Efficacy and tolerability of zolmitriptan nasal spray for the treatment of acute migraine in adolescents: Results of a randomized, double-blind, multi-center, parallel-group study (TEENZ).

OBJECTIVE: The primary objective of the TEENZ Study (NCT01211145) was to assess the efficacy of zolmitriptan nasal spray in the acute treatment of adolescent migraine patients (ages 12 to 17 years), as measured by the primary outcome variable of pain-free status at 2 hours post-treatment. METHODS: This randomized, double-blind, placebo-controlled, four-arm parallel group study compared zolmitriptan nasal spray with placebo in the treatment of a single episode of adolescent migraine. Patients completed a 30-day run-in period to treat a single migraine attack with single-blind placebo nasal spray. Eligible patients, who had not responded to placebo, were randomized to one of three zolmitriptan nasal spray doses (5, 2.5, or 0.5 mg) or placebo in a ratio of 5:3:3:5 according to a computer-generated randomization scheme. Patients completed diaries for 24 hours after treatment, recording headache pain scores, adverse events (AEs), and medications taken. RESULTS: In an interim futility analysis, zolmitriptan nasal spray doses of 0.5 and 2.5 mg were declared futile relative to placebo and further randomization to these treatment arms was discontinued. Of 1653 patients enrolled into the study, 855 patients failed to meet study eligibility criteria and were considered screen failures. The most common reason for screen failure was response to placebo challenge (325 patients [38.0%]). Of the 798 patients who were randomized to treatment, 721 (90.4%) completed the study period. Of these, 657 (82.3%) treated a migraine within the study period and contributed data for analysis. Zolmitriptan nasal spray 5 mg was significantly more effective than placebo in achieving pain-free status at 2 hours after treatment (P < .001), with 30% of patients achieving pain-free status at 2 hours vs 17% of placebo-treated patients (OR 2.18; 95% CI 1.40, 3.39). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving pain-free status at 3 and 4 hours post-treatment (45 vs 24%, and 56 vs 39%; both P < .001). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving headache response at 2, 3, and 4 hours after treatment (51 vs 39%, 61 vs 48%, and 69 vs 57%, respectively; all P ≤ .011). Zolmitriptan nasal spray was well-tolerated at all doses. Dysgeusia was the most frequently reported AE, with greater frequencies reported in active treatment groups versus placebo. No serious AEs or AEs leading to discontinuation were reported. Most AEs were mild or moderate in severity, and consistent with the known profile of zolmitriptan in adult and adolescent populations. CONCLUSION: Zolmitriptan nasal spray was well-tolerated in the acute treatment of adolescent (ages 12 to 17 years) migraine. Zolmitriptan 5 mg nasal spray demonstrated superior efficacy compared with placebo for the primary efficacy endpoint of pain-free status 2 hours after treatment and the efficacy of the 5 mg dose was supported by the majority of secondary efficacy endpoints.

Bipolar II compared with bipolar I disorder: baseline characteristics and treatment response to quetiapine in a pooled analysis of five placebo-controlled clinical trials of acute bipolar depression.

BACKGROUND: Bipolar I and II represent the most common and severe subtypes of bipolar disorder. Although bipolar I disorder is relatively well studied, the clinical characteristics and response to treatment of patients with bipolar II disorder are less well understood. METHODS: To compare the severity and burden of illness of patients with bipolar II versus bipolar I disorder, baseline demographic, clinical, and quality of life data were examined in 1900 patients with bipolar I and 973 patients with bipolar II depression, who were enrolled in five similarly designed clinical placebo-controlled trials of quetiapine immediate-release and quetiapine extended-release. Acute (8 weeks) response to treatment was also compared by assessing rating scale scores, including Montgomery-Åsberg depression rating scale, Hamilton rating scale for anxiety, Young mania rating scale, and clinical global impression-severity scores, in the bipolar I and II populations in the same pooled database. RESULTS: Patients with bipolar I and bipolar II depression were similar in demographics, baseline rating scale scores (depression, anxiety, mania, and quality of life), and mood episode histories. Symptom improvements in response to quetiapine were greater versus comparators (lithium, paroxetine, and placebo) at 4 and 8 weeks in both bipolar I and II patients. Patients with the bipolar II subtype initially showed slower responses to all treatments, but, by 8 weeks, attained similar symptom improvement as patients with bipolar I depression. CONCLUSIONS: Pooled analysis of five clinical trials of quetiapine demonstrated that patients with bipolar II depression have a similar burden of illness and quality of life to patients with bipolar I. Bipolar II patients consistently showed a slower response to treatments than bipolar I patients, but, after 8 weeks of treatment with quetiapine, symptom improvements were similar between bipolar I and II disorder subtypes.

