Sustained response of galcanezumab in migraine prevention: Patient-level data from a post hoc analysis in patients with episodic or chronic migraine.

OBJECTIVE: To evaluate, at population and individual patient levels, the sustained response of reduction in migraine headache days in patients with migraine treated with galcanezumab. METHODS: This was a post hoc analysis of double-blind galcanezumab studies in patients with migraine: two 6-month episodic migraine (EM; EVOLVE-1/EVOLVE-2), one 3-month chronic migraine (CM; REGAIN), and one 3-month treatment-resistant migraine (CONQUER). Patients received monthly subcutaneous galcanezumab 120 mg (after 240 mg initial loading dose), galcanezumab 240 mg, or placebo. In the EM and CM studies, the proportions of patients with ≥50% and ≥75% (EM only) reduction from baseline in average monthly migraine headache days from Months 1 to 3 and Months 4 to 6 were evaluated. A mean monthly response rate was estimated. The sustained effect was defined as maintaining ≥50% response for ≥3 consecutive months in the patient-level data for EM and CM. RESULTS: A total of 3348 patients with EM or CM from the EVOLVE-1/EVOLVE-2 (placebo, n = 894, galcanezumab, n = 879), REGAIN (placebo, n = 558, galcanezumab, n = 555), and CONQUER (EM: placebo, n = 132, galcanezumab, n = 137; CM: placebo, n = 98, galcanezumab, n = 95) studies were included. Patients were predominantly female, White, and had monthly migraine headache day averages ranging from 9.1 to 9.5 days (EM) and 18.1 to 19.6 days (CM). In patients with EM and CM, 19.0% and 22.6% of galcanezumab-treated patients, respectively, had significantly higher maintenance of ≥50% response for all months in the double-blind period compared to 8.0% and 1.5% of placebo-treated patients. The odds ratios (OR) of achieving clinical response for EM and CM were double with galcanezumab (OR = 3.0 [95% CI 1.8, 4.8] and OR = 6.3 [95% CI 1.7, 22.7], respectively). At the individual patient level, of patients who had ≥75% response at Month 3 in the galcanezumab 120 and 240 mg dose groups and placebo group, 39.9% (55/138) and 43.0% (61/142), respectively, of galcanezumab-treated patients maintained ≥75% response during Months 4-6 compared to 32.7% (51/156) with placebo. CONCLUSION: More galcanezumab-treated patients achieved ≥50% response within the first 3 months of treatment compared to placebo; responses were sustained during Months 4-6. The odds of achieving ≥50% response were double with galcanezumab.

A phase IV clinical trial of gastrointestinal motility in adult patients with migraine before and after initiation of a calcitonin gene-related peptide ligand (galcanezumab) or receptor (erenumab) antagonist.

OBJECTIVE: To compare effects of an initial dose of calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) antagonists on gastrointestinal (GI) motility in patients with migraine and to explore if the mechanistic difference contributes to GI adverse events (AEs). BACKGROUND: Different frequencies of constipation have been observed between CGRP mAbs that target the ligand (galcanezumab [GMB]) or receptor (erenumab [ERE]). METHODS: Patients (n = 65) with migraine without significant GI symptoms were enrolled in a multi-center, single-blind phase IV clinical trial (NCT04294147) and randomized 1:1 to receive GMB (240 mg; n = 33) or ERE (140 mg; n = 32). GI whole and regional transit times were assessed using a wireless motility capsule 1 week before and 2 weeks after mAb administration. The primary endpoint was change from baseline in colonic transit time (CTT) within each treatment group. Other measures included GI Symptom Rating Scale (GSRS), Bristol Stool Form Scale (BSFS), and spontaneous bowel movement (SBM) evaluation. AEs were monitored throughout the study. RESULTS: Baseline characteristics indicated significant GI transit time variability with minimal GI reported symptoms. While not statistically significant, a numerical mean increase in CTT was observed in ERE patients (n = 28, mean [SD] at baseline: 33.8 [29.4] h; least square [LS] mean [SE] change: 5.8 [5.7] h, 95% confidence interval [CI] -5.7 to 17.2, p = 0.320), while GMB decreased CTT (n = 31, mean [SD] at baseline: 29.3 [24.5] h; LS mean [SE] change: -5.4 [5.4] h, 95% CI -16.2 to 5.5, p = 0.328) compared to baseline. No meaningful changes were observed in other regional transit times. ERE significantly reduced BSFS (LS mean [SE] score -0.5 [0.2], p = 0.004) and SBM (LS mean [SE] -1.2 [0.5], p = 0.0120), and increased GSRS-constipation compared to baseline (LS mean [SE] score 0.3 [0.1], p = 0.016). GMB increased GSRS-constipation (LS mean [SE] score 0.4 [0.1], p = 0.002). There were no discontinuations due to or serious AEs. A higher percentage of treatment-emergent AEs were reported with ERE than GMB (ERE: nine of 32 [28.1%] versus GMB: three of 33 [9.1%]), with constipation the most frequently reported (ERE: five of 32 [15.6%] versus GMB one of 33 [3.0%]). CONCLUSION: While the primary endpoint of this study was not met, secondary and tertiary endpoints support a within- and between-treatment change in GI effects suggesting possible mechanistic differences between ligand (GMB) and receptor (ERE) antagonism.

