Denái Milton

Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study.

BACKGROUND Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of exenatide in combination with oral antidiabetic agents. OBJECTIVE The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone. METHODS This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto Rico, Romania, Russia, and India. Patients aged >or=18 years with type 2 diabetes were randomly assigned to receive exenatide 5 microg, exenatide 10 microg, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA(1c)); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA(1c) values <or=6.5% and <or=7.0%; weight; and homeostasis model of beta-cell function (HOMA-B, a clinical measure of pancreatic beta-cell function). Tolerability measures included patient-reported adverse events, hypoglycemia, and blood pressure. RESULTS A total of 232 patients were included in the intent-to-treat population (130 men, 102 women; 68% white; mean [SD] age, 54 [10] years; duration of type 2 diabetes, 2 [3] years; weight, 86 [16] kg; body mass index, 31 [5] kg/m(2); HbA(1c), 7.8% [0.9%]). At end point, least-squares mean (SE) HbA(1c) reductions (%) from baseline were significantly greater with exenatide 5 and 10 microg than placebo (-0.7 [0.1] and -0.9 [0.1] vs -0.2 [0.1]; P = 0.003 and P < 0.001, respectively), as were FSG reductions (mg/dL) (-17.5 [4.0] and -18.7 [4.0] vs -5.2 [4.0]; P = 0.029 and P = 0.016, respectively). Changes in daily mean postprandial glucose excursions (mg/dL) from baseline to end point were significantly greater with exenatide 5 and 10 microg than placebo (-21.3 [2.7] and -24.7 [2.7] vs -8.3 [2.5]; both, P < 0.001). With exenatide 5 and 10 microg, 31% and 35% of patients achieved HbA(1c) <or=6.5% at end point versus 19% with placebo (P = NS and P = 0.026, respectively), while 48% and 46% versus 29% achieved HbA(1c) <or=7.0% (P = 0.024 and P = 0.036, respectively). Changes in weight (kg) at 24 weeks were greater with exenatide 5 and 10 (2)g than placebo (-2.8 [0.3] and -3.1 [0.3] vs -1.4 [0.3]; P = 0.004 and P < 0.001, respectively). HOMA-B values increased from baseline to end point by 32% and 28% in the exenatide 5- and 10-microg groups, respectively, versus 6% for placebo. Improvements from baseline to end point in HOMA-B were significantly greater with exenatide 5 and 10 microg than placebo (P = 0.002 and P = 0.010, respectively). Significant improvements in mean systolic and diastolic blood pressure (mm Hg) from baseline to end point were also observed with exenatide (systolic, both 5 and 10 microg, -3.7 [1.2] [P = 0.037]; diastolic, 10 microg, -2.3 [0.7] [P = 0.046]) versus placebo (systolic, -0.3 [1.2]; diastolic, -0.3 [0.7]). Overall, 25% of patients reported >or=1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 microg, 3%; 10 microg, 13%; placebo, 0%; P = 0.010 for the combined exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the exenatide 5- and 10-microg and placebo groups, respectively (P = NS), with no incidents of severe hypoglycemia reported. CONCLUSIONS In these patients with type 2 diabetes naive to treatment with antidiabetic agents, exenatide monotherapy was associated with improved HbA(1c), improved fasting and postprandial glucose control, reduced weight, improved beta-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes.

Atomoxetine and Methylphenidate Treatment in Children With ADHD: A Prospective, Randomized, Open-Label Trial

ABSTRACT Objective To assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine. The name was recently changed in order to avoid any potential confusion with tamoxifen that might lead to errors in dispensing drug.) Method Children with ADHD were randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response was assessed with the ADHD-IV Rating Scale. Results Two hundred twenty-eight patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs were associated with marked improvement in inattentive and hyperactive-impulsive symptom clusters as assessed by parents and investigators. No statistically significant differences between treatment groups were observed on the primary outcome measure (investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4 [8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint: 19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2 drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine and 5/44 (11.4%) for methylphenidate; p = .175. Conclusion These data provide preliminary evidence that atomoxetine is associated with therapeutic effects comparable to those of methylphenidate.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders

Objective: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. Methods: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders–IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. Results: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (–5.5 ± 6.9 vs –3.0 ± 8.7, p = 0.063) and Tic Symptom Self-Report total score (–4.7 ± 6.5 vs –2.9 ± 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (–0.7 ± 1.2 vs –0.1 ± 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (–10.9 ± 10.9 vs –4.9 ± 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (–0.8 ± 1.1 vs –0.3 ± 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. Conclusions: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

