Effect of age on pharmacokinetics, efficacy, and safety of galcanezumab treatment in adult patients with migraine: results from six phase 2 and phase 3 randomized clinical trials.

BACKGROUND: Migraine clinical profile may change with age, making it necessary to verify that migraine treatments are equally safe and effective in older patients. These analyses evaluated the effects of patient age on the pharmacokinetics (PK), efficacy, and safety of galcanezumab for prevention of migraine. METHODS: Analyses included efficacy data from three double-blind phase 3 clinical trials: two 6-month studies in episodic migraine (EVOLVE-1, EVOLVE-2: N = 1773) and one 3-month study in chronic migraine (REGAIN:N = 1113). Patients were randomized 2:1:1 to placebo, galcanezumab 120 mg, or galcanezumab 240 mg. Safety and PK data included additional phase 2 and phase 3 trials for a larger sample size of patients > 60 years (range = 18-65 for all studies). Subgroup analyses assessed efficacy measures, adverse event (AE) occurrence, and cardiovascular measurement changes by patient age group. Galcanezumab PK were evaluated using a population analysis approach, where age was examined as a potential covariate on apparent clearance (CL/F) and apparent volume of distribution (V/F) of galcanezumab. RESULTS: Numbers of baseline monthly migraine headache days were similar across age groups. There were no statistically significant treatment-by-age group interactions for any efficacy measures, except in episodic migraine studies where older patients appeared to have a larger reduction than younger patients in the number of monthly migraine headache days with acute medication use. Age (18-65) had a minimal effect on CL/F, and no effect on V/F. Galcanezumab-treated patients ≥60 years experienced no clinically meaningful increases in blood pressure and no increased frequency in treatment-emergent AEs, discontinuations due to AEs, serious adverse events (SAEs) overall, or cardiovascular SAEs, compared to age-matched placebo-treated patients. CONCLUSIONS: Age (up to 65 years) does not affect efficacy in migraine prevention and has no clinically meaningful influence on galcanezumab PK to warrant dose adjustment. Furthermore, older galcanezumab-treated patients experienced no increases in frequency of AEs or increases in blood pressure compared with age-matched placebo-treated patients. TRIAL REGISTRATIONS: EVOLVE-1 (NCT02614183, registered 23 November 2015), EVOLVE-2 (NCT02614196, 23 November 2015), REGAIN (NCT02614261, 23 November 2015), ART-01 (NCT01625988, 20 June 2012, ), I5Q-MC-CGAB (NCT02163993, 12 June 2014, ), I5Q-MC-CGAJ (NCT02614287, 23 November 2015, ), all retrospectively registered.

Evaluation of injection-site-related adverse events with galcanezumab: a post hoc analysis of phase 3 studies in participants with migraine.

BACKGROUND: Injection-site reactions have been reported with biologicals. In this post hoc analysis of Phase 3 studies in participants with migraine, we provide a comprehensive overview and detailed summary of injection-site reaction with galcanezumab. METHODS: Data were obtained from two randomised clinical studies in participants with episodic migraine (EVOLVE-1 and EVOLVE-2), one randomised study in participants with chronic migraine (REGAIN) and one open-label study (Study CGAJ) in participants with episodic or chronic migraine. The injection-site reactions were measured for two different cohorts: 1) six-month double-blind treatment phase in the EVOLVE-1 and EVOLVE-2 studies and three-month double-blind treatment phase in the REGAIN study, where participants received placebo and galcanezumab (placebo-controlled analysis set); 2) three month double-blind (Month 0 to Month 3; 1:1:placebo:galcanezumab) + 9 months open-label extension phase (Month 3 to Month 12) of REGAIN and twelve month open-label phase of Study CGAJ, where participants received only galcanezumab (galcanezumab exposure analysis set). RESULTS: A total of 477 participants in the placebo-controlled analysis set (galcanezumab 240 mg, 166/730 [22.7%]; galcanezumab 120 mg, 128/705 [18.2%]; placebo, 183/1451 [12.6%]) reported at least one injection-site reaction. Most of the injection-site reactions were reported as injection-site pain, unspecified injection-site reaction, injection-site erythema, and injection-site pruritus. The incidence of injection-site pain was highest among all reported injection-site reactions and were reported with similar frequency by participants receiving galcanezumab (galcanezumab 120 mg, 10.1%; galcanezumab 240 mg, 11.6%) and placebo (9.5%) and was the most common injection-site reaction reported within 60 min of injection (~ 86% of participants). The frequency of unspecified injection-site reaction, injection-site erythema and injection-site pruritus was significantly (P < 0.001) higher in participant receiving galcanezumab versus placebo. In the galcanezumab exposure analysis set participants received up to 12 doses and the frequency of injection-site reactions reported for both doses combined was 21.8%. The reporting of injection-site reactions did not increase with the number of doses received. No ISR-related serious adverse events were reported in both the placebo-controlled and galcanezumab exposure analysis sets. CONCLUSIONS: The most common adverse event of galcanezumab is injection-site reactions. However, these events were generally mild-to-moderate in severity, non-serious, resolved spontaneously, and discontinuations due to injection-site reactions were low (1%).