Does "wearing off" of efficacy occur in galcanezumab-treated patients at the end of the monthly treatment cycle? Post hoc analyses of four phase III randomized trials.

OBJECTIVE: The purpose of this study was to propose a definition of "wearing off" at the individual patient-level and determine the percentage of patients with migraine who experience "wearing off" of efficacy of galcanezumab at the end of a treatment cycle using this predefined threshold. BACKGROUND: Anecdotal reports suggest that some patients may experience "wearing off" of efficacy during the last week of their calcitonin gene-related peptide monoclonal antibody treatment cycle. A previous post hoc analysis of galcanezumab demonstrated consistent efficacy at each week throughout all monthly dosing intervals at the population-level, but "wearing off" has not been assessed at the individual patient-level. METHODS: Post hoc analyses of clinical trial data from four galcanezumab phase III, randomized, placebo-controlled studies in a total of 2680 patients with high-frequency episodic migraine (EVOLVE-1, EVOLVE-2, and CONQUER studies) or chronic migraine (CM; REGAIN and CONQUER studies) were conducted. "Wearing off" was defined as an increase of greater than or equal to 2 weekly migraine headache days in the last week of the treatment cycle compared to the second week for at least 2 months. The analyses were conducted (1) in all patients and (2) in patients with a clinically meaningful response to treatment. RESULTS: The percentage of patients meeting the threshold of "wearing off" was not statistically significantly different among the placebo, galcanezumab 120 mg, and galcanezumab 240 mg treatment groups, both in the total population and in patients with a clinically meaningful response (all ≤9.0%). Although the frequency of "wearing off" in patients with CM and prior preventive failures was numerically greater in the galcanezumab groups (8/89 or 9.0%) compared to placebo (3/95 or 3.2%), these differences were not statistically significant. CONCLUSIONS: Consistent with previous analyses at the population-level that showed no evidence of decreased efficacy at the end of a treatment cycle, rates of individual patients meeting the threshold of "wearing off" in this analysis were low and similar among placebo, galcanezumab 120 mg, and galcanezumab 240 mg treatment groups.

Migraine Headache Day Response Rates and the Implications to Patient Functioning: An Evaluation of 3 Randomized Phase 3 Clinical Trials of Galcanezumab in Patients With Migraine.

OBJECTIVE: This post hoc study investigated the relationship between patient response in terms of migraine headache day reduction and patient-reported outcomes of health-related quality of life (HRQoL) and disability categories. BACKGROUND: Migraine causes considerable disease-related disability and negatively impacts HRQoL of patients. Calcitonin gene-related peptide inhibitors improve these outcomes and may eliminate disability due to migraine in some patients. METHODS: Analyses used data from 3 double-blind, placebo (PBO)-controlled, phase 3 studies in adults with episodic migraine (EM) (EVOLVE-1: N = 858 and EVOLVE-2: N = 915) or chronic migraine (CM) (REGAIN: N = 1113). Patients were randomized 2:1:1 to subcutaneous injection of PBO, galcanezumab (GMB) 120 mg, or GMB 240 mg once monthly for 6 months in EVOLVE-1 and -2 and for 3 months in REGAIN. Primary endpoint was overall mean change from baseline in monthly migraine headache days. Patients were divided into 4 response-level groups based on percent change from baseline (<30%, ≥30% to <50%, ≥50% to <75%, ≥75%). Patient-reported outcomes included the 14-item Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ) and Migraine Disability Assessment (MIDAS) questionnaire. RESULTS: Among patients with migraine, mean improvements from baseline in MSQ domain scores increased with each successive level of migraine headache day response. On a 100-pt scale, increases in Role Function-Restrictive score in EM were 16.8 and 36.0 at the <30% and ≥75% response levels, respectively, and for CM were 10.7 and 46.5. Similar patterns in scores were observed for the Role Function-Preventive and Emotional Function domains. Examination of improvement in MSQ item score by treatment group showed that, in patients with EM, approximately 10 to 20% more GMB-treated patients (N = 796 for GMB 120 mg and GMB 240 mg) had improvements in all 14 MSQ items compared with PBO-treated patients (N = 773) (all P < .001). In patients with CM, 3 to 16% more GMB-treated patients (N = 507) had improvements in the 14 MSQ items compared with PBO (N = 494), though differences were statistically significant in only 19 of 28 comparisons. At baseline, mean MIDAS scores (EM, 33.1; CM, 67.2) indicated severe mean disability for patients with EM and very severe disability for patients with CM. Among patients with EM, 215 of 425 (50.6%) of those treated with GMB 120 mg and 212 of 413 (51.3%) treated with 240 mg had little/no disability due to migraine after 6 months (PBO: 277 of 832 (33.3%), P < .001 for both). Among patients with CM, 50 of 254 (19.7%) of those treated with GMB 120 mg and 54 of 258 (20.9%) treated with 240 mg reached the level of little/no disability after 3 months of treatment (PBO: 70 of 504 (13.9%), P = .045 for 120 mg, P = .017 for 240 mg). CONCLUSIONS: Because migraine greatly impairs an individual's ability to participate in activities of daily living, measurements of HRQoL are essential in clinical research. This study showed that function in daily life, as measured by MSQ score, improved as migraine headache days were reduced and that GMB-treated patients were more likely to see improvement in MSQ item scores compared with PBO-treated patients. Elimination of migraine-related disability was also more frequent in GMB-treated patients compared with placebo-treated patients.

Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine.

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Lasmiditan is an effective acute treatment for migraine: A phase 3 randomized study.

OBJECTIVE: To assess the efficacy and safety of lasmiditan in the acute treatment of migraine. METHODS: Adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours after dosing, patients used an electronic diary to record headache pain and the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS). RESULTS: Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardiovascular risk factors in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI] 2.0-3.6, p< 0.001), similar to those dosed with lasmiditan 100 mg (28.2%; OR 2.2, 95% CI 1.6-3.0, p< 0.001). Furthermore, compared with those dosed with placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; OR 1.6, 95% CI 1.3-2.1, p< 0.001) and lasmiditan 100 mg (40.9%; OR 1.7, 95% CI, 1.3-2.2, p< 0.001) were free of their MBS at 2 hours after dosing. Adverse events were mostly mild or moderate in intensity. CONCLUSIONS: Lasmiditan dosed at 200 and 100 mg was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors. CLINICALTRIALSGOV IDENTIFIER: NCT02439320. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for adult patients with migraine, lasmiditan increases the proportion of subjects who are headache pain free at 2 hours after treating a migraine attack.

Effect of Atomoxetine Treatment on Reading and Phonological Skills in Children with Dyslexia or Attention-Deficit/Hyperactivity Disorder and Comorbid Dyslexia in a Randomized, Placebo-Controlled Trial.

OBJECTIVES: Evaluated the effects of atomoxetine on the reading abilities of children with dyslexia only or attention-deficit/hyperactivity disorder (ADHD) and comorbid dyslexia. METHODS: Children aged 10-16 years (N = 209) met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for dyslexia only (n = 58), ADHD and comorbid dyslexia (n = 124), or ADHD only (n = 27) and were of normal intelligence. Patients were treated with atomoxetine (1.0-1.4 mg/kg/day) or placebo in a 16-week, randomized, placebo-controlled, double-blind trial. The dyslexia-only and ADHD and comorbid dyslexia groups were randomized 1:1; the ADHD-only group received atomoxetine in a blinded manner. Reading abilities were measured with the Woodcock Johnson III (WJIII), Comprehensive Test of Phonological Processing (CTOPP), Gray Oral Reading Tests-4, and Test of Word Reading Efficiency. RESULTS: Atomoxetine-treated dyslexia-only patients compared with placebo patients had significantly greater improvement (p < 0.02) with moderate to approaching high effect sizes (ES) on WJIII Word Attack (ES = 0.72), Basic Reading Skills (ES = 0.48), and Reading Vocabulary (ES = 0.73). In the atomoxetine-treated ADHD and comorbid dyslexia group, improvement on the CTOPP Elision measure (ES = 0.50) was significantly greater compared with placebo (p < 0.02). Total, inattentive, and hyperactive/impulsive ADHD symptom reductions were significant in the atomoxetine-treated ADHD and comorbid dyslexia group compared with placebo, and from baseline in the ADHD-only group (p ≤ 0.02). ADHD symptom improvements in the ADHD and comorbid dyslexia group were not correlated with improvements in reading. CONCLUSIONS: Atomoxetine treatment improved reading scores in patients with dyslexia only and ADHD and comorbid dyslexia. Improvements for patients with dyslexia only were in critical components of reading, including decoding and reading vocabulary. For patients with ADHD and comorbid dyslexia, improvements in reading scores were distinct from improvement in ADHD inattention symptoms alone. These data represent the first report of improvements in reading measures following pharmacotherapy treatment in patients with dyslexia only evaluated in a randomized, double-blind trial.

