Gender, age, disease severity, body mass index and diabetes may not affect response to subcutaneous tanezumab in patients with osteoarthritis after 16 weeks of treatment. A subgroup analysis of placebo-controlled trials.

AIM: To assess the impact of pre-specified patient characteristics on efficacy and safety of subcutaneous tanezumab in patients with osteoarthritis (OA). METHODS: Data were pooled from two (efficacy; N = 1545) or three (safety; N = 1754) phase 3 placebo-controlled trials. Change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and patient global assessment of OA (PGA-OA) scores was compared between tanezumab (2.5 and 5 mg) and placebo groups via analysis of covariance. Treatment-emergent adverse events (TEAEs) were summarised descriptively. Analyses were done in patient subgroups (men or women; age <65, ≥65, or ≥75 years; body mass index [BMI] <25, 25 to <30, 30 to <35 or ≥35 kg/m2 ; diabetes or no diabetes; baseline WOMAC Pain score <7 or ≥7; and Kellgren-Lawrence [KL] grades 2, 3 or 4 in the index joint) and the overall population. RESULTS: In all subgroups, improvements in WOMAC Pain were numerically greater and often statistically significant (P < .05) for both tanezumab groups compared with placebo. Results were similar for WOMAC Physical Function and PGA-OA. TEAE profiles were generally consistent across subgroups and similar to the overall population (ie slightly higher rates of TEAEs, serious TEAEs and severe TEAEs with tanezumab relative to placebo) with a few exceptions. Exceptions included women reporting slightly more TEAEs with tanezumab than men, and patients with diabetes reporting slightly more severe TEAEs with tanezumab than patients without diabetes. Additionally, TEAEs were more frequent with tanezumab than placebo in the age ≥65 and ≥75 years, but not the age <65 years, subgroups. CONCLUSIONS: Efficacy and safety/tolerability of tanezumab may not be meaningfully impacted by gender, age, BMI, diabetes status, baseline pain severity or KL grade in the index joint. Conclusions are limited by low patient number in some subgroups. Clinicaltrials.gov: NCT02697773, NCT02709486, NCT01089725.

Pregabalin adjunctive therapy for focal onset seizures in children 1 month to <4 years of age: A double-blind, placebo-controlled, video-electroencephalographic trial.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin as adjunctive treatment for children (aged 1 month-<4 years) with focal onset seizures (FOS) using video-electroencephalography (V-EEG). METHODS: This randomized, placebo-controlled, international study included V-EEG seizure monitoring (48-72 hours) at baseline and over the last 3 days of 14-day (5-day dose escalation; 9-day fixed dose) double-blind pregabalin treatment (7 or 14 mg/kg/d in three divided doses). This was followed by a double-blind 1-week taper. The primary efficacy endpoint was log-transformed seizure rate (loge [24-hour seizure rate + 1]) for all FOS recorded during the double-blind V-EEG monitoring, evaluated in subjects who took ≥1 dose of study medication, experienced ≥1 baseline seizure(s), and had a treatment phase V-EEG. Safety and tolerability were assessed by adverse events (AEs), clinical laboratory data, physical/neurological examinations, vital signs, and electrocardiograms. RESULTS: Overall, 175 patients were randomized (mean age = 28.2 months; 59% male, 69% white, 30% Asian) in a 2:1:2 ratio to pregabalin 7 or 14 mg/kg/d (n = 71 or n = 34, respectively), or placebo (n = 70). Pregabalin 14 mg/kg/d (n = 28) resulted in a statistically significant 35% reduction of loge (24-hour seizure rate + 1) versus placebo (n = 53; P = .022), an effect that was not observed with pregabalin 7 mg/kg/d (n = 59; P = .461). The most frequently reported treatment-emergent AEs for pregabalin 7 mg/kg/d, 14 mg/kg/d, and placebo, respectively, were somnolence (11.3%, 17.6%, and 5.7%) and upper respiratory tract infection (7.0%, 11.8%, and 11.4%). All AEs were mild to moderate in severity. SIGNIFICANCE: Pregabalin 14 mg/kg/d (but not 7 mg/kg/d) significantly reduced seizure rate in children with FOS, when assessed using V-EEG, compared with placebo. Both pregabalin dosages were generally safe and well tolerated in children 1 month to <4 years of age with FOS. Safety and tolerability were consistent with the known profile of pregabalin in older children with epilepsy.

