Atomoxetine versus placebo in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: a double-blind, randomized, multicenter trial in Germany.

OBJECTIVES: The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX, target dose 1.2 mg/kg daily) on symptoms of oppositional defiant disorder (ODD) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). A secondary objective was to compare fast versus slow up-titration of ATX. METHODS: This was a 3-arm, 9-week, randomized, placebo-controlled, double-blind study in ADHD patients (6-17 years) with comorbid ODD (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria A-C) or conduct disorder (CD). ATX-treatment arms were as follows-ATX-fast: 7 days 0.5 mg/kg, then 1.2 mg/kg; ATX-slow: 7 days each at 0.5 and 0.8 mg/kg, then 1.2 mg/kg. Primary outcome was the Swanson, Nolan, and Pelham Rating Scale-Revised (SNAP-IV) ODD-score after 9 weeks (Mixed Effects Model for Repeated Measures, ATX-up-titration groups pooled). RESULTS: In total, 181 patients were randomized, and 180 evaluated (ATX-fast/ATX-slow/placebo: 60/61/59). Baseline characteristics were comparable (84.4% boys; mean age 11.0 years; DSM-IV: 100% ADHD, 75.6% with combined type, 74.4% ODD, 24.4% CD; SNAP-IV ODD-scores, mean ± standard deviation 15.5 ± 4.35). At week 9, SNAP-IV ODD scores were significantly lower versus placebo in both ATX-groups (least square mean [95% confidence interval]: ATX-fast 8.6 [7.2;9.9]; ATX-slow 9.0 [7.7;10.3]; placebo 12.0 [10.6;13.5]; least square mean, ATX-pooled minus placebo: -3.2 [-5.0, -1.5], effect size: -0.69, p < 0.001). SNAP-IV ADHD-scores, CD symptoms (investigator-rated Attention-Deficit and Disruptive Behavior Disorders Instrument, disruptive behavior), Clinical Global Impressions-Severity, and individual treatment behaviors showed corresponding results. Post-hoc analyses indicated interrelationships between the medication effects on ADHD, ODD, and CD symptom scores. For ATX-slow, time to early dropout was significantly longer versus placebo (Hazard Ratio [95% confidence interval]: 3.57 [1.42;8.94]; p = 0.007). Clinically relevant adverse effects (fatigue, sleep disorders, nausea, and gastrointestinal complaints; weeks 1-3) were reported in 60.0% of ATX-fast, 44.3% of ATX-slow, and 18.6% of placebo group patients. CONCLUSIONS: ATX for 9 weeks significantly reduced symptoms of ODD/CD and ADHD; slower ATX-up-titration may be better tolerated.

Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia.

OBJECTIVE: Hypoglycemia causes recurrent morbidity in patients with type 2 diabetes. This study evaluated if exenatide twice daily (BID) was noninferior to premixed insulin aspart 70/30 BID (PIA) for glycemic control and associated with less hypoglycemia. RESEARCH DESIGN AND METHODS: In this open-label study, metformin-treated adults with type 2 diabetes were randomized to 26-week treatment with exenatide BID (4 weeks 5 µg, then 10 µg) or PIA. RESULTS: Exenatide BID (n = 181) was noninferior to PIA (n = 173) for A1C control (least squares [LS] mean change -1.0 vs. -1.14%; difference [95% CI] 0.14 [-0.003 to 0.291]) and associated with a lower risk for hypoglycemia (8.0 vs. 20.5%, P < 0.05). LS mean weight decreased by 4.1 kg and increased by 1.0 kg with PIA (P < 0.001). A total of 39.2 vs. 20.8% of patients reached the composite end point of A1C <7.0%, no weight gain, and no hypoglycemia (P < 0.001; post hoc analysis). CONCLUSIONS: In metformin-treated patients, exenatide BID was noninferior to PIA for glycemic control but superior for hypoglycemia and weight control.

Effect of atomoxetine on quality of life and family burden: results from a randomized, placebo-controlled, double-blind study in children and adolescents with ADHD and comorbid oppositional defiant or conduct disorder.

