Efficacy and safety of quetiapine in children and adolescents with mania associated with bipolar I disorder: a 3-week, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of quetiapine monotherapy in children and adolescents with mania associated with bipolar I disorder. METHOD: Patients aged 10 to 17 years, with a DSM-IV-TR diagnosis of a manic episode associated with bipolar I disorder and Young Mania Rating Scale (YMRS) total score ≥ 20 were randomized to 3 weeks of quetiapine (400 or 600 mg/d) or placebo. The primary efficacy measure was change in YMRS total score. The study was conducted at 34 centers in the United States between August 2004 and July 2006. RESULTS: The intent-to-treat population included 277 patients. Least squares mean change in YMRS score from baseline to end point by mixed-model, repeated-measures analysis was -14.25, -15.60, and -9.04 for quetiapine 400 mg/d, quetiapine 600 mg/d, and placebo, respectively (P < .001, each quetiapine dose vs placebo). Significant improvement in YMRS score versus placebo was first observed at day 4 (P = .015) with quetiapine 400 mg/d and day 7 (P < .001) with quetiapine 600 mg/d. Mean changes in body weight at day 21 (observed cases) were 1.7 kg for both quetiapine doses and 0.4 kg for placebo. Numerically larger mean increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed with quetiapine than placebo. Adverse events associated with quetiapine were mostly mild to moderate in intensity. CONCLUSIONS: In this 3-week study, quetiapine was significantly more effective than placebo in improving manic symptoms in youth with mania associated with bipolar disorder. Treatment was generally well tolerated and adverse events were broadly consistent with the known profile of quetiapine in adults with bipolar disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00090311.

Efficacy and safety of quetiapine in adolescents with schizophrenia investigated in a 6-week, double-blind, placebo-controlled trial.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of acute quetiapine monotherapy in adolescents with schizophrenia. METHODS: Patients ages 13-17 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score ≥60 were randomized to 6 weeks of quetiapine (400 or 800 mg/day) or placebo treatment. The primary efficacy measure was change in PANSS total score from baseline to day 42. Safety endpoints included adverse events and assessments of clinical chemistry values, suicidality, and extrapyramidal symptoms. RESULTS: The intent-to-treat population included 220 patients. Least-squares mean change in PANSS total score from baseline to endpoint was -27.31 with quetiapine 400 mg/day, -28.44 with quetiapine 800 mg/day, and -19.15 with placebo (p=0.043 and 0.009 for quetiapine 400 and 800 mg/day, respectively, vs. placebo; mixed-model, repeated-measures analysis). Several secondary efficacy outcomes, including Clinical Global Impressions-Improvement score, supported the primary outcome measure in demonstrating significantly greater improvement in quetiapine groups than in the placebo group. Mean changes in body weight at day 42 were 2.2 kg and 1.8 kg for quetiapine 400 and 800 mg/day, respectively, and -0.4 kg for placebo. Mean changes in certain clinical chemistry parameters, including total cholesterol and triglycerides, were numerically greater in the quetiapine groups than in the placebo group. Adverse events associated with quetiapine were mostly mild to moderate in intensity and were consistent with its known profile in adults with schizophrenia. CONCLUSIONS: In this 6-week study of adolescent patients, quetiapine at doses of 400 and 800 mg/day provided significant improvements in symptoms associated with schizophrenia in adolescent patients, including the primary efficacy measure of PANSS total score change. Quetiapine was generally well tolerated with a profile broadly similar to that reported in adult and adolescent populations. CLINICAL TRIAL REGISTRATION INFORMATION: Quetiapine Fumarate (SEROQUEL(™)) Compared to Placebo in the Treatment of Adolescent Patients With Schizophrenia (ANCHOR 112). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00090324?term=quetiapine+112&rank=1.

Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial.