Effect size varies based on calculation method and may affect interpretation of treatment effect: an illustration using randomised clinical trials in osteoarthritis.

BACKGROUND: To illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting. METHODS: Data from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI). RESULTS: ES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were - 0.416 (- 0.796, - 0.060), - 0.195 (- 0.371, - 0.028), and - 0.196 (- 0.373, - 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab. CONCLUSION: Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

The relationship between weight gain during chemotherapy and outcomes in patients with advanced non-small cell lung cancer.

BACKGROUND: This post hoc, pooled analysis examined the relationship between different weight gain categories and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy. METHODS: Data were pooled from the control arms of three phase III clinical studies (NCT00596830, NCT00254891, and NCT00254904), and the maximum weight gain in the first 3 months from treatment initiation was categorised as >0%, >2.5%, and >5.0%. Cox proportional hazard modelling of OS was used to estimate hazard ratios (HRs) for each category, including baseline covariates, time to weight gain, and time to confirmed objective response (RECIST Version 1.0). RESULTS: Of 1030 patients with advanced NSCLC (IIIB 11.5% and IV 88.5%), 453 (44.0%), 252 (24.5%), and 120 (11.7%) experienced weight gain from baseline of >0%, >2.5%, and >5.0%, respectively. The median time to weight gain was 23 (>0%), 43 (>2.5%), and 45 (>5.0%) days. After adjusting for a time-dependent confirmed objective response, the risk of death was reduced for patients with any weight gain (>0% vs. ≤0% [HR 0.71; 95% confidence interval-CI 0.61, 0.82], >2.5% vs. ≤2.5% [HR 0.76; 95% CI 0.64, 0.91] and >5.0% vs. ≤5.0% [HR 0.77; 95% CI 0.60, 0.99]). The median OS was 13.5 versus 8.6 months (weight gain >0% vs. ≤0%), 14.4 versus 9.4 months (weight gain >2.5% vs. ≤2.5%), and 13.4 versus 10.2 months (weight gain >5.0% vs. ≤5.0%). CONCLUSIONS: Weight gain during treatment was associated with a reduced risk of death, independent of tumour response. The survival benefit was comparable for weight gain >0%, >2.5%, and >5.0%, suggesting that any weight gain may be an early predictor of survival with implications for the design of interventional cancer cachexia studies.

Examining the Relationships Among Treatment, Pain, and Physical Function in Patients With Osteoarthritis: A Mediation-Modeling Approach.

OBJECTIVES: To better understand the relationships among treatment, pain, and physical function (PF). METHODS: Data were collected from 2 published randomized clinical trials of osteoarthritis patients who received tanezumab or a placebo. PF was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) PF domain. Pain (WOMAC pain domain) was a mediator of the effect of treatment on PF. A set of mediation models were investigated. Variables were treatment (tanezumab vs placebo), WOMAC pain domain, and WOMAC PF domain. Cross-sectional mediation models were assessed separately at different weeks. Longitudinal mediation models used data from all weeks simultaneously. Results could identify a steady-state period. RESULTS: The cross-sectional and longitudinal mediation models showed a stable indirect effect of treatment through the pain on PF across time, indicating that a pseudo-steady-state model was appropriate. Therefore, the longitudinal steady-state mediation models were used with all available data assuming relationships among variables in the model being the same at all time points; results showed that the indirect effect of the treatment on PF was 77.8% in study 1 (NCT02697773) and 74.1% in study 2 (NCT02709486), both P <0.0001, whereas the direct effect was 22.2% for study 1 ( P = 0.0003) and 25.9% for study 2 ( P = 0.0019). DISCUSSION: At least 75% of the treatment effect of tanezumab on physical functioning can be explained by the improvements in pain. However, tanezumab had an additional effect on physical functioning (~25%) that, was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms.

Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: did baseline characteristics impact trial outcome?

Two randomized, double-blind, placebo-controlled, 6-week studies comparing ziprasidone versus placebo for treatment of bipolar depression (BPD) failed to meet their primary study objectives, indicating that either ziprasidone is ineffective in the treatment of BPD or the study failed. Adult outpatients with bipolar I depression with 17-item Hamilton Rating Scale for Depression total score more than 20 at screening and baseline received either ziprasidone 40 to 80 mg/d, 120 to 160 mg/d, or placebo (study 1), or ziprasidone 40 to 160 mg/d or placebo (study 2). Primary efficacy measure in both studies was change from baseline in Montgomery-Åsberg Depression Rating Scale total scores at week 6 (end of the study). Mixed-model repeated-measures methodology was used to analyze the primary efficacy measure in both studies. Secondary efficacy measures in both studies included Hamilton Rating Scale for Depression total score and Clinical Global Impression-Improvement score. Post hoc analyses were conducted for both studies to examine potential reasons for study failure. In both, ziprasidone treatment groups failed to separate statistically from placebo for change from baseline Montgomery-Åsberg Depression Rating Scale score at week 6. Response rates were 49%, 53%, and 46% for placebo, ziprasidone 40 to 80 mg/d, and ziprasidone 120 to 160 mg/d, respectively (study 1), and 51% and 53% for placebo and ziprasidone 40 to 160 mg/d, respectively (study 2). Ziprasidone 40 to 160 mg/d did not show superiority over placebo at week 6 in the treatment of BPD. Post hoc analyses revealed serious inconsistencies in subject rating that may have limited the ability to detect a difference between drug and placebo response. Rating reliability warrants further investigation to improve clinical trial methodology in psychiatry.

Efficacy and safety of tanezumab, NSAIDs, and placebo in patients with moderate to severe hip or knee osteoarthritis and a history of depression, anxiety, or insomnia: post-hoc analysis of phase 3 trials.

Objective: Treatment outcomes for chronic pain can be poor in patients with depression, anxiety, or insomnia. This analysis evaluated the efficacy and safety of subcutaneous tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), and placebo in patients with osteoarthritis (OA) and a history of these conditions using data from three phase 3 studies.Methods: A post-hoc analysis of data from two pooled placebo-controlled studies and one NSAID-controlled study of subcutaneous tanezumab. All patients had moderate to severe knee or hip OA that was inadequately controlled with standard-of-care analgesics. Efficacy outcomes were least-squares mean change from baseline to Week 16 in Western Ontario McMaster Universities OA Index (WOMAC) Pain, WOMAC Physical Function, Patient's global assessment of OA, and EQ-5D-5L scores. Results were summarized for patients with and without a history of depression, anxiety, or insomnia at baseline.Results: 1545 patients were treated in the pooled placebo-controlled studies (history of depression, 12%; anxiety, 8%; insomnia, 10%; any, 23%) and 2996 in the NSAID-controlled study (16%, 11%, 13%, 28%, respectively). In groups with positive histories, 38-80% took antidepressant or anxiolytic medications at baseline. Within treatments, largely similar improvements in efficacy outcomes were observed in patients with and without a history of depression, anxiety, or insomnia; the types of treatment-emergent adverse events were similar.Conclusions: Patients with OA and a history of depression, anxiety, or insomnia did not appear to experience reduced efficacy outcomes or an altered safety profile in response to tanezumab or NSAID treatment as compared with those without. NCT02697773; NCT02709486; NCT02528188.

Clinical Meaningfulness of Response to Tanezumab in Patients with Chronic Low Back Pain: Analysis From a 56-Week, Randomized, Placebo- and Tramadol-Controlled, Phase 3 Trial.

INTRODUCTION: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment. METHODS: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100-300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56. RESULTS: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints. CONCLUSIONS: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo. CLINICALTRIALS: gov: NCT02528253.