PURPOSE: To evaluate the effect of atomoxetine on quality of life (QoL) and family burden in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant (ODD) or conduct disorder (CD). METHODS: This secondary analysis was based on a randomized, double-blind, 9-week study of atomoxetine (target dose 1.2 mg/kg body weight) versus placebo. The study included 180 patients (atomoxetine 121, placebo 59), aged 6-17 years. QoL was measured using the KINDL-R questionnaire. The total score encompasses six dimensions (or subscales) measuring QoL in terms of "physical well-being", "emotional well-being", "self-esteem", "friends", "family", and "school". Family burden of illness was measured using the FaBel questionnaire. RESULTS: With atomoxetine, the KINDL-R total score improved significantly (P = 0.021) more than with placebo. This improvement also applied to the subscales except for "physical well-being" (opposite effect) and "school" (no effect). No significant treatment group differences were seen on the FaBel questionnaire. No differences were found between the fast and slow titration groups in terms of ADHD, ODD, and disruptive behavior severity. Furthermore, no such differences were observed for QoL and family burden. CONCLUSIONS: This study suggests positive effects of atomoxetine on quality of life, as measured by the KINDL-R scores on emotional well-being, self-esteem, friends and family, in children and adolescents with ADHD and comorbid ODD/CD. No significant treatment effects were seen on family burden, as measured by FaBel total score.

Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study.

BACKGROUND: Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. OBJECTIVE: To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1-3). DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1-3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), > or = pT2 disease, or intraoperative complications, patients were discontinued. INTERVENTION: We used a single, postoperative 30-40-min instillation of GEM (2000 mg/100 ml of saline) or PBO (100 ml of saline) followed by continuous bladder irrigation for > or = 20 h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guérin (BCG) instillations were allowed. MEASUREMENTS: Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, alpha = 0.050). RESULTS AND LIMITATIONS: Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1-3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1-G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8-84.3]; PBO: 75.3% [66.3-82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64-1.39], log-rank test, p=0.777). CONCLUSIONS: In this study of NMIBC, the immediate single instillation of GEM 2000 mg/100 ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.

Morning and evening behavior in children and adolescents treated with atomoxetine once daily for attention-deficit/hyperactivity disorder (ADHD): findings from two 24-week, open-label studies.

BACKGROUND: The impact of once daily atomoxetine treatment on symptoms in children and adolescents with ADHD may vary over the day. In order to capture such variations, two studies were undertaken in children and adolescents with ADHD using two instruments that capture morning and evening behavior and ADHD-related difficulties over the day. This secondary measure analysis builds on two primary analyses that were conducted separately for children and adolescents and also published separately. METHODS: In two open-label studies, ADHD patients aged 6-17 years (n = 421), received atomoxetine in the morning (target-dose 0.5-1.2 mg/kg/day) for up to 24 weeks. Morning and evening behavior was assessed using the investigator-rated Weekly Rating of Evening and Morning Behavior (WREMB-R) scale. ADHD-related difficulties at various times of the day (morning, during school, during homework, evening) were assessed using the Global Impression of Perceived Difficulties (GIPD) scale, rated by patients, parents and physicians. Data from both studies were combined for this secondary measure analysis. RESULTS: Both WREMB-R subscores decreased significantly over time, the evening subscore from 13.7 (95% CI 13.2;14.2) at baseline to 8.0 (7.4;8.5) at week 2, the morning subscore from 4.3 (4.0;4.5) to 2.4 (2.2;2.6). Scores then remained stable until week 24. All GIPD items improved correspondingly. At all times of the day, patients rated ADHD-related difficulties as less severe than parents and physicians. CONCLUSION: These findings from two open-label studies suggest that morning and evening behavior and ADHD-related difficulties in the mornings and evenings improve over time with once daily atomoxetine treatment.

Patterns of physician and patient rated quality of life during antipsychotic treatment in outpatients with schizophrenia.