Evaluation of Cardiovascular Outcomes in Adult Patients With Episodic or Chronic Migraine Treated With Galcanezumab: Data From Three Phase 3, Randomized, Double-Blind, Placebo-Controlled EVOLVE-1, EVOLVE-2, and REGAIN Studies.

OBJECTIVE: Blood pressure (BP), pulse, electrocardiogram (ECG), and clinical cardiovascular (CV) outcomes in patients with episodic or chronic migraine treated for up to 6 months with galcanezumab compared to placebo were evaluated. BACKGROUND: Calcitonin gene-related peptide, a potent microvascular vasodilator, has a hypothesized protective role in CV health. Increased CV risks have been reported in patients with migraine. METHODS: In 2 similarly designed episodic migraine 6-month studies and 1 chronic migraine 3-month study, data from patients randomized (1:1:2) to subcutaneous injection of galcanezumab 120 mg/month (following initial 240 mg loading dose) or 240 mg/month or placebo were pooled. Treatment comparisons for cardiovascular treatment-emergent adverse events (CV TEAE) and categorical and mean changes in BP, pulse, and ECG were evaluated using the Cochran-Mantel-Haenszel test. Mean changes from baseline in BP, pulse, and ECG were evaluated using the analysis of covariance model. RESULTS: Overall, among galcanezumab 120 mg (n = 705) and 240 mg (n = 730), and placebo (n = 1451) groups, the percentage of patients reporting ≥1 CV TEAE was low and was similar between the galcanezumab 120 mg (2.6%; odds ratio [OR] = 0.9; 95% confidence interval [CI]: 0.5,1.5) and galcanezumab 240 mg (3.3%; OR = 1.1; 95% CI: 0.7,1.9), and placebo (2.9%) groups. The frequency of any individual CV TEAE, broad or narrow term, was ≤1.4%. The CV-related serious adverse events that occurred in the galcanezumab 240 mg group (n = 3; acute myocardial infarction, pulmonary embolism, and transient ischemic attack) and placebo group (n = 3; pulmonary embolism, deep vein thrombosis, and myocardial infarction) were not considered treatment related. Four placebo- and 1 galcanezumab-treated patient discontinued due to a CV TEAE. Least squares mean and categorical changes from baseline in BP, pulse, and QT interval corrected using Fridericia's correction were similar across treatment groups. CONCLUSIONS: In this 6-month treatment trial, the percentages of galcanezumab- and placebo-treated patients that reported CV TEAEs or serious adverse events were low and similar between groups with few discontinuations. Thus, no clinically meaningful treatment group differences were observed for changes in BP, pulse, or ECG parameters. Additional longer-term studies in a broader and larger cohort are required to better characterize CV safety.

A phase 3, long-term, open-label safety study of Galcanezumab in patients with migraine.

BACKGROUND: Galcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, has demonstrated in previous Phase 2 and Phase 3 clinical studies (≤6-month of treatment) a reduction in the number of migraine headache days and improved patients' functioning. This study evaluated the safety and tolerability, as well as the effectiveness of galcanezumab for up to 12 months of treatment in patients with migraine. METHODS: Patients diagnosed with episodic or chronic migraine, 18 to 65 years old, that were not exposed previously to galcanezumab, were randomized to receive galcanezumab 120 mg or 240 mg, administered subcutaneously once monthly for a year. Safety and tolerability were evaluated by frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to study discontinuation. Laboratory values, vital signs, electrocardiograms, and suicidality were also analyzed. Additionally, overall change from baseline in the number of monthly migraine headache days, functioning, and disability were assessed. RESULTS: One hundred thirty five patients were randomized to each galcanezumab dose group. The majority of patients were female (> 80%) and on average were 42 years old with 10.6 migraine headache days per month at baseline. 77.8% of the patients completed the open-label treatment phase, 3.7% of patients experienced an SAE, and 4.8% discontinued due to AEs. TEAEs with a frequency ≥ 10% of patients in either dose group were injection site pain, nasopharyngitis, upper respiratory tract infection, injection site reaction, back pain, and sinusitis. Laboratory values, vital signs, or electrocardiograms did not show anyclinically meaningful differences between galcanezumab dosesOverall mean reduction in monthly migraine headache days over 12 months for the galcanezumab dose groups were 5.6 (120 mg) and 6.5 (240 mg). Level of functioning was improved and headache-related disability was reduced in both dose groups. CONCLUSION: Twelve months of treatment with self-administered injections of galcanezumab was safe and associated with a reduction in the number of monthly migraine headache days. Safety and tolerability of the 2 galcanezumab dosing regimens were comparable. TRIAL REGISTRATION: ClinicalTrials.gov as NCT02614287 , posted November 15, 2015. These data were previously presented as a poster at the International Headache Congress 2017: PO-01-184, Late-Breaking Abstracts of the 2017 International Headache Congress. (2017). Cephalalgia, 37(1_suppl), 319-374.

