Effect of galcanezumab in women with episodic migraine meeting criteria for menstrually related migraine: A post hoc analysis of EVOLVE-1 and EVOLVE-2.

BACKGROUND: We evaluated galcanezumab for migraine prevention in patients who met International Classification of Headache Disorders, 3rd edition criteria for menstrually related migraine (MRM). METHODS: Patients were identified post hoc from three double-blind, randomized, phase 3 clinical trials in patients with episodic migraine. Patients completed a 1-month prospective baseline period and up to 6 months (EVOLVE-1 and -2, studies pooled) of double-blind treatment with galcanezumab (120 mg/month) or placebo. Menses and headache information were recorded by electronic daily diary. Patients with a migraine attack starting during the 5-day perimenstrual interval (first day of bleeding ± 2 days) for ≥2 of their first three diary-recorded menstrual cycles were categorized as having MRM. The primary efficacy measure was mean change in monthly migraine headache days from baseline, averaged over Months 4 through 6. Response rates, change in monthly perimenstrual migraine headache days, monthly non-perimenstrual migraine headache days, and quality of life were also assessed. RESULTS: Post hoc MRM analysis criteria were met by 462/1133 women (41%). Mean (standard deviation) baseline monthly migraine headache days were 9.7 (±3.1; n = 146) for galcanezumab-treated patients and 9.6 (±2.8; n = 316) for placebo-treated patients. The mean change (standard error [SE]) in migraine headache days over Months 4 through 6 was -5.1 days (±0.39) for galcanezumab versus -3.2 (±0.35) for placebo (p < 0.001). The mean change (SE) in perimenstrual migraine headache days over Months 4 through 6 was -0.75 days (±0.08) for galcanezumab versus -0.49 (±0.07) for placebo (p = 0.004). For migraine headache days outside the perimenstrual period, the mean change in migraine headache days was -4.6 (±0.38) for galcanezumab and -2.8 (±0.33) for placebo (p < 0.001). Improvements in response rates and the Migraine-Specific Quality of Life Questionnaire were also observed over Months 4 through 6. CONCLUSION: Galcanezumab was effective for migraine prevention in women with MRM.

Changes in migraine interictal burden following treatment with galcanezumab: Results from a phase III randomized, placebo-controlled study.

OBJECTIVE: To evaluate changes in interictal burden with galcanezumab versus placebo in patients with episodic (EM) or chronic migraine (CM). BACKGROUND: The disruptive effects of migraine occur both during attacks (ictal period) and between attacks (interictal period), affecting work, school, family, and social life. Migraine clinical trials typically assess ictal burden endpoints, neglecting interictal burden. METHODS: CONQUER was a 3-month, double-blind study that randomized adult patients with EM or CM who had experienced failure of two to four standard-of-care migraine preventive medication categories to receive monthly galcanezumab (n = 232) or placebo (n = 230), followed by 3 months of open-label galcanezumab. The mean change in interictal burden, a secondary objective, was measured using the four-item Migraine Interictal Burden Scale (MIBS-4). The total score for MIBS-4 can range from zero to 12, with scores ≥5 indicating severe interictal burden. Post hoc analyses evaluated shifts in MIBS-4 severity categories and item-level improvement. RESULTS: The MIBS-4 total score indicated severe interictal burden at baseline (mean [SD]: all patients, 5.5 [3.5]; EM, 5.0 [3.4]; CM, 6.2 [3.5]). Reductions in the MIBS-4 score were significantly greater with galcanezumab versus placebo at Month 3 (mean [SE]: all patients -1.9 [0.2] vs. -0.8 [0.2], p < 0.0001; EM, -1.8 [0.3] vs. -1.1 [0.3], p = 0.033; CM, -1.8 [0.4] vs. -0.3 [0.4], p < 0.001), with further improvement at Month 6 after all patients had received galcanezumab (mean [SE]: all patients, -2.4 [0.2] vs. -2.0 [0.2]; EM, -2.3 [0.3] vs. -2.2 [0.3]; CM, -2.1 [0.4] vs. -1.5 [0.4]). The percentage of patients with severe interictal burden decreased substantially for the galcanezumab-treated patients, from 59% (137/232) at baseline to 27% (58/217) at Month 6 (EM from 51% [70/137] to 23% [30/131]; CM from 71% [67/95] to 33% [28/86]). CONCLUSION: In addition to the known efficacy of galcanezumab in the ictal period, these findings suggest treatment with galcanezumab results in a significant reduction in interictal burden.