Quality of life (QoL) in patients with schizophrenia has been assessed both from physician and patient perspectives, but little is known about agreement between these perspectives and predictors of agreement. The aim of this study was to analyze a large sample of patients with schizophrenia to discover patterns of physician and patient-rated QoL in patients with schizophrenia and identify predictors for these patterns. This study (EASE) was designed to investigate the QoL and subjective well-being in out-patients with schizophrenia during antipsychotic treatment in a naturalistic setting. Assessments were carried out at baseline and at 3, 6, 9 and 12 months, using the quality of life scale (QLS) and the subjective well-being on neuroleptics scale (SWN-K). A hierarchical cluster analysis was used to define groups of patients based on the SWN-K and QLS total scores at all visits. 1174 patients were included in the cluster analyses that were based on SWN-K and QLS total scores over time. Four distinct clusters were identified: patients with: (1) continuously high QoL (23.2%), (2) continuously moderate QoL (45.8%), (3) continuously low QoL (11.2%), and (4) improving QoL (19.9%). Clusters 1-3 were stable in terms of QoL, whilst cluster 4 changed towards improvement. Various predictors for the four clusters were identified. In the cluster with improving QoL, the absence of treatment with an oral conventional antipsychotic pre-study and no medication change due to lack of efficacy at baseline were predictors for improvement. In the cluster with continuously high QoL, no medication change due to lack of efficacy and lowest CGI-S scores at baseline were predictors. Oral conventional antipsychotic treatment pre-study was predictive for the cluster with continuously moderate QoL. In the cluster with continuously low QoL, medication change due to lack of efficacy and highest CGI-S scores were predictors. These findings suggest that various factors may predict whether a patient with schizophrenia experiences a continuously high QoL, a continuously moderate QoL, a continuously low QoL, or improving QoL whilst on antipsychotic treatment.

Correlation of physician and patient rated quality of life during antipsychotic treatment in outpatients with schizophrenia.

Perception of quality of life (QOL) may differ depending on the perspective. This 12-month, prospective, naturalistic study compared QOL ratings in outpatients on antipsychotic treatment for schizophrenia both from a "subjective" patient rated and an "objective" physician rated perspective. Included were 1462 patients. Two scales were used to assess patient and physician perspectives: the Subjective Well-being on Neuroleptics (SWN) scale and the Quality of Life Scale (QLS). Linear correlation was found between both ratings: 10 points on the SWN corresponded to 9.35 points on the QLS. Spearman's correlation coefficients increased over time up to r=0.71 at Month 12. Patients were grouped into four cohorts depending on the degree of concordance between SWN and QLS ratings. Several factors affecting the concordance of both ratings were identified. Compared to the cohort with QLS=SWN, higher QOL ratings by the physician (QLS>>SWN) were more likely in females than in males (OR=1.36; 95% CI 1.00 - 1.85) and in older than in younger patients (50 years: OR=0.58, 95% CI 0.34 - 0.998), but less likely in patients with high baseline CGI-severity (CGI >4; OR=0.63; 95% CI 0.47 - 0.86) or treatment with oral typicals before baseline (OR=0.53; 95% CI 0.31 - 0.91). Higher QOL ratings by the patient (SWN>>QLS) were less likely in patients with psychotherapy before baseline (OR=0.54; 95% CI 0.36 - 0.81), medication intolerability before baseline (OR=0.53; 95% CI 0.36 - 0.78) or patient request of treatment change at baseline (OR=0.64; 95% CI 0.42 - 0.96). The combination of several factors predicted concordant ratings, including male sex, young age, high CGI at baseline, and psychotherapy prior to the study.

Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy.