Safety of galcanezumab in patients with episodic migraine: A randomized placebo-controlled dose-ranging Phase 2b study.

Background Safety findings from a Phase 2b study of galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, for prevention of migraine (NCT02163993) are reported here. Methods Patients aged 18-65 years with episodic migraine were evaluated in this multicenter, double-blind, randomized study. After randomization, 410 patients were administered 5, 50, 120 or 300 mg of galcanezumab or placebo subcutaneously once every 4 weeks for 12 weeks, followed by a post-treatment off-drug period lasting 12 weeks. Results Treatment-emergent adverse events (TEAEs) were primarily rated as mild to moderate. Serious adverse events reported in galcanezumab dose groups were appendicitis, Crohn's disease, suicidal ideation, and congenital ankyloglossia in an infant of a paternal pregnancy; each of these were reported by one patient. Adverse events leading to discontinuation with galcanezumab treatment were abdominal pain, visual impairment, and upper limb fracture, each reported by one patient. Treatment-emergent injection-site reactions were reported significantly more frequently ( p = 0.013) with galcanezumab (13.9%) than with placebo (5.8%). Injection-site pain was the most common injection-site reaction (galcanezumab 11.4%; placebo 2.9%, p = 0.004). Upper respiratory tract infection (galcanezumab 10.0%; placebo 8.8%) and nasopharyngitis (galcanezumab 7.0%; placebo 2.2%) also occurred more frequently with galcanezumab treatment. Potential hypersensitivity events were reported at similar frequencies in galcanezumab (3.3%) and placebo (5.1%) groups. Incidence of treatment-emergent anti-drug antibodies in galcanezumab dose groups (4.6% of patients during treatment period) did not appear to have any meaningful effects on safety, the pharmacokinetics of galcanezumab, or its ability to bind to the target ligand. Conclusion The results from this 3-month Phase 2b study support the initiation of larger Phase 3 trials of longer duration.

Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention: A Randomized Clinical Trial.

Importance: Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention. Objective: To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention. Design, Setting, and Participants: A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug. Interventions: Short-term migraine treatments were allowed as needed except for opioids or barbiturates. Main Outcomes and Measures: To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization. Results: Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab. For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability -4.8 days; 90% BCI, -5.4 to -4.2 days vs 95% superiority threshold [Bayesian analysis] -3.7 days; 90% BCI, -4.1 to -3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea. Conclusions and Relevance: Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine. Trial Registration: clinicaltrials.gov Identifier: NCT02163993.

Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials.

The safety profile of atomoxetine in the treatment of attention deficit hyperactivity disorder has been studied in many clinical trials. We performed an integrated safety analysis of 15 clinical trials in adults with attention deficit hyperactivity disorder. The analysis pooled patient data into three groups: acute placebo-controlled trials; long-term placebo-controlled trials; all trials. In total, 4829 adults (18-77 years, median: 36 years) were exposed to atomoxetine. Statistically significantly more atomoxetine-treated than placebo-treated patients experienced treatment-emergent adverse events (81.3% vs. 68.3% acute; 90.6% vs. 76.8% long term) and discontinued due to adverse events (8.9% vs. 4.0% acute; 17.9% vs. 6.3% long term). No statistically significant differences were observed in the proportion of patients experiencing serious adverse events. No previously unknown adverse events were identified. The most common adverse events included nausea, dry mouth, decreased appetite, insomnia and erectile dysfunction. Mean increases in heart rate (+5.2 beats per min) and blood pressure (systolic +2 mmHg, diastolic +1.9 mmHg) were modest. The proportion of patients experiencing clinically significant increases in blood pressure and heart rate at any time was statistically significantly higher with atomoxetine (systolic blood pressure 13-17%, diastolic blood pressure 37-40%, heart rate 42-43%) compared to placebo (systolic blood pressure 8-13%, diastolic blood pressure 29-34%, heart rate 21-26%). There was no increased risk of suicidal ideation or behaviour. Our findings confirm atomoxetine's known safety profile. From a safety perspective, atomoxetine is a useful treatment option for adults with attention deficit hyperactivity disorder.