Changes in patient functioning and disability: results from a phase 3, double-blind, randomized, placebo-controlled clinical trial evaluating galcanezumab for chronic migraine prevention (REGAIN).

PURPOSE: To evaluate secondary outcomes including changes in functioning and disability associated with galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, in patients with chronic migraine. METHODS: Patients randomly received galcanezumab (120 mg n = 278, 240 mg n = 277) or placebo (n = 558) during 3 months of double-blind treatment, followed by a 9-month open-label extension. The Migraine-Specific Quality-of-Life Questionnaire v2.1 (MSQv2.1) measured the impact of migraine on patient functioning. The Migraine Disability Assessment (MIDAS) quantified headache-related disability. Changes from baseline were analyzed with mixed model repeated measures or analysis of covariance. RESULTS: Total MSQ score at baseline was 44.88 ± 18.02 (mean ± SD), indicating significant functional impairment. At Month 3, least squares (LS) mean change ± SE in total MSQ for galcanezumab-treated patients were 20.51 ± 1.49 (120 mg) and 20.49 ± 1.49 (240 mg), both statistically significantly greater vs placebo-treated patients (14.55 ± 1.21; both P < 0.001). Total MIDAS score at baseline was 67.24 ± 57.31 (mean ± SD). At Month 3, LS mean change ± SE from baseline in total MIDAS for galcanezumab-treated patients was statistically significantly greater than placebo for 120 mg group (placebo: - 11.53 ± 3.38 vs 120 mg: - 20.27 ± 4.07; P < 0.05) but not for 240 mg group (- 17.02 ± 4.05). At Month 12, within-group mean changes from baseline for total MSQ (28.56 ± 1.19 previous placebo; 29.53 ± 1.51 previous 120 mg; 25.83 ± 1.49 previous 240 mg) and MIDAS scores (- 28.47 ± 2.95 previous placebo; - 31.47 ± 3.69 previous 120 mg; - 31.13 ± 3.62 previous 240 mg) were statistically significant (P < 0.001) for the open-label treatment population regardless of previous double-blind treatment assignment. CONCLUSIONS: Galcanezumab-treated patients with chronic migraine reported statistically significant improvements in functioning and disability, representing a clinically significant change. TRIAL REGISTRATION: ClinicalTrials.gov registry: NCT02614261. Registered 25 November 2015.

Rapid Onset of Effect of Galcanezumab for the Prevention of Episodic Migraine: Analysis of the EVOLVE Studies.

OBJECTIVE: To evaluate onset of effect of galcanezumab in patients with episodic migraine. BACKGROUND: Galcanezumab is a monoclonal antibody that binds to calcitonin gene-related peptide and is indicated for preventive treatment of migraine. DESIGN/METHODS: Data on the primary outcome measure were analyzed from 2 previously published double-blind, Phase 3 studies (EVOLVE-1 [N = 858] and EVOLVE-2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240-mg loading dose) or 240 mg or placebo for up to 6 months. Monthly onset of effect was defined as the earliest month at which galcanezumab achieved and subsequently maintained statistical superiority to placebo on the mean change from baseline in the number of monthly migraine headache days (MHDs). If onset occurred in Month 1, weekly onset was evaluated and defined as the earliest week at which galcanezumab statistically separated from placebo and maintained statistical separation for remaining weeks in that month. Day of onset of effect was also analyzed, as were monthly and weekly onset, for occurrence of ≥50% reduction from baseline in number of MHDs. RESULTS: For both studies, change from baseline in monthly MHDs showed a statistically significant separation of galcanezumab from placebo at Month 1 and each subsequent month (each P < .001). Analysis of the first month for both studies indicated onset of effect in the first week, with galcanezumab-treated patients having significantly higher odds of having fewer MHDs in the first week (odds ratio [95% confidence interval] for EVOLVE-1, 2.71 [2.00, 3.66], and for EVOLVE-2, 2.88 [2.16, 3.86]; both P < .001) and each subsequent week compared with placebo-treated patients (P ≤ .004). Daily analysis showed onset of effect at Day 1 (first day after injection day). Galcanezumab also demonstrated superiority to placebo on occurrence of ≥50% reduction in MHDs starting at Week 1 (percentage of patients with 50% response in galcanezumab group vs placebo group for EVOLVE-1, 54.3% vs 32.4% [P < .001], and for EVOLVE-2, 59.4% vs 38.0% [P < .001]). CONCLUSION: Rapid onset of preventive effect on the first day after injection of galcanezumab was confirmed in both studies of episodic migraine.