PURPOSE: To compare the effects of prandial insulin therapy focusing on postprandial glucose control vs. basal insulin therapy focusing on fasting glucose control in patients with type 2 diabetes. METHODS: This was an open-label, randomized, parallel, three-arm multicenter trial in patients with type 2 diabetes starting insulin treatment. Patients (n=159) were randomly assigned to 24-week treatment with 3x daily insulin lispro, 3x daily lispro mid mixture (MidMix; 50% lispro, 50% protaminated lispro), or 1x daily insulin glargine; oral antihyperglycemic agents were discontinued. Primary end point was the postprandial glucose excursion 2 h after breakfast at the end of study. Secondary outcomes included HbA1c, self-monitored blood glucose profiles, hypoglycemic episodes, body weight, and patient satisfaction. RESULTS: At the end of study, glucose excursions 2 h after breakfast were significantly lower with lispro and MidMix than with glargine (P<.001 for each vs. glargine): lispro, -0.6+/-2.0 mmol/l; MidMix, +0.8+/-2.4 mmol/l; glargine, +2.5+/-2.4 mmol/l. Fasting glucose decreases were significantly greater with glargine (-2.6+/-2.4 mmol/l) than with lispro or MidMix (-0.9+/-2.2 mmol/l; +0.9+/-1.8 mmol/l). Nevertheless, HbA1c decreased by 1.1% (lispro) and 1.2% (MidMix), vs. 0.3% with glargine. Hypoglycemic episodes were rare with 1-1.5 self-reported episodes per 100 patient-days. CONCLUSIONS: In patients with type 2 diabetes starting insulin, 3x daily prandial treatment with a rapid-acting analog focusing on postprandial glucose values enabled better control of postprandial and circadian blood glucose profiles than once-daily glargine, in spite suboptimal fasting glucose levels, which targets fasting glucose values. These results support studies suggesting that control of postprandial hyperglycemia plays a key role in achieving HbA1c targets.

[Gemcitabine in the first line therapy of advanced and metastatic non-small-cell lung carcinoma (NSCLC): review of the results of phase III studies]. / Gemcitabin in der First-line-Therapie des lokal fortgeschrittenen und metastasierten nicht-kleinzelligen Bronchialkarzinoms (NSCLC): Ergebnisübersicht randomisierter Phase-III-Studien.

Modern platinum-based combination therapies containing gemcitabine, vinorelbine or taxanes produce response rates of 30-40%, median survival times of 8-10 months and 1-year survival rates of approximately 35% in patients with advanced non-small-cell lung cancer (NSCLC). Of the new drugs available, gemcitabine (Gemzar, Lilly, Bad Homburg, Germany) has been the most extensively researched in clinical trials and exhibits a consistent database. A total of 37 randomized phase III trials involving more than 15,000 patients have been published to evaluate gemcitabine as first-line therapy for treating locally advanced and/or metastatic NSCLC. One trial studied gemcitabine exclusively as a single agent and another four trials investigated the drug in monotherapy and combination therapy. Of the 36 combination treatment studies, 21 included gemcitabine plus cisplatin treatment arms, 6 investigated gemcitabine plus carboplatin, and another 12 evaluated platinum-free gemcitabine combinations with other third generation cytostatic agents (multiple nominations possible). In single-agent treatment, gemcitabine was similarly effective to older platinum-based combinations such as vindesine-cisplatin but was less toxic. Thrombocytopenia was the main dose-limiting toxicity but was rarely clinically relevant. A 3-week cycle with gemcitabine on days 1 and 8 was confirmed as being the most convenient of the gemcitabine-based combinations studied. No other modern platinum-based doublet with vinorelbine or taxanes was superior to gemcitabine plus cisplatin in terms of survival or time to progression in any of the eight phase III studies performed. These results are consistent with previous phase II data and with a recent meta-analysis of 11 phase III and 2 randomized phase II studies involving more than 4,500 patients (1,861 in gemcitabine-based treatment arms). This meta-analysis also demonstrated a statistically significant benefit regarding overall and progression-free survival for gemcitabine-platinum- based regimens compared with other platinum combinations. In summary, currently available data indicate that gemcitabine-platinum 2-agent combinations given in 3-week cycles may at present have the best benefit-risk ratio in the treatment of advanced NSCLC. In contrast, platinum based 3-agent schedules do not offer any survival benefit. In elderly patients with poor performance status single agent treatment with a modern cytotoxic agent should be considered. Furthermore, according to the experiences from phase III studies so far, platinum- free combinations open up the possibility of a more feasible and clinically practical, active and well tolerated treatment which is associated with a positive impact on patient quality of life.