BACKGROUND: Fibrinolytic therapy for acute myocardial infarction (AMI) results in normal flow in only about half of patients. Adjunctive treatment with potent antiplatelet and antithrombin agents increases arterial patency but is associated with excessive bleeding. Cangrelor (formerly AR-C69931MX) is a rapidly acting, specific antagonist of platelet aggregation via binding to the adenosine diphosphate P2Y12 receptor subtype. The aim of this study was to assess the safety and coronary artery patency of cangrelor as an adjunct to alteplase (tissue plasminogen activator [t-PA]). METHODS: Patients with AMI received aspirin, heparin, and an intravenous infusion of either cangrelor alone, full-dose t-PA alone, or 1 of 3 doses of cangrelor along with half-dose t-PA. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 60 minutes. Secondary end points included TIMI frame count, TIMI myocardial perfusion grade, extent of ST-segment resolution, composite clinical events, and bleeding. RESULTS: Ninety-two of planned 180 patients were enrolled. The combination of cangrelor and half-dose t-PA resulted in similar 60-minute patency as full-dose t-PA alone (55% vs 50%, P = not significant) and greater patency than with cangrelor alone (55% vs 18%, P < .05). The percentage of patients achieving >70% ST-segment resolution at 60 minutes tended to be greater with combination therapy than with either cangrelor or t-PA alone (28% vs 13%, P = .13 and 28% vs 14%, P = .30, respectively). Bleeding and adverse clinical events were comparable among the groups. CONCLUSION: This first experience with the intravenous P2Y12 receptor inhibitor, cangrelor, suggests the potential of this compound as an adjunct to fibrinolysis during treatment of AMI.

Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial.

BACKGROUND: Platelet-initiated acute thrombosis and coronary embolization are fundamental in the pathophysiology of complications during percutaneous coronary intervention (PCI). Cangrelor (formerly AR-C69931MX) is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation via binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype. The primary aims of this study were to assess the initial safety and pharmacodynamics of cangrelor in patients undergoing PCI. METHODS: In part 1, patients undergoing PCI were randomized to an 18- to 24-hour of either placebo, 1-, 2-, or 4-microg/kg per minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 microg/kg per minute) or abciximab before PCI. The primary end point was the composite incidence of major and minor bleeding through 7 days. Secondary end points included the occurrence of major adverse coronary events (death, MI, and unplanned repeat coronary intervention) through 30 days plus ex vivo platelet aggregation and bleeding times. RESULTS: Two hundred patients (3 dosage groups and placebo) were studied in part 1, and 199 additional patients were then randomized in the second part, comparing 1 dose of cangrelor and abciximab. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% in those randomized to placebo (P = non significant [NS]) during part 1 and in 7% receiving cangrelor compared with 10% randomized to abciximab (P = NS), during part 2. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs 5.3%, respectively, P = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 micromol/L ADP at steady state was 100% for both cangrelor 4 microg/kg per minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. There was a trend toward longer bleeding time prolongation and lower platelet count with abciximab compared with cangrelor. CONCLUSIONS: This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y12 platelet receptor with less prolongation of bleeding time then the glycoprotein IIb/IIIa receptor antagonist abciximab.

Zolmitriptan oral tablet in migraine treatment: high placebo responses in adolescents.

OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and tolerability of the zolmitriptan conventional tablet at three different doses for the treatment of a single migraine attack in adolescents. BACKGROUND: Preliminary data from an open-label study suggested that the zolmitriptan conventional tablet could be effective in the treatment of acute migraine in adolescent patients. METHODS: Migraine patients aged 12 to 17 years (n = 850) were randomized to receive zolmitriptan 2.5, 5, or 10 mg, or placebo for treatment of a single migraine attack. Patients recorded migraine headache intensity before and after treatment using a 4-point scale. RESULTS: There was no statistically significant improvement between zolmitriptan 10 mg (2 x 5 mg tablet) and placebo for the primary efficacy variable, headache response at 2 hours, nor any of the secondary variables tested. Two-hour headache response rates were 54%, 53%, and 57% for zolmitriptan 10, 5, and 2.5 mg, respectively, and 58% for placebo. Two-hour pain-free rates were 25%, 19%, and 23% for zolmitriptan 10, 5, and 2.5 mg, respectively, and 20% for placebo. Zolmitriptan was well tolerated, with a tolerability profile similar to the pattern seen in adults. CONCLUSION: The similar efficacy between zolmitriptan and placebo appears to be the result of the high placebo response rate. This is a recognized issue in pediatric migraine studies and there is an ongoing debate on ways to address this problem. Since this study was initiated, there has been some debate on the appropriateness of the 2-hour endpoint for response rates in adolescent studies, given the shorter duration of headache pain in adolescents compared with adults. Furthermore, accurate information regarding the timeliness of treatment and reporting of headache-related information by adolescents is difficult.