Efficacy and Safety Extrapolation Analyses for Atomoxetine in Young Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: This extrapolation analysis qualitatively compared the efficacy and safety profile of atomoxetine from Lilly clinical trial data in 6-7-year-old patients with attention-deficit/hyperactivity disorder (ADHD) with that of published literature in 4-5-year-old patients with ADHD (two open-label [4-5-year-old patients] and one placebo-controlled study [5-year-old patients]). METHODS: The main efficacy analyses included placebo-controlled Lilly data and the placebo-controlled external study (5-year-old patients) data. The primary efficacy variables used in these studies were the ADHD Rating Scale-IV Parent Version, Investigator Administered (ADHD-RS-IV-Parent:Inv) total score, or the Swanson, Nolan and Pelham (SNAP-IV) scale score. Safety analyses included treatment-emergent adverse events (TEAEs) and vital signs. Descriptive statistics (means, percentages) are presented. RESULTS: Acute atomoxetine treatment improved core ADHD symptoms in both 6-7-year-old patients (n=565) and 5-year-old patients (n=37) (treatment effect: -10.16 and -7.42). In an analysis of placebo-controlled groups, the mean duration of exposure to atomoxetine was ∼ 7 weeks for 6-7-year-old patients and 9 weeks for 5-year-old patients. Decreased appetite was the most common TEAE in atomoxetine-treated patients. The TEAEs observed at a higher rate in 5-year-old versus 6-7-year-old patients were irritability (36.8% vs. 3.6%) and other mood-related events (6.9% each vs. <3.0%). Blood pressure and pulse increased in both 4-5-year-old patients and 6-7-year-old patients, whereas a weight increase was seen only in the 6-7-year-old patients. CONCLUSIONS: Although limited by the small sample size of the external studies, these analyses suggest that in 5-year-old patients with ADHD, atomoxetine may improve ADHD symptoms, but possibly to a lesser extent than in older children, with some adverse events occurring at a higher rate in 5-year-old patients.

Maintenance of Response After Open-Label Treatment with Atomoxetine Hydrochloride in International European and Non-European Adult Outpatients with Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled, Randomised Withdrawal Study

Background and Objectives: We evaluated maintenance of response to atomoxetine during a 25-week, double-blind, placebo-controlled, randomised withdrawal period in adults with attention-deficit/hyperactivity disorder (ADHD) who previously responded to atomoxetine during a 12 week open-label treatment period and maintained that response during a 12-week double-blind maintenance period. Methods: Patients (N = 2017), 18 to 50 years of age, diagnosed with ADHD from 152 outpatient sites in 18 countries received 12 weeks of open-label atomoxetine (40-100 mg/day) followed by 12 weeks of double-blind maintenance (80 or 100 mg/day). Responders were randomized to atomoxetine (N = 266) or placebo (N = 258) for 25-weeks of double-blind treatment. The percentage of patients with a reduction >30% in their baseline Conners' ADHD Rating Scale Investigator-Rated: Screening Version (CAARS-Inv:SV) total score and a score of <3 on the Clinical Global Impression ADHD-Severity (CGI-ADHD-S) after 25 weeks was compared between treatment groups with a Fisher's exact test. Mean changes from baseline in the CAARS-Inv:SV and Adult Attention-Deficit/Hyperactivity Disorder Quality of Life (AAQoL) were analysed. Results: Most patients enrolled (60%) were from Europe. More atomoxetine- than placebo-treated patients maintained a satisfactory response postrandomisation (64.3% vs. 50.0%; p < .001). Time-to-relapse was significantly longer for atomoxetine than placebo (p = .004). Atomoxetine maintained greater improvements in ADHD symptoms compared with placebo (LS mean worsening in the CAARS-Inv:SV total score was 0.9 vs. 4.8 [p < .001] and in the CGI-ADHD-S rating was 0.0 vs. 0.5 [p < .001]). These results were supported by self- or observer-rated measures. Lastly, atomoxetine maintained greater improvements in quality of life compared with placebo (AAQoL total score was 0.4 vs. -4.0; p = .002). Conclusions: This study demonstrated that atomoxetine was superior to placebo in maintaining significantly greater treatment responses for up to 1 year in adults with ADHD (AU)

Safety and Tolerability of Atomoxetine Hydrochloride in a Long-Term, Placebo-Controlled Randomized Withdrawal Study in European and Non-European Adults with Attention-Deficit/ Hyperactivity Disorder