Atomoxetine-Related Change in Sluggish Cognitive Tempo Is Partially Independent of Change in Attention-Deficit/Hyperactivity Disorder Inattentive Symptoms.

OBJECTIVES: To evaluate effects of atomoxetine versus placebo on sluggish cognitive tempo (SCT) and determine factors affecting improvement of SCT in children with attention-deficit/hyperactivity disorder (ADHD) with dyslexia (ADHD+D) or dyslexia only. METHODS: This is a post hoc analysis of a 16-week placebo-controlled, double-blind randomized phase of a previously reported atomoxetine study in children aged 10-16 years with ADHD+D, Dyslexia-only, or ADHD-only (no placebo arm). Least squares mean changes from baseline to endpoint for atomoxetine versus placebo on the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) (Parent, Teacher, and Youth) were analyzed using analysis of covariance and multiple regression (partial R2) analyses to test contributions of ADHD and dyslexia to improvements in K-SCT scores. RESULTS: Results were examined for the three informants within the three diagnostic groups (nine outcomes). Atomoxetine treatment was associated with significant reductions from baseline in seven of the nine outcomes using the p = 0.05 significance level, appropriate for exploratory analysis. When change in ADHD symptom severity was controlled, all of the seven SCT outcomes remained significant; changes in effect sizes were minimal. Regression analyses using SCT change as the criterion found a significant contribution by inattention change only for parent report, whereas, baseline SCT severity was a significant predictor in the randomized groups with the exception of teacher report in the Dyslexia-only group. CONCLUSION: Given that controlling for change in ADHD symptoms had little effect on change in SCT scores, findings suggest that change in SCT is substantially independent of change in ADHD. By inference, SCT and its response to treatment is a partially distinct phenomenon from ADHD response. Regression analyses did not reveal global effects of inattention change on SCT change; instead, baseline SCT severity was the strongest predictor of placebo-controlled treatment effect on SCT. Atomoxetine effects on SCT appear to be best predicted by how much room for improvement exists for SCT rather than by severity or improvement in inattention. CLINICAL TRIAL REGISTRATION: NCT00607919, www.clinicaltrials.gov.

Atomoxetine Increased Effect over Time in Adults with Attention-Deficit/Hyperactivity Disorder Treated for up to 6 Months: Pooled Analysis of Two Double-Blind, Placebo-Controlled, Randomized Trials.

INTRODUCTION: Changes in the magnitude of efficacy throughout 26 weeks of atomoxetine treatment, along with impact of dosing, were evaluated in adults with ADHD from two randomized, double-blind, placebo-controlled studies. AIMS: Pooled placebo (n = 485) and atomoxetine (n = 518) patients, dosed 25, 40, 60, 80 (target dose), or 100 mg daily, were assessed. Change from baseline in Conners' Adult ADHD Rating Scale-Investigator Rated Scale: Screening Version (CAARS) total ADHD symptoms score and Adult ADHD Investigator Symptom Rating Scale (AISRS) total score were analyzed using mixed-model repeated measures, with least squares mean change, effect size, and response rate calculated at 1, 2, 4, 8, 12, 16, 22, and 26 weeks. RESULTS: Decreases on CAARS for atomoxetine- versus placebo-treated patients were consistently statistically significantly greater at every time point beginning at one week (P ≤ 0.006, 0.28 effect size). By 4 weeks, comparison was -13.19 compared with -8.84 (P < 0.0001, 0.45 effect size). By 26 weeks, mean change was -15.42 versus -9.71 (0.52 effect size); increase in effect size over time was most pronounced in the 80 mg group (0.82 effect size). AISRS demonstrated similar results. Atomoxetine response rate (CAARS 50% decrease) continued to increase throughout 26 weeks. CONCLUSIONS: Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment. The data support increased effect size and response rate over time during longer-term treatment at target dose.

Differential response profiles in children and adolescents with attention-deficit/hyperactivity disorder: treatment with atomoxetine.