Single and Composite Endpoints of Within-Patient Improvement in Symptoms: Pooled Tanezumab Data in Patients with Osteoarthritis.

INTRODUCTION: Combining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo. METHODS: Endpoints at week 16 included proportions of responders (≥ 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, and sustained weekly average pain responders. RESULTS: Pooled population comprised 1545 patients. Of patients who had a ≥ 30% improvement in WOMAC Pain and/or WOMAC Physical Function, 88.5% were WOMAC Pain/Function composite responders, 7.0% were WOMAC Pain (but not Function) responders, and 4.4% were WOMAC Function (but not Pain) responders. Of weekly average pain responders, 43.1% were PASS composite responders. Odds ratios (tanezumab 2.5 mg and 5 mg groups, respectively, vs placebo) were 1.75 and 1.86 (WOMAC Pain/Function composite responders), 1.41 and 1.65 (weekly average pain responders), 1.60 and 1.73 (PASS composite responders), 1.52 and 1.68 (MCII composite responders), 1.75 and 1.88 (OMERACT-OARSI responders), and 1.85 and 1.48 (sustained weekly average pain responders). Subgroup analyses suggested a greater magnitude of effect for patients with a knee index joint compared with hip on some endpoints. CONCLUSION: Responders on single pain endpoints were in many cases also responders on function or composite endpoints. Separation of tanezumab from placebo was similar and consistent across single and composite endpoints.

Effect size varies based on calculation method and may affect interpretation of treatment effect: an illustration using randomised clinical trials in osteoarthritis

Abstract Background To illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting. Methods Data from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI). Results ES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were - 0.416 (- 0.796, - 0.060), - 0.195 (- 0.371, - 0.028), and - 0.196 (- 0.373, - 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab. Conclusion Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies. Trial Registration Clinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

Long-term changes in weight and plasma lipids during maintenance treatment with ziprasidone.

To measure the long-term changes in weight and plasma lipids after switching antipsychotic treatment to ziprasidone, three 52-week, open-label extension studies of ziprasidone in outpatients (N=185) with schizophrenia or schizoaffective disorder successfully completing one of three, 6-week switch studies were carried out. Pre-switch treatment consisted of risperidone (n=43), olanzapine (n=71), or conventional antipsychotic agents (n=71). The maximum length of exposure to ziprasidone was 58 weeks. Nonfasting total cholesterol and triglyceride levels were obtained at baseline and at weeks 6, 19, 32, 45, and 58. Weight was measured at baseline and during each follow-up visit; height was recorded at baseline for the purpose of body mass index (BMI) calculation. Efficacy measures included the Positive and Negative Syndrome Scale and Clinical Global Impression-Severity scale which were obtained at baseline and major follow-up points. Clinically significant sustained improvements in weight, BMI, total cholesterol, and triglyceride levels were observed among patients switched to ziprasidone from risperidone or olanzapine. Switching from conventional antipsychotics was not associated with significant changes in weight and lipid parameters. Mean reductions in weight from baseline to study endpoint were 9.8 kg (p<0.001) and 6.9 kg (p<0.005) for patients previously treated with olanzapine and risperidone, respectively. These findings demonstrate that switching from risperidone or olanzapine to ziprasidone is associated with sustained, clinically significant improvements in weight and plasma lipids.

Long-term improvement in efficacy and safety after switching to ziprasidone in stable outpatients with schizophrenia.