Atomoxetine Treatment of ADHD in Children With Comorbid Tourette Syndrome

Objective: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). Method: Subjects (7-17 years old) with ADHD (Diagnostic and Statistical Manual of Mental Disorders, DSM-IV) and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine (0.5-1.5 mg/kg/day, n = 61) for approximately 18 weeks. Results: Atomoxetine subjects showed significantly greater improvement on ADHD symptom measures. Treatment was also associated with significantly greater reduction of tic severity on two of three measures. Significant increases were seen in mean pulse rate and rates of treatment-emergent nausea, decreased appetite, and decreased body weight. No other clinically relevant treatment differences were observed in any other vital sign, adverse event, laboratory parameter, or electrocardiographic measure. Conclusion: Atomoxetine is efficacious for treatment of ADHD and its use appears well tolerated in ADHD patients with comorbid TS. (J. of Att. Dis. 2008; 11(4) 470-481)

Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: A prospective, placebo-controlled assessment

Abstract: Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued.

Detecting treatment emergent adverse events in clinical trials : a comparison of spontaneously reported and solicited collection methods.

AbstractBackground: The collection of adverse event data is an important component of clinical trials, but it is not clear whether solicited or unsolicited collection methods are better at distinguishing drug effects from the effects of placebo. The objective of this analysis is to compare the reporting rates and the ability to detect drug-placebo differences with spontaneous versus solicited adverse event collection methods. Methods: Adverse events were collected by spontaneous (unsolicited) reporting and by structured questionnaires in three randomised, double-blind clinical trials. For both spontaneous and solicited adverse event collection methods, a drug/placebo (D/P) reporting ratio was computed by dividing the reporting rate for the experimental drug by the reporting rate for placebo for each adverse event. An index (Sp-So index) was calculated by dividing the spontaneous D/P ratio by the solicited D/P ratio. A number >1.0 indicates that the spontaneous adverse event collection method is more effective in distinguishing the drug from placebo and a number <1.0 suggests that the solicited adverse event collection method is more effective in distinguishing the drug from placebo. Results: Reporting rates were greater when events were solicited than when the spontaneous reporting approach was used. The Sp-So index was >1.0 for 22 of the 29 (75.9%) events examined, suggesting that spontaneous collection of adverse events is more effective in distinguishing drug effect from placebo than the solicited approach. However, more statistically significant differences between drug and placebo were detected by the solicited method (nine events) than the spontaneous method (five events). This is due, in part, to the fact that differences in the percentages of adverse events between drug and placebo (rather than ratios of event rates) were more often greater when the solicited approach was used. Conclusions: As expected, adverse events collected by solicitation leads to higher reporting rates. However, it is not clear that solicitation of events leads to greater ability to detect drug-placebo differences. By using a ratio to assess drug-placebo differences, spontaneous reporting provided larger drug-placebo differences more often than solicitation.

Social and emotional difficulties in children with ADHD and the impact on school attendance and healthcare utilization

BackgroundThe objective of this study was to examine the impact of co-occurring social and emotional difficulties on missed school days and healthcare utilization among children with attention deficit/hyperactivity disorder (ADHD).MethodsData were from the 2007 U.S. National Health Interview Survey (NHIS) and were based on parental proxy responses to questions in the Sample Child Core, which includes questions on demographics, health, healthcare treatment, and social and emotional status as measured by questions about depression, anxiety, and phobias, as well as items from the brief version of the Strength and Difficulties Questionnaire (SDQ). Logistic regression was used to assess the association between co-occurring social and emotional difficulties with missed school days and healthcare utilization, adjusting for demographics.ResultsOf the 5896 children aged 6–17 years in the 2007 NHIS, 432 (7.3%) had ADHD, based on parental report. Children with ADHD and comorbid depression, anxiety, or phobias had significantly greater odds of experiencing > 2 weeks of missed school days, ≥ 6 visits to a healthcare provider (HCP), and ≥ 2 visits to the ER, compared with ADHD children without those comorbidities (OR range: 2.1 to 10.4). Significantly greater odds of missed school days, HCP visits, and ER visits were also experienced by children with ADHD who were worried, unhappy/depressed, or having emotional difficulties as assessed by the SDQ, compared with ADHD children without those difficulties (OR range: 2.2 to 4.4).ConclusionsIn children with ADHD, the presence of social and emotional problems resulted in greater odds of missed school days and healthcare utilization. These findings should be viewed in light of the limited nature of the parent-report measures used to assess social and emotional problems.