Atomoxetine has been shown to be safe and effective in the treatment of attention-deficit/hyperactivity disorder (ADHD). The purpose of this post hoc analysis was to examine response trajectories of pediatric patients treated with atomoxetine. Data were pooled from 7 atomoxetine double-blind, placebo-controlled clinical trials conducted in pediatric patients between November 1998 and June 2004. Growth mixture modeling was applied to the investigator-rated ADHD rating scale (ADHDRS-Inv) and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scores in the randomized acute phase (6-9 weeks) to explore whether there were groups of patients who differed in their response to atomoxetine. Classification and regression tree analyses were performed to identify predictors that can help categorize subjects to different response profiles. Patients (N = 925) were mostly male (73%) and of the combined subtype (74%). Most patients had a response pattern characterized by gradual, modest improvement, while a smaller group experienced early, robust improvement.

Reading outcomes of children and adolescents with attention-deficit/hyperactivity disorder and dyslexia following atomoxetine treatment.

UNLABELLED: Abstract Objective: This study assessed the efficacy of atomoxetine on attention-deficit/hyperactivity disorder (ADHD) symptoms in children and adolescents having ADHD with comorbid dyslexia (ADHD+D) and the effects of the treatment on reading measures. METHODS: The analyses in this report used data from a study designed to examine the effects of a nonstimulant pharmacological agent, atomoxetine, on reading in children with ADHD+D. Patients ages 10-16 years with ADHD or ADHD+D received open-label atomoxetine for 16 weeks. The ADHD Rating Scale (ADHD-RS) and reading subtests of the Kaufman Test of Educational Achievement (K-TEA) were assessed. Changes in ADHD symptoms and reading scores were also analyzed by ADHD subtype. Treatment effect sizes and correlations between changes in ADHDRS and K-TEA scores were calculated. RESULTS: After atomoxetine treatment, both ADHD and ADHD+D patient groups showed significant reduction in ADHD symptom and improvements in K-TEA reading scores. The range of treatment effect sizes on K-TEA scores was 0.35-0.53 for the ADHD group and 0.50-0.62 for the ADHD+D group. Pearson's correlation coefficients revealed only a few weak correlations between changes in ADHD symptoms and reading scores, regardless of diagnostic group. CONCLUSIONS: ADHD symptoms and K-TEA reading scores improved for both the ADHD and ADHD+D groups following atomoxetine treatment. Correlation analyses indicate that improvements in reading outcomes cannot be explained by a reduction of ADHD symptoms alone. These findings support further exploration of the potential effects of atomoxetine on reading in children with ADHD and dyslexia or dyslexia alone.

Meta-analysis of suicide-related behavior or ideation in child, adolescent, and adult patients treated with atomoxetine.

OBJECTIVE: This meta-analysis examined suicide-related events in the acute phases of double-blind, placebo-controlled atomoxetine trials in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 3883 pediatric and 3365 adult patients were included. Potential events were identified from the adverse events database using a text-string search. Mantel-Haenszel risk ratios (MHRR) were calculated for potential suicide-related events categorized according to United States Food and Drug Administration defined codes. RESULTS: In this data set, no completed suicides were reported in the pediatric or adult populations. One pediatric (attempted suicide) (and no adult patient events) was categorized as suicidal behavior in the atomoxetine group. The frequency of combined suicidal behavior or ideation with atomoxetine treatment was 0.37% in pediatric patients (vs. 0.07% with placebo) and 0.11% in adults (vs. 0.12% with placebo) and the risk compared with placebo was not statistically significant (MHRR=1.57; p=0.42 and MHRR=0.96; p=0.96, respectively). In pediatric patients, suicidal ideation only was reported more frequently compared with placebo (MHRR=1.63; p=0.41). CONCLUSIONS: Overall in this data set, no completed suicides and 1 pediatric patient suicidal behavior event were reported in atomoxetine-treated pediatric and adult patients. Suicidal ideation was uncommon among atomoxetine-treated pediatric and adult patients, although it was reported more frequently in atomoxetine-treated pediatric patients compared with placebo; the reporting rate difference was not statistically significant. The MHRR of suicidal ideation was consistent with a previous meta-analysis of similar design. There was no evidence of increased risk for suicidal behavior in atomoxetine-treated pediatric or adult patients. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov . The data reported are from an analysis of 23 pediatric and 9 adult clinical trials completed between 1998 and 2011. Ten pediatric (Studies HFBD, HFBK, LYAC, LYAS, LYAT, LYAW, LYAX, LYBG, LYBI, and LYBP) and two adult trials (Studies LYAA and LYAO) were conducted before the requirement to post trials at initiation (ongoing as of July 1, 2005) and, therefore, do not have a registration number. The registration numbers for the 13 pediatric trials meeting this requirement are: NCT00191698 (LYBX), NCT00486122 (LYCC), NCT00386581 (LYCZ), NCT00485459 (S010), NCT00191542 (LY15), NCT00191295 (LYBC), NCT00191906 (LYCK), NCT00192023 (LYCY), NCT00191945 (LYDM), NCT00546910 (LYDV), NCT00406354 (LYDW), NCT00380692 (S017), and NCT00607919 (LYEB). For the seven adult trials, the registration numbers are: NCT00190931 (LYBV), NCT00190957 (LYBY), NCT00190736 (LYCU), NCT00190775 (LYCW), NCT00190879 (LYDQ), NCT00510276 (LYDZ), and NCT00962104 (LYEE).