INTRODUCTION: The long-term efficacy and tolerability of treatment with ziprasidone following a switch from prior antipsychotics was evaluated in outpatients with schizophrenia or schizoaffective disorder in three open-label, flexible-dose, 1-year extension studies. METHODS: These studies enrolled completers of 6-week trials in which subjects were switched to ziprasidone from conventional antipsychotics, olanzapine, or risperidone. Identical study designs and the small number of patients entering the extensions supported pooling of the data. RESULTS: Of 185 pooled subjects entering the extension studies, 72 completed 58 weeks of treatment. Median treatment duration was 34.6 weeks; median dose was 120 mg/day at endpoint. The intent-to-treat population showed significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores (-4.3 [P< or =.01]), PANSS negative scores (-2.4 [P< or =.0001]), and Clinical Global Impression of severity score (-0.3 [P< or =.001]). Completers showed significant improvement in mean PANSS total scores (-10.2 [P<.0001]), PANSS positive scores (-2.7 [P< .0001]), PANSS negative scores (-2.7 [P< .001]), and Clinical Global Impression of severity scores (-0.6 [P< .0001]). CONCLUSION: Ziprasidone was well tolerated, and patients demonstrated significant improvement in metabolic parameters and in all movement disorder assessments. Insomnia and somnolence were the only adverse events with an incidence >10% in pooled subjects. No subject had a corrected QT interval > or =500 msec.

Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial.

The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries-the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150-600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, - 0.22 points (95% confidence interval, 0.54-0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population.ClinicalTrials.gov NCT01701362.

Efficacy and safety of pregabalin for painful diabetic peripheral neuropathy in a population of Chinese patients: A randomized placebo-controlled trial.

BACKGROUND: Limited information exists regarding the efficacy of pregabalin in Chinese patients with painful diabetic peripheral neuropathy (pDPN). METHODS: An 11-week double-blind placebo-controlled trial was performed in Chinese pDPN patients randomized (1 : 1) to 300 mg/day pregabalin or placebo. The primary outcome was change from baseline to endpoint in mean pain score (MPS; 0, no pain; 10, worst possible pain; using the mean of the last seven daily pain scores). Secondary outcomes included weekly MPS and responder status (MPS reduced by ≥30% or ≥50% vs baseline). Subgroup analysis assessed patients with severe (≥7) baseline MPS. Adverse events (AEs) were reported. RESULTS: In all, 620 patients were randomized (pregabalin, n = 313; placebo, n = 307). Improvement in MPS with pregabalin versus placebo was not significant (P = 0.0559). Post hoc sensitivity analyses, excluding one patient/site due to Good Clinical Practice (GCP) non-compliance, showed pregabalin significantly improved MPS when excluding the patient (P = 0.0448) or site (P = 0.0142). Pregabalin significantly improved weekly MPS (P = 0.0164) and ≥50% responders at endpoint (P = 0.0384). Improvement in proportion of ≥30% responders, impression of change, pain intensity, and sleep did not differ significantly between the treatment groups. In the severe pDPN subpopulation, pregabalin significantly improved MPS versus placebo (P = 0.0040). The most commonly reported AE was dizziness (9.6% vs 3.9% with placebo). CONCLUSIONS: Pregabalin did not significantly improve the primary measure of pain in the trial. Significant reductions in MPS were observed when excluding the GCP non-compliant patient/site and in the severe pDPN subpopulation. Pregabalin was well tolerated in Chinese pDPN patients.

Comparison of ziprasidone and aripiprazole in acutely ill patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, 4-week study.

We compared the efficacy and safety of ziprasidone and aripiprazole in the treatment of acutely ill patients with schizophrenia. Patients were randomized to receive double-blind treatment with ziprasidone (80-160 mg/day), or aripiprazole (10-30 mg/day) for up to 4 weeks. Primary efficacy measures were the Clinical Global Impression of Severity scale (CGI-S) and Brief Psychiatric Rating Scale (BPRSd) total (derived from the Positive and Negative Syndrome Scale). Noninferiority for ziprasidone (N=125) relative to aripiprazole (N=128) was established for CGI-S score (P=0.007), but was not confirmed for BPRSd total score (P=0.248). Effect sizes for within-group improvement, however, were robust for both ziprasidone and aripiprazole (effect size range 1.0-1.1 for CGI-S; and range 1.1-1.2 for BPRSd total). A mixed model repeated measures analysis of BPRSd total score favored ziprasidone at day 4 compared with aripiprazole (P=0.04), with no significant differences between treatment groups at other visits (P=0.001 for interaction between treatment and visit). No statistically significant difference was found in CGI-S score between groups across all visits. Our findings suggest that ziprasidone and aripiprazole exhibit similar efficacy and tolerability profiles in the treatment of acute schizophrenia. Differences between the two drugs in the onset of therapeutic effect warrant further investigation.