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.

Olanzapine long-acting injection: a review of first experiences of post-injection delirium/sedation syndrome in routine clinical practice.

BACKGROUND: Olanzapine long-acting injection (LAI) for the treatment of schizophrenia was associated with a cluster of symptoms termed post-injection delirium/sedation syndrome (PDSS) in a small percentage (~2%) of patients during clinical trials. The objective of this analysis was to evaluate the rate and clinical characteristics of PDSS since olanzapine LAI entered commercial use. METHODS: Cases of PDSS were identified from all reported adverse events during worldwide commercial use of olanzapine LAI through to 1 March 2014. Data sources included two ongoing post-marketing safety studies as well as spontaneously reported adverse events from routine clinical practice over a 5-year period (1 March 2009 to 1 March 2014). RESULTS: A total of 338 PDSS events were identified. Of these, 91% occurred within 1 hour of injection, and 52% of these occurred within 15 minutes. None of the PDSS events in this analysis were fatal, and most resolved within 72 hours. The most common symptoms (occurring in >30% of cases) were sedation (61%), confusion (56%), dysarthria (54%), somnolence (46%), dizziness (45%) and disorientation (35%). Overall, PDSS occurred with approximately 0.07% of injections and in 0.46-1.03% of patients (reporting and incidence rates from spontaneous reports and post-marketing safety studies, respectively). CONCLUSIONS: The PDSS events reported during routine clinical use of olanzapine LAI are generally similar in incidence and presentation to those reported in clinical trials. Caution should be applied when interpreting spontaneously reported rates of adverse events, however, due to potential under-reporting. Implemented risk-minimisation activities may contribute substantially to the identification and appropriate management of patients with PDSS in clinical practice.

Baseline characteristics and hospitalizations in patients with schizophrenia receiving olanzapine long-acting injection: an interim analysis from a non-interventional, prospective observational safety study.

BACKGROUND: Depot antipsychotics are a treatment option for medication nonadherence in patients with schizophrenia. Nonadherence can lead to increased relapse and hospitalization rates. This article reports hospitalization data before and after initiation of olanzapine long-acting injection (LAI), a depot antipsychotic. METHODS: Data were assessed from an ongoing, multinational, prospective, observational post-authorisation safety study being conducted to evaluate post-injection delirium/sedation syndrome (PDSS), an adverse reaction that can occur following injection of olanzapine LAI. Eligible patients were aged ≥18 years, diagnosed with schizophrenia, were prescribed olanzapine LAI, and lived outside the United States. Psychiatric hospitalization and medication data were collected retrospectively for the 6-month period before study entry and prospectively throughout the study. Paired t-tests and McNemar's tests were used to assess changes in hospitalization incidence and duration. Stepwise Cox proportional hazards models assessed factors associated with hospitalizations. Analyses were based on data from the first 3 years of the continuously enrolling study (N = 668). RESULTS: The average duration of olanzapine LAI exposure for all patients was 0.768 years. Of the 529 patients who received at least 1 injection of olanzapine LAI and were not hospitalized at study entry, 8.1% had at least 1 subsequent psychiatric hospitalization with a mean duration of 2.0 days. Of the 288 patients who had a >6-month follow-up, 8.3% had at least 1 post-baseline psychiatric hospitalization with a mean duration of 2.3 days. The incidence of hospitalizations in the 6-month period after treatment was significantly lower than that in the 6-month period prior to treatment (8.3 vs 32.6%, respectively; P < 0.001). Furthermore, mean hospitalization duration decreased from 11.5 days in the 6-month period before treatment to 2.3 days in the 6-month period after treatment (P < 0.001). Psychiatric hospitalization in the prior 12 months (P < 0.0001) and recreational drug use within 24 h of baseline visit (P = 0.015) were identified as potential predictors of time to first psychiatric hospitalization after beginning to take olanzapine LAI. At the time of interim analysis, 5 PDSS events had occurred, which was too few for a full analysis of those events. CONCLUSIONS: Results indicate a significant reduction in the incidence and days of hospitalization from the 6-month period before to the 6-month period after olanzapine LAI initiation, which suggests reduced relapse and hospitalization during treatment. Results should be interpreted with caution due to the observational nature of the study and use of retrospective baseline data.

Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia.