Atomoxetine improved attention in children and adolescents with attention-deficit/hyperactivity disorder and dyslexia in a 16 week, acute, randomized, double-blind trial.

OBJECTIVE: The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept. METHODS: Children and adolescents (10-16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0-1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale-Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C). RESULTS: At week 16, atomoxetine treatment resulted in significant (p<0.05) improvement from baseline in subjects with ADHD+D versus placebo on ADHDRS-IV-Parent:Inv Total (primary outcome) and subscales, ADHDRS-IV-Teacher-Version Inattentive subscale, K-SCT Interview Parent and Teacher subscales, and WMTB-C Central Executive component scores; in subjects with Dyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and MSCS Academic and Competence subscale scores. CONCLUSIONS: Atomoxetine treatment improved ADHD symptoms in subjects with ADHD+D and ADHD-only, but not in subjects with dyslexia-only without ADHD. This is the first study to report significant effects of any medication on SCT. CLINICAL TRIALS REGISTRATION: This study was registered at: http://clinicaltrials.gov/ct2/home, NCT00607919.

Atomoxetine tolerability in pediatric and adult patients receiving different dosing strategies.

OBJECTIVE: Examine how different dosing schedules and recent stimulant therapy effect incidence, time to onset, and duration of common treatment-emergent adverse events (TEAEs) during atomoxetine treatment. METHOD: Post hoc analyses including safety data (open-ended questions) from 22 pediatric and 3 adult atomoxetine trials (1998-2009) in patients with attention-deficit/hyperactivity disorder. Most common TEAEs were determined by incidence rates and frequency of consumer and clinician inquiries. Onset and duration of TEAEs with slow versus fast titration, once-daily versus twice-daily dosing, and previous stimulant exposure were compared among treatment groups using Kaplan-Meier methods. RESULTS: In pediatric patients, the most commonly reported TEAEs were abdominal pain, decreased appetite, fatigue, nausea, somnolence, and vomiting; time to onset of TEAEs was significantly shorter for once-daily versus twice-daily dosing for all TEAEs (P ≤ .007) and for fast versus slow titration for abdominal pain, decreased appetite, and somnolence (all P values ≤ .009); duration of TEAEs with once-daily dosing was significantly longer for decreased appetite (P = .001) and nausea (P = .041); and more common in stimulant-naive patients versus patients with prior stimulant use were abdominal pain, decreased appetite, and fatigue (P ≤ .047). In adult patients, the most commonly reported TEAEs (erectile dysfunction data were excluded) were nausea, insomnia, decreased appetite, urinary hesitation/urinary retention, and fatigue; insomnia had a significantly shorter time to onset and longer duration with twice-daily versus once-daily dosing (P ≤ .032) and fast versus slow titration (P ≤ .007). CONCLUSIONS: Time to onset and resolution of TEAEs appear dependent on dosing schedule and titration speed. These findings can help to better manage tolerability issues and set appropriate expectations for clinicians and patients during atomoxetine titration, potentially improving treatment adherence and success.

Atomoxetine once daily for 24 weeks in adults with attention-deficit/hyperactivity disorder (ADHD): impact of treatment on family functioning.

OBJECTIVE: To assess the efficacy of atomoxetine (ATX) and impact of treatment on family functioning in adults with ADHD. METHODS: Adults with attention-deficit/hyperactivity disorder (ADHD) having both a spouse/partner and child were randomized to placebo (n = 234) or ATX (n = 268) for 24 weeks. Attention-deficit/hyperactivity disorder measures included the Conners Adult ADHD Rating Scale total ADHD Symptoms score and Clinical Global Impression-ADHD-Severity. Marital measures included the Dyadic Adjustment Scale and the Family Assessment Measure Dyadic Relationship Scale (FAM III). Parenting measures included the Parenting Stress Index, Alabama Parenting Questionnaire, and Parenting Sense of Competence Scale (PSCS). RESULTS: Improvement was greater with ATX over placebo at 24 weeks on the Conners Adult ADHD Rating Scale (-16.43 vs -8.65; P < 0.001, repeated measures) and Clinical Global Impression (P < 0.001, last observation carried forward). Baseline-to-end point changes in marital and parenting measures were significant but not between treatment groups. Post hoc analyses showed significant interaction of treatment and impairment for the FAM III Task Accomplishment (patient) and Role Performance (patient and spouse) items and PSCS efficacy. Further stratification by sex or presence of a child with ADHD yielded significant interaction and treatment differences for the FAM III Task Accomplishment and the FAM III and Dyadic Adjustment Scale affective expression items, PSCS total score, Alabama Parenting Questionnaire Corporal Punishment, and Parenting Stress Index attachment items. CONCLUSIONS: Atomoxetine demonstrated significant ADHD symptom reduction over 24 weeks. Although both groups demonstrated baseline-to-end point changes on many marital and parenting measure items, there were no treatment differences. Maladaptive behaviors of long-standing ADHD may benefit from both medication and behavioral-psychosocial intervention.

