Jeffrey Miceli

A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome

OBJECTIVE This study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS). METHODS This six-arm, double-blind, placebo-controlled, dose-response study randomized patients (N=137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose-response was characterized using an exponential decay model, which estimates the maximal effect (E(max)) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety. RESULTS The separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED(50)) and 90% (ED(90)) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related. CONCLUSIONS In this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.

Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome.

STUDY OBJECTIVES To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. DESIGN Randomized, double-blinded, crossover trial. SETTING Twenty-three US sleep centers. PARTICIPANTS Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance. INTERVENTIONS Participants were randomized across 6 treatment sequences comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole 0.5 mg/day (n = 76), or placebo (n = 73). MEASUREMENTS AND RESULTS Polysomnography was conducted over 2 nights at the end of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo) and key secondary endpoints were analyzed for statistical significance, with descriptive statistics for other endpoints. Pregabalin improved sleep maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P < 0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7 vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8 vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement arousal index (PLMAI) with pregabalin was similar to pramipexole and greater than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in sleep was less than for pramipexole. CONCLUSIONS This study demonstrated improvements in objective and subjective measures of sleep maintenance and sleep architecture with pregabalin compared with placebo and pramipexole. Effects of pregabalin on periodic limb movement arousal index were comparable to pramipexole. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT00991276; http://clinicaltrials.gov/show/NCT00991276.

Effects of Oral Ziprasidone and Oral Haloperidol on QTc Interval in Patients with Schizophrenia or Schizoaffective Disorder

Study Objective. To characterize the effect of oral ziprasidone and haloperidol on the corrected QT (QTc) interval under steady‐state conditions.

Ziprasidone and the corrected QT interval: A comprehensive summary of clinical data

AbstractBackground: Prolongation of the corrected QT interval (QTc) is understood to be a predictor of risk for ventricular arrhythmia; consequently, data on QTc effects of drugs are used by regulatory bodies to evaluate potential safety risks. Clinical pharmacology studies in adults receiving oral ziprasidone demonstrated a dose-dependent mean increase (4.5–19.5 milliseconds [ms]) in QTc over the range of 40–160mg/d with a small incremental increase (22.5 ms) at 320 mg/d. In a comparative study of ziprasidone versus five antipsychotics, the mean QTc increase at steady state maximum concentration (Cmax) for ziprasidone was 15.9 ms. Accordingly, the effects of ziprasidone on QTc were studied in phase II-IV randomized controlled trials (RCTs). Objective: The objective of this study was to provide clinicians and clinical researchers with a comprehensive analysis of QTc changes associated with ziprasidone based on data from Pfizer-sponsored phase II-IV RCTs in schizophrenia or bipolar disorder patients, safety reports and post-marketing surveillance. Methods: The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone: (i) post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies; (ii) post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults; (iii) post hoc analyses from phase II-IV adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and paediatric (5 studies) subjects; (iv) cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia; (v) a large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18 154 subjects with schizophrenia (the only previously reported results included here); and (vi) cardiac-related AEs presented in a ziprasidone post-marketing surveillance report created in 2007. Results: A total of 4306 adults received ziprasidone in placebo- and activecomparator phase II-IV RCTs and had evaluable QTc data. One subject reached a QTc ≥480 ms; 33 (0.8%) had a QTc ≥450 ms. QTc prolongation ≥30 ms was observed in 389 subjects (9.0%); ≥60 ms in 30 (0.7%); and ≥75 ms in 12 (0.3%). In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (± 20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (± 20.6) ms. Data from IM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate or lamotrigine, demonstrated similar QTc effects. A scatterplot of QTc prolongation against baseline QTc showed QTc prolongation ≥60 ms exclusively in adult subjects with a baseline QTc ≤400 ms. The final concentration-response analysis model, comprising 2966 data points from 1040 subjects, estimates an increase in QTc of 6 ms for each 100ng/mL increase in ziprasidone concentration. The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use. Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs. Conclusions: These analyses provide the first comprehensive summary of QTc changes associated with ziprasidone based on Pfizer-sponsored phase II-IV RCTs, safety reports and post-marketing surveillance. The results of the analyses of pooled data from phase II-IV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation ≥60ms (<1.0%) and rare observation of QTc ≥480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and post-marketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder.

Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: A randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder

BACKGROUND Antipsychotic agents have been associated with a prolonged QT interval. Data on the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE This study aimed to characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc interval at T(max). METHODS This randomized, single-blind study enrolled patients with schizophrenia or schizoaffective disorder in whom long-term antipsychotic therapy was indicated. Patients were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or haloperidol (7.5 and 10 mg) separated by 4 hours. The primary outcome measure was the mean change from baseline in QTc at the T(max) of each injection. Each dose administration was followed by serial ECG and blood sampling for pharmacokinetic determinations. Twelve-lead ECG data were obtained immediately before and at predetermined times after injections. ECG tracings were read by a blinded central reader. Blood samples were obtained immediately before and after injections. Point estimates and 95% CIs for mean QTc and changes from baseline in QTc were estimated. No between-group hypothesis tests were conducted. For the assessments of tolerability and safety profile, patients underwent physical examination, including measurement of vital signs, clinical laboratory evaluation, and monitoring for adverse events (AEs) using spontaneous reporting. RESULTS A total of 59 patients were assigned to treatment, and 58 received study medication (ziprasidone, 31 patients; haloperidol, 27; age range, 21-72 years; 79% male). After the first injection, mean (95% CI) changes from baseline were 4.6 msec (0.4-8.9) with ziprasidone (n = 25) and 6.0 msec (1.4-10.5) with haloperidol (n = 24). After the second injection, these values were 12.8 msec (6.7-18.8) and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate and blood pressure were observed with both treatments. None of the patients had a QTc interval >480 msec. Two patients in the ziprasidone group experienced QTc prolongation >450 msec (457 and 454 msec) and QTc changes that exceeded 60 msec (62 and 76 msec) relative to the time-matched baseline values. With haloperidol, QTc interval values were <450 msec with no changes >60 msec. Treatment-emergent AEs were reported in 29 of 31 patients (93.5%) in the ziprasidone group and 25 of 27 patients (92.6%) in the haloperidol group; most events were of mild or moderate severity. Frequently reported AEs were somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and 33.3%), agitation (6.5% and 18.5%), and insomnia (0% and 14.8%). CONCLUSIONS In this study of the effects of high-dose ziprasidone and haloperidol in patients with schizophrenic disorder, none of the patients had a QTc interval >480 msec, and changes from baseline QTc interval were clinically modest with both drugs. Both drugs were generally well tolerated.

Pharmacokinetics, Safety, and Tolerability of Intramuscular Ziprasidone in Healthy Volunteers

Little has been published regarding the pharmacokinetics of the intramuscular (IM) formulation of Ziprasidone. The authors report results from 2 early phase I studies in healthy volunteers: a trial of single 5‐, 10‐, or 20‐mg IM doses of ziprasidone in 24 subjects and an open‐label 3‐way crossover trial of 5‐mg intravenous (IV), 5‐mg IM, and 20‐mg oral ziprasidone in 12 subjects. Absorption of IM ziprasidone was rapid (Tmax < 1 hour). The IM pharmacokinetic profile was consistent between studies and linear, with dose‐related increases in exposure observed. The mean IM elimination t1/2 was short and approximately 2.5 hours. The mean bioavailability for the 5‐mg IM ziprasidone dose was approximately 100%. Adverse events were generally mild to moderate, and no subjects were discontinued from the study. No significant effects on renal function or other laboratory values were noted. These results support the use of IM ziprasidone in treating acutely agitated patients with schizophrenia.

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil

BackgroundSymptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg.MethodsThis was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data.ResultsAt the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment).ConclusionsSAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists.Trial registrationClinicaltrials.gov, NCT01712074. Registered 19 October 2012.