Efficacy and Safety of Once-Daily Controlled-Release Pregabalin for the Treatment of Patients With Postherpetic Neuralgia: A Double-Blind, Enriched Enrollment Randomized Withdrawal, Placebo-Controlled Trial.

OBJECTIVES: To assess efficacy and safety of once-daily controlled-release (CR) formulation of pregabalin in patients with postherpetic neuralgia. METHODS: An enriched enrollment, randomized withdrawal trial, with 6-week single-blind pregabalin treatment phase and 13-week double-blind phase, where patients with ≥50% decrease in mean pain score at single-blind end point from baseline were randomized (1:1) to pregabalin CR (82.5 to 660 mg/d) or placebo. Primary efficacy outcome was time to loss of therapeutic response (LTR) (<30% decrease in weekly mean pain score from single-blind baseline or discontinuation due to adverse event or lack of efficacy). Secondary efficacy outcomes included change in weekly mean pain score (1-wk recall period) at double-blind end point. RESULTS: In total, 801 patients were randomized and treated in the single-blind phase, and 413 in the double-blind phase (208, pregabalin CR; 205, placebo). Pregabalin CR significantly increased time to LTR versus placebo (Kaplan-Meier analysis) with significantly fewer LTR events with pregabalin CR than with placebo (29 [13.9%] vs. 63 [30.7%]; P<0.0001). Median time to LTR was not estimable. Pregabalin CR significantly improved weekly mean pain score versus placebo: LS mean difference (95% CI) of -1.11 (-1.47, -0.75) and -1.00 (-1.34, -0.65) (P<0.0001) from single-blind baseline and double-blind baseline, respectively. Most commonly reported adverse events in the single-blind phase were dizziness, somnolence, and peripheral edema. Pregabalin CR was well tolerated. DISCUSSION: Time to LTR was significantly longer with pregabalin CR than with placebo. Safety profile of pregabalin CR was comparable to that reported for the immediate-release formulation in patients with postherpetic neuralgia.

Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q): reliability and validity.

OBJECTIVE: The pediatric version of the Short Form of the Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) was developed to aid in the assessment of an important aspect of life experience in children and adolescents. METHOD: The reliability and validity of the PQ-LES-Q was tested using data from a sample of 376 outpatient children (6-11 years old) and adolescents (12-17 years old) with major depressive disorder. RESULTS: The internal consistency coefficients at screening, baseline, and endpoint were high (0.87, 0.90, 0.89, respectively) as was the 1-week test-retest intraclass correlation coefficient of reliability (0.78). The correlations of the PQ-LES-Q total score with concurrent measures of severity of illness were in the moderate range (e.g., Global Clinical Impression of Severity, -0.40; Children's Global Assessment Scale, 0.36; Children's Depression Rating Scale total score, -0.45), as were the correlations with measures of change between baseline and endpoint (e.g., Clinical Global Impression of Severity, -0.34; Children's Global Assessment Scale, 0.33; Children's Depression Rating Scale total score, -0.45). CONCLUSIONS: These findings support the use of the PQ-LES-Q as an additional measure of current clinical status and outcome because it taps dimensions that are not covered by the commonly used global severity of illness or symptomatic measures.

Sertraline in children and adolescents with major depressive disorder.