Once-daily treatment with atomoxetine in adults with attention-deficit/hyperactivity disorder: a 24-week, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Atomoxetine (ATX) once daily was compared with placebo (PBO) in adults with attention-deficit/hyperactivity disorder (ADHD) at 12 and 24 weeks. METHODS: Patients were randomized to PBO (n = 234) or ATX (60-100 mg; n = 268) for 24 weeks following a 2-week on-label (40 mg for 3 days then 80 mg) or slow (40 mg for 7 days then 80 mg) titration. After 24 weeks, PBO patients were rerandomized to either ATX titration strategy. Efficacy measures included the Conners' Adult ADHD Rating Scale Total ADHD Symptoms score, Clinical Global Impression-ADHD-Severity, Montgomery-Asberg Depression Rating Scale, and State-Trait Anxiety Inventory. General and titration safety measures and tolerability were evaluated. RESULTS: Conners' Adult ADHD Rating Scale Total ADHD Symptoms score reduction was greater with ATX over PBO at 12 weeks (-14.33 vs -10.05; P < 0.001) and 24 weeks (-16.43 vs -8.65; P < 0.001; effect size, 0.57). Response (25% decrease on Conners' Adult ADHD Rating Scale Total ADHD Symptoms) was greater for ATX (68%) than PBO (42%; P < 0.001) at 24 weeks. Clinical Global Impression-ADHD-Severity improvement was greater for ATX over PBO at 8 and 24 weeks (P < 0.001; effect sizes, 0.45 and 0.46, respectively). There were no significant changes in depressive or anxiety measures for either group. Discontinuation due to an adverse event was greater for on-label versus slow titration, although the rate of patients experiencing adverse events were comparable. Common adverse events included dry mouth, nausea, and decreased appetite. CONCLUSIONS: Atomoxetine demonstrated significant improvement in ADHD symptoms at 12 and 24 weeks over PBO. Adverse events overall and for on-label or slow titration to ATX were similar and consistent with previous adult ATX studies.

Economic burden and comorbidities of attention-deficit/hyperactivity disorder among pediatric patients hospitalized in the United States.

BACKGROUND: This retrospective database analysis used data from the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) to examine common primary diagnoses among children and adolescents hospitalized with a secondary diagnosis of attention- deficit/hyperactivity disorder (ADHD) and assessed the burden of ADHD. METHODS: Hospitalized children (aged 6-11 years) and adolescents (aged 12-17 years) with a secondary diagnosis of ADHD were identified. The 10 most common primary diagnoses (using the first 3 digits of the ICD-9-CM code) were reported for each age group. Patients with 1 of these conditions were selected to analyze demographics, length of stay (LOS), and costs. Control patients were selected if they had 1 of the 10 primary diagnoses and no secondary ADHD diagnosis. Patient and hospital characteristics were reported by cohort (i.e., patients with ADHD vs. controls), and LOS and costs were reported by primary diagnosis. Multivariable linear regression analyses were undertaken to adjust LOS and costs based on patient and hospital characteristics. RESULTS: A total of 126,056 children and 204,176 adolescents were identified as having a secondary diagnosis of ADHD. Among children and adolescents with ADHD, the most common diagnoses tended to be mental health related (i.e., affective psychoses, emotional disturbances, conduct disturbances, depressive disorder, or adjustment reaction). Other common diagnoses included general symptoms, asthma (in children only), and acute appendicitis. Among patients with ADHD, a higher percentage were male, white, and covered by Medicaid. LOS and costs were higher among children with ADHD and a primary diagnosis of affective psychoses (by 0.61 days and $51), adjustment reaction (by 1.71 days and $940), or depressive disorder (by 0.41 days and $124) versus controls. LOS and costs were higher among adolescents with ADHD and a primary diagnosis of affective psychoses (by 1.04 days and $352), depressive disorder (by 0.94 days and $517), conduct disturbances (by 0.86 days and $1,330), emotional disturbances (by 1.45 days and $1,626), adjustment reaction (by 1.25 days and $702), and neurotic disorders (by 1.60 days and $541) versus controls. CONCLUSION: Clinicians and health care decision makers should be aware of the potential impact of ADHD on hospitalized children and adolescents.