Early Symptom Improvement as a Predictor of Response to Extended Release Quetiapine in Major Depressive Disorder.

The aim of this post-hoc analysis was to determine whether early symptom improvement with extended release quetiapine (quetiapine XR) may predict treatment outcome in patients with major depressive disorder. Data were from 6, double-blind, placebo-controlled studies of quetiapine XR (2 fixed-dose and 2 flexible-dose monotherapy and 2 adjunct studies) in adult patients with major depressive disorder. Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression-Severity Score (CGI-S) were assessed at baseline, weeks 2, 4, and 6. Hamilton Rating Scale for Depression (HAM-D) was assessed at baseline and week 6. The MADRS improvement at week 2 (15%, 20%, 25%, 30%) was used to predict response and remission, based on MADRS (50% improvement; total score ≤ 12) or HAM-D (50% improvement; total score ≤ 7). The CGI-S improvement (1 point) at week 2 was used to predict final outcome (CGI-S score ≤ 2). The predictive value for early improvement with quetiapine XR was found to be "very strong" (Yule's Q coefficient, a combined measure of sensitivity and specificity) using 30% MADRS improvement as the threshold. This was relatively comparable for response and remission and for fixed-dose, flexible-dose, and adjunct studies. This was also observed for placebo. Exceptions were: adjunct studies (where predictivity was lower for ongoing antidepressant/placebo), and for remission (predictivity for remission appeared lower than for response with placebo). In conclusion, outcome at week 6 with quetiapine XR for a major depressive episode could be predicted by 30% improvement after 2 weeks, a finding that could give doctors confidence to continue treatment and may facilitate adherence in patients.

Safety and antibody response, including antibody persistence for 5 years, after primary vaccination or revaccination with pneumococcal polysaccharide vaccine in middle-aged and older adults.

BACKGROUND: This study assessed antibody levels for 5 years after primary vaccination or revaccination with 23-valent pneumococcal polysaccharide vaccine (PN23). METHODS: Subjects were enrolled into 4 study groups by age (50-64 or > or = 65 years) and prior vaccination status (no prior vaccination or 1 vaccination 3-5 years previously). Blood was obtained on day 0 (before primary vaccination or revaccination), day 30, day 60, and annually during years 2-5. Levels of immunoglobulin G (IgG) to 8 vaccine serotypes were measured by enzyme-linked immunosorbent assay. RESULTS: Of 1008 enrolled subjects, 551 completed year 5. For each serotype and age group, baseline geometric mean concentrations (GMCs) of IgG were higher in revaccination than primary vaccination subjects. Primary vaccination or revaccination with PN23 induced significant increases in levels of antibody to all serotypes tested. Although day 30 and 60 antibody levels tended to be modestly lower after revaccination, study groups had similar GMCs at later time points. For serotypes 4, 6B, 8, 9V, 12F, 14, and 23F, GMCs during years 2-5 after primary vaccination or revaccination remained higher than in vaccine-naive persons. Levels of antibody to serotype 3 returned to baseline by year 2. CONCLUSIONS: Both primary vaccination and revaccination with PN23 induce antibody responses that persist during 5 years of observation.

Predictors of the placebo analgesia response in randomized controlled trials of chronic pain: a meta-analysis of the individual data from nine industrially sponsored trials.

A large number of analgesics have failed to prove superiority over placebo in randomized controlled trials (RCTs), and as this has been related to increasing placebo responses, there is currently an interest in specifying predictors of the placebo response. The literature on placebo mechanisms suggests that factors related to patients' expectations of treatment efficacy are pivotal for the placebo response. Also, general characteristics of RCTs have been suggested to influence the placebo response. Yet, only few meta-analyses have directly tested these hypotheses. Placebo data from 9 industrially sponsored, randomized, double-blind, placebo-controlled, multicenter phase III trials in 2017 adult patients suffering from chronic painful osteoarthritis (hip or knee) or low back pain were included. The primary outcome was pain intensity. Based on previous studies, we chose 3 expectancy-related primary predictors: type of active medication, randomization ratio, and number of planned face-to-face visits. In addition, explorative analyses tested whether RCT and patients' characteristics predicted the placebo response. Opioid trials, a high number of planned face-to-face visits, and randomization ratio predicted the magnitude of the placebo response, thereby supporting the expectancy hypothesis. Exploratory models with baseline pain intensity, age, washout length, and discontinuation because of adverse events accounted for approximately 10% of the variability in the placebo response. Based on these results and previous mechanisms studies, we think that patients' perception of treatment allocation and expectations toward treatment efficacy could potently predict outcomes of RCTs.