Background and Objectives: Safety and tolerability of atomoxetine were studied in the largest double-blind, placebo-controlled, randomised withdrawal trial of atomoxetine (80 or 100 mg/day) in adults with attention-deficit/hyperactivity disorder (ADHD). Methods: Patients (N = 2017), 18 to 50 years of age, with ADHD were enrolled from 18 countries. Patients who responded to atomoxetine during a 12-week open-label treatment phase and maintained that response during a 12-week double-blind maintenance phase were randomised to atomoxetine (N = 266) or placebo (N = 258) for 25 weeks of double-blind treatment. Treatment differences were compared for serious adverse events (AEs), treatment-emergent AEs (TEAEs), discontinuation due to AEs, vital signs, body weight, and electrocardiograms. Results: During the 25-week double-blind treatment phase, discontinuations due to AEs were similar between atomoxetine and placebo (3.4% vs. 1.9%; P = .418). The percentage of patients experiencing >1 TEAE(s) was significantly higher for atomoxetine than placebo (47.0% vs. 37.6%; P = .034), but there were no significant differences for any individual TEAE. Diastolic blood pressure (-0.1 vs. -2.3 mmHg), heart rate (-1.4 vs. -5.3 bpm), and weight (-0.2 vs. 1.1 kg) were significantly different between atomoxetine and placebo (P <.001). There were no significant differences between atomoxetine and placebo in the frequencies of patients showing an increase from baseline >30 ms in Fridericia's QT correction (QTcF; 1.4% vs. 2.6%) or Bazett's QT correction (QTcB; 2.8% vs. 2.6%). During the entire study, no patient had a QTcF or QTcB >500 ms, or an increase from baseline >60 ms. Conclusions: This study demonstrated that atomoxetine exhibited an acceptable safety profile in adults with ADHD after 1 year of treatment, and no clinically meaningful safety-related rebound effects were observed following abrupt discontinuation after 24 weeks of treatment (AU)

Profile of sexual and genitourinary treatment-emergent adverse events associated with atomoxetine treatment: a pooled analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder that begins in childhood. Atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter. Several studies have demonstrated the safety and efficacy of atomoxetine in the treatment of ADHD. OBJECTIVE: The objective of this analysis was to provide additional information on the frequency, time to onset and time to resolution of sexual and genitourinary (GU) treatment-emergent adverse events (TEAEs) reported during atomoxetine treatment in clinical trials. METHODS: Data from all adult atomoxetine placebo-controlled ADHD trials were pooled for this analysis, for a total of 3,314 patients (atomoxetine, n = 1,738; placebo, n = 1,576). Additionally, data from all adolescent patients (baseline age ≥13 to <18 years) within all ADHD placebo-controlled trials were pooled for analysis, for a total of 538 patients (atomoxetine, n = 329; placebo, n = 209). Rates of sexual and GU TEAEs were summarized by sex for each age group. Time to onset and resolution of sexual and GU TEAEs were summarized and compared using Kaplan-Meier methods. RESULTS: Overall, the baseline characteristics of randomized patients in the atomoxetine and placebo groups were similar. Profiles of sexual and GU TEAEs for atomoxetine appeared clinically similar to placebo in female patients and in adolescent male patients. Adult male patients reported relatively more sexual and GU TEAEs when taking atomoxetine compared with placebo, with libido decreased (4.6 vs. 3.0 %), dysuria (3.7 vs. 1.5 %), urinary hesitation (6.9 vs. 2.4 %), urine flow decreased (2.5 vs. 0.6 %), ejaculation disorder (2.8 vs. 1.1 %) and erectile dysfunction (8.0 vs. 1.9 %) being the most common. The time to onset of the most common TEAEs in adult male patients tended to occur relatively early in dosing: within the first 2 weeks for GU TEAEs, and during the second and third week of dosing for erectile and ejaculation issues. The median time to resolution for these events ranged from around 3-8 weeks after event onset, depending on the event. While the common sexual and GU TEAEs showed numerically higher percentages of discontinuations in atomoxetine-treated patients compared with placebo, most incidences of the sexual and GU TEAEs were not considered severe. CONCLUSIONS: The sexual and GU TEAE profiles of patients taking atomoxetine were generally similar to those of patients taking placebo in the female and adolescent male populations, with greater frequency of TEAEs reported in adult males taking atomoxetine compared with placebo. The time to onset of the TEAEs tended to be shorter, and time to resolution tended to be longer in adult male patients treated with atomoxetine compared with those receiving placebo. The conclusions must be interpreted with caution because the TEAEs were likely underreported.