We compared long-term treatment effectiveness of monthly olanzapine long-acting injection (LAI) with that of oral olanzapine. Outpatients with 2 or more episodes of psychotic worsening in the past 24 months with Positive and Negative Syndrome Scale total score of lower than 70 were randomized to 405 mg/4 weeks of olanzapine LAI (n = 264) or 10 mg/d of oral olanzapine (n = 260) for 2 years of open-label treatment. Dosing thereafter was flexible (150-405 mg/4 weeks of LAI vs 5-20 mg/d of oral). Primary outcome was time to all-cause discontinuation. At baseline, patients were clinically stable (mean Positive and Negative Syndrome Scale total score of 57). Seventeen percent of patients had been psychiatrically hospitalized in the previous 6 months, and 4.6% were rated nonadherent in the month before study entry. The groups did not differ significantly in median time to all-cause discontinuation (645 days for LAI, 678 days for oral; P = 0.61), discontinuation rate (53.8% for LAI, 51.2% for oral; P = 0.60), or relapse rate (20.1% for LAI, 18.5% for oral; P = 0.66). Postbaseline psychiatric hospitalization rate was low for both groups (7.6% for LAI, 9.2% for oral), but mean hospitalization duration was significantly longer for oral patients (1.80 days [20 for those hospitalized] vs 0.43 days [6 for those hospitalized], P = 0.02). There were no clinically significant group differences in adverse events or safety measures. No post-injection delirium/sedation syndrome events occurred. In conclusion, olanzapine LAI and oral olanzapine were similarly effective and well tolerated for up to 2 years of treatment in patients with schizophrenia. Treatment discontinuation for olanzapine LAI was similar to that of oral olanzapine, despite the 3-hour post-injection observation period and other precautionary procedures related to risk of post-injection delirium/sedation syndrome.

A pooled analysis of injection site-related adverse events in patients with schizophrenia treated with olanzapine long-acting injection.

BACKGROUND: Depot antipsychotic injections are an important tool for the management of patients with schizophrenia who have difficulty with adherence to oral medication. However, pain and discomfort at the injection site can be a potential impediment to the use of these long-acting formulations. We report here the results of a pooled analysis of injection site-related adverse events (AEs) collected during treatment with the olanzapine long-acting injection (olanzapine LAI). METHODS: Unsolicited injection site-related AEs were pooled from 7 olanzapine LAI clinical trials conducted in patients between March 2001 and December 2010. All patients had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of schizophrenia or schizoaffective disorder and were between the ages of 18 and 75. Doses ranged from 45 to 405 mg olanzapine LAI, and injection intervals were 2, 3, or 4 weeks. Events were evaluated for severity, timing, possible risk factors, and outcome. A criterion of p < .05 for statistical significance was used for all tests. RESULTS: A total of 1752 patients received at least 1 olanzapine LAI injection. Of these, 92 patients (5.3%) reported at least 1 injection site-related AE, with "pain" being the most common type (2.9%). Most events were mild (81.4%) and the median duration was 3 days. Four patients (0.2%) discontinued due to injection site-related AEs. Dose volume and body mass index did not appear to affect the probability of injection site-related AEs. However, patients who experienced a post-injection delirium/sedation syndrome event (n = 37) were more likely to have or have had an injection site-related AE at some time during the study. Incidence of injection site-related AEs appeared to decrease over time. In 94.2% of the injection site-related AEs, no specific treatment or concomitant medication was reported; in 9 cases, patients received pharmacologic treatment for reaction, mass, abscess, rash, or pain. CONCLUSIONS: Injection site-related AEs with olanzapine LAI were generally mild. The incidence and nature of these injection site-related AEs were generally similar to those occurring during treatment with other injectable antipsychotics. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Predictors of psychiatric hospitalization during 6 months of maintenance treatment with olanzapine long-acting injection: post hoc analysis of a randomized, double-blind study.