OBJECTIVE: To explore time to first response and time to first persistent response of sertraline versus placebo and compare these parameters between children (6-11 years old, n = 177) and adolescents (12-17 years old, n = 199) with major depressive disorder. METHOD: A 10-week placebo-controlled treatment was followed by a 24-week open-label sertraline treatment. The double-blind studies were not powered to detect efficacy differences between age groups. A post hoc analysis explored time to first response and first persistent response using the Children's Depression Rating Scale-Revised and Clinical Global Impressions-Improvement predefined criteria. RESULTS: There were no statistically significant differences in time to first response or first persistent response between sertraline and placebo in children, except for time to first response on Clinical Global Impressions-Improvement. Sertraline had a significantly faster time to first persistent response in adolescents compared to placebo. Within treatment groups, children had a significantly faster time to first response than adolescents, whether treated with placebo or sertraline, but not on time to first persistent response. Both age groups showed similar improvement over 34 weeks of treatment. CONCLUSION: In the double-blind studies, children and adolescents had different patterns of response with sertraline vs. placebo.

Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study.

We compared the efficacy of ziprasidone and amisulpride in the treatment of negative symptoms and overall psychopathology in subjects who had chronic schizophrenia with predominantly negative symptoms. This multicentre, 12-week, double-blind study randomly assigned subjects with predominantly negative-symptom schizophrenia [i.e. Positive and Negative Syndrome Scale (PANSS) Negative Subscale score >or=6 points greater than Positive Subscale score] to ziprasidone (40-80 mg b.i.d.; n=60) or amisulpride (50-100 mg b.i.d.; n=63). The primary efficacy variable was the change from baseline in PANSS Negative Subscale score. Secondary efficacy variables included change in scores for PANSS Total, Global Assessment of Functioning, Brief Psychiatric Rating Scale derived from PANSS Total and Core, Clinical Global Impression (CGI)-Severity and CGI-Improvement. For the change in PANSS Negative Subscale score, a ratio to assess the equivalence of the treatment groups was calculated from the least squares mean changes from baseline, with equivalence claimed if the lower limit of the 95% confidence interval of the ratio exceeded 0.60. Mean daily dose, adjusted for differential numbers of subjects and differential days between visits, was 118.0 mg for ziprasidone and 144.7 mg for amisulpride. Mean PANSS Negative Subscale scores improved over the 12-week treatment period for intent-to-treat subjects, evaluable subjects (subjects with >or=4 weeks of double-blind treatment and no protocol deviations) and completers in both treatment groups. Ziprasidone demonstrated efficacy comparable to amisulpride in improving negative symptoms and global psychopathology. The groups demonstrated comparable improvements in secondary efficacy variables. Both agents were generally well tolerated, with comparably low incidences of movement disorders. In subjects with negative symptom-prominent schizophrenia, ziprasidone in mean daily doses of 118 mg was equivalent to amisulpride in mean daily doses of 148 mg in ameliorating negative symptoms and comparable in improving overall psychopathology and global illness severity.

Long-term sertraline treatment of children and adolescents with major depressive disorder.

OBJECTIVE: The aim of this study was to assess the long-term safety, tolerability, and efficacy of sertraline 50-200 mg once-daily in children (6-11 year olds) and adolescents (12-18 year olds) with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of major depressive disorder (MDD). METHODS: This study consisted of a 24-week open-label observational study of children and adolescents who had completed either of two 10-week double-blind, placebo-controlled trials. The Children's Depression Rating Scale-Revised (CDRS-R) was the primary measure of efficacy. RESULTS: Two hundred ninety nine (299) patients completed the acute studies and were eligible for the extension study. Of these, 226 enrolled, but 5 did not receive treatment. Of 221 patients (107 children and 114 adolescents), 62.4% completed the study. The endpoint mean daily dose was 109.9 mg/day. The mean decrease in CDRS-R score from double-blind baseline was 34.8 points (p < 0.001), with patients showing continued improvement in CDRS-R scores regardless of which treatment they received in the double-blind studies. At endpoint, 86% of patients met CDRS-R responder and 58% CDRS-R remitter criteria. CONCLUSIONS: Sertraline appears to be well tolerated and safe over 24 weeks of treatment in children and adolescents with MDD. Children and adolescents treated with sertraline appear to have increased improvement over that seen in the first 10 weeks of treatment. These findings need confirmation in placebo-controlled studies.