Effects of atomoxetine on self-reported high-risk behaviors and health-related quality of life in adolescents with ADHD.

OBJECTIVE: This study measured the effects of atomoxetine HCl on high-risk behaviors and health-related quality of life in adolescents with attention-deficit/hyperactivity disorder (ADHD), using a subgroup analysis of data from a previous clinical trial. RESEARCH DESIGN AND METHODS: In the base study, which was conducted at 26 sites in the United States, patients ages 13-16 years were randomized in a double-blind manner to atomoxetine treatment by one of two dose titration schedules for 8 weeks. Patients who responded to treatment were rerandomized to atomoxetine at a daily dose of 0.8 or 1.4 mg/kg for 40 weeks. Patients in the highest-risk quartile for each category of behavior or domain were included and the dosing groups combined. MAIN OUTCOME MEASURES: Efficacy measures included the Youth Risk Behavior Surveillance (YRBS) and Child Health and Illness Profile - Adolescent Edition (CHIP-AE). The YRBS has six categories of behavior, and the CHIP-AE has six domains. Data for mean change from baseline were analyzed using a last-observation-carried-forward analysis. RESULTS: A total of 267 patients were randomized, but the high-risk subgroup analyzed in the present study was much smaller (range of n = 5-68 per group). YRBS scores for tobacco use, unhealthful dietary behaviors, inadequate physical activity, and behaviors contributing to unintentional injuries showed statistically significant improvements (p < 0.05) by atomoxetine treatment at Week 8. At the end of the 40-week maintenance period, unhealthful dietary behaviors, inadequate physical activity, and behaviors contributing to unintentional injuries continued to show statistically significant improvements (p < 0.001). When the highest-risk quartile of the CHIP-AE data was analyzed, there were statistically significant improvements on all six domains after atomoxetine treatment at 8 weeks (p < 0.001) and on five of the six domains at 40 weeks (p < or = 0.01). CONCLUSIONS: Atomoxetine improved self-reported high-risk behaviors and overall health-related quality of life in adolescents with ADHD. Potential limitations of this study include small sample sizes and the fact that it involved a subgroup analysis, which is by nature hypothesis-generating. Further, well-controlled, prospective studies in larger and more heterogeneous ADHD populations, including older patients, are warranted to confirm or reject these findings.

Atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder.

INTRODUCTION: This study compared two atomoxetine titration dosing schedules and two atomoxetine maintenance doses for treating adolescent attention-deficit/hyperactivity disorder (ADHD) inattention and hyperactivity/impulsivity. METHODS: Adolescents (N = 267) were randomized to a slow or fast titration schedule. Patients who responded continued on a 40-week maintenance treatment, randomized to either 0.8 or 1.4 mg/kg/day. RESULTS: During the acute period, significant benefit was demonstrated with both titration schedules on the ADHD Rating Scale total score. Although patients in both groups maintained benefit relative to week 0, statistically significant loss of benefit was found for patients maintained on 0.8 mg/kg/day but not on 1.4 mg/kg/day. A similar pattern was observed on the Clinical Global Impressions-ADHD-Severity scores and Life Participation Scale for ADHD-Child Version scores. Mean grades for most subjects improved for patients in both maintenance treatment groups although most improvements were not statistically significant. CONCLUSIONS: In adolescents with ADHD, treatment benefit at 8 weeks was better maintained long-term with 1.4 mg/kg/day than with 0.8 mg/kg/day. Improvement in adaptive functioning and age-appropriate developmental function was also demonstrated. Atomoxetine 0.8 and 1.4 mg/kg/day were equally well tolerated. CLINICAL TRIALS REGISTRY: Maintenance of benefit with atomoxetine hydrochloride in adolescents with ADHD, NCT00191035.

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children with ADHD and dyslexia.

BACKGROUND: The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD), on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D). METHODS: Patients with ADHD (n = 20) or ADHD+D (n = 36), aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV), Kaufman Test of Educational Achievement (K-TEA), Working Memory Test Battery for Children (WMTB-C), and Life Participation Scale for ADHD-Child Version (LPS-C) were assessed. RESULTS: Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months) were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported. CONCLUSIONS: Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov: NCT00191048.