placebo and active comparator controlled, 12 week study conducted at 88 US sites. Eligible patients were chronic nonsteroidal antiinflammatory drug (NSAID) users with clinical worsening of RA upon withdrawal of prestudy NSAID. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures: patient and investigator global assessments of disease activity and direct assessment of arthritis by counts of tender and swollen joints. Key secondary measures: patient global assessment of pain, the Stanford Health Assessment Questionnaire, and the percentage of patients both completing the study and meeting the ACR20 criteria. Tolerability was assessed by tabulation of adverse events and routine laboratory evaluations. RESULTS: In all, 816 patients were randomized (placebo = 323, etoricoxib = 323, naproxen = 170), and 448 completed 12 weeks of treatment (placebo = 122, etoricoxib = 230, naproxen = 96). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p < 0.01). Compared with patients receiving naproxen, patients receiving etoricoxib demonstrated significant improvements (p < 0.05) on all primary endpoints and most other endpoints including ACR20 criteria. The percentage of patients who achieved an ACR20 response and who completed the study was 21%, 53%, and 39% in the placebo, etoricoxib and naproxen groups, respectively. Etoricoxib and naproxen were both generally well tolerated. CONCLUSION: In this study, etoricoxib 90 mg once daily was more effective than either placebo or naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in patients with RA.

A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273].

BACKGROUND: Etoricoxib is a highly selective COX-2 inhibitor which was evaluated for the treatment of rheumatoid arthritis (RA). METHODS: Double-blind, randomized, placebo and active comparator-controlled, 12-week study conducted at 67 sites in 28 countries. Eligible patients were chronic NSAID users who demonstrated a clinical worsening of arthritis upon withdrawal of prestudy NSAIDs. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures included direct assessment of arthritis by counts of tender and swollen joints, and patient and investigator global assessments of disease activity. Key secondary measures included the Stanford Health Assessment Questionnaire, patient global assessment of pain, and the percentage of patients who achieved ACR20 responder criteria response (a composite of pain, inflammation, function, and global assessments). Tolerability was assessed by adverse events and routine laboratory evaluations. RESULTS: 1171 patients were screened, 891 patients were randomized (N = 357 for placebo, N = 353 for etoricoxib, and N = 181 for naproxen), and 687 completed 12 weeks of treatment (N = 242 for placebo, N = 294 for etoricoxib, and N = 151 for naproxen). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p<0.05). Treatment responses were similar between the etoricoxib and naproxen groups for all endpoints. The percentage of patients who achieved ACR20 responder criteria response was 41% in the placebo group, 59% in the etoricoxib group, and 58% in the naproxen group. Etoricoxib and naproxen were both generally well tolerated. CONCLUSIONS: In this study, etoricoxib 90 mg once daily was more effective than placebo and similar in efficacy to naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in RA patients.

A comparison of visual analog scale and categorical ratings of headache pain in a randomized controlled clinical trial with migraine patients.

A visual analog scale (VAS) method of assessing headache pain was compared with a standard categorical four-grade scale (4GS) in a randomized, placebo-controlled, double-blind, clinical trial involving 792 treated migraine outpatients who received oral rizatriptan 5 mg, sumatriptan 50 mg, or placebo for a moderate or severe headache. The VAS and 4GS were equally useful in demonstrating that the active drugs were superior to placebo at reducing headache pain, and in showing that the active drugs were similarly effective. For both rizatriptan and sumatriptan, slightly larger effect sizes were observed with the 4GS compared with the VAS. In analyses using data combined across all treatment groups, VAS and 4GS scores were highly correlated. Use of the VAS imposed additional administrative burdens. These findings suggest that the 4GS may be the preferred scale for assessing headache pain in clinical trials involving adult migraineurs.