BACKGROUND: Hospitalization is a costly and distressing event associated with relapse during schizophrenia treatment. No information is available on the predictors of psychiatric hospitalization during maintenance treatment with olanzapine long-acting injection (olanzapine-LAI) or how the risk of hospitalization differs between olanzapine-LAI and oral olanzapine. This study aimed to identify the predictors of psychiatric hospitalization during maintenance treatment with olanzapine-LAI and assessed four parameters: hospitalization prevalence, incidence rate, duration, and the time to first hospitalization. Olanzapine-LAI was also compared with a sub-therapeutic dose of olanzapine-LAI and with oral olanzapine. METHODS: This was a post hoc exploratory analysis of data from a randomized, double-blind study comparing the safety and efficacy of olanzapine-LAI (pooled active depot groups: 405 mg/4 weeks, 300 mg/2 weeks, and 150 mg/2 weeks) with oral olanzapine and sub-therapeutic olanzapine-LAI (45 mg/4 weeks) during 6 months' maintenance treatment of clinically stable schizophrenia outpatients (n=1064). The four psychiatric hospitalization parameters were analyzed for each treatment group. Within the olanzapine-LAI group, patients with and without hospitalization were compared on baseline characteristics. Logistic regression and Cox's proportional hazards models were used to identify the best predictors of hospitalization. Comparisons between the treatment groups employed descriptive statistics, the Kaplan-Meier estimator and Cox's proportional hazards models. RESULTS: Psychiatric hospitalization was best predicted by suicide threats in the 12 months before baseline and by prior hospitalization. Compared with sub-therapeutic olanzapine-LAI, olanzapine-LAI was associated with a significantly lower hospitalization rate (5.2% versus 11.1%, p < 0.01), a lower mean number of hospitalizations (0.1 versus 0.2, p = 0.01), a shorter mean duration of hospitalization (1.5 days versus 2.9 days, p < 0.01), and a similar median time to first hospitalization (35 versus 60 days, p = 0.48). Olanzapine-LAI did not differ significantly from oral olanzapine on the studied hospitalization parameters. CONCLUSIONS: In clinically stable schizophrenia outpatients receiving olanzapine-LAI maintenance treatment, psychiatric hospitalization was best predicted by a history of suicide threats and prior psychiatric hospitalization. Olanzapine-LAI was associated with a significantly lower incidence of psychiatric hospitalization and shorter duration of hospitalization compared with sub-therapeutic olanzapine-LAI. Olanzapine-LAI did not differ significantly from oral olanzapine on hospitalization parameters. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00088491.

Open-label treatment with olanzapine for patients with borderline personality disorder.

This report presents efficacy and safety outcomes for patients with borderline personality disorder (BPD) treated with olanzapine for up to 24 weeks. In 2 concurrent studies, patients received open-label olanzapine for 12 weeks after 12 weeks of double-blind olanzapine or placebo. Open-label dosing started at 2.5 or 5 mg/d and could be increased up to 20 mg/d (study 1) or 15 mg/d (study 2). The primary efficacy measure was open-label baseline-to-endpoint change in Zanarini Rating Scale for BPD (ZAN-BPD) total score. Of 472 patients who completed the double-blind acute phase, 444 entered and 320 (72.1%) completed 12 weeks of open-label extension treatment. Mean ZAN-BPD total scores at the start of the acute phase were approximately 17, indicating moderate symptom severity. Mean ZAN-BPD total scores ranged from 7.8 to 10.5 at the start of the open-label treatment and decreased to 5.7 to 6.5, indicating mild symptom severity, by the end of the open-label treatment. Patients taking placebo during the acute phase showed increases in weight, prolactin level, and other laboratory values during open-label olanzapine treatment similar in magnitude to increases seen in olanzapine-treated patients during the acute phase. Patients proceeding from olanzapine during the acute phase to open-label olanzapine showed smaller changes in weight and laboratory values. In conclusion, these results suggest that continued therapy with olanzapine may sustain and build upon improvements seen with acute olanzapine treatment of patients with BPD. However, no medication is currently approved for treatment of BPD, and physicians should carefully weigh potential benefits and risks of antipsychotic treatment in this population.

Efficacy of olanzapine long-acting injection in patients with acutely exacerbated schizophrenia: an insight from effect size comparison with historical oral data.

BACKGROUND: To treat acute schizophrenia, a long-acting injectable antipsychotic needs a rapid onset of action and therapeutic profile similar to that of oral agents. The present post-hoc analyses compared results from a randomized, double-blind, placebo-controlled trial of olanzapine long-acting injection (LAI) for acute schizophrenia with those observed in similarly designed trials of oral olanzapine. METHODS: Six-week results from the olanzapine LAI study (N = 404) were compared with those of 3 oral studies (study 1: olanzapine vs. haloperidol vs. placebo [N = 335]; study 2: olanzapine vs. haloperidol vs. low-dose olanzapine [N = 431]; study 3: olanzapine vs. placebo vs. low-dose olanzapine [N = 152]). All patients had baseline Brief Psychiatric Rating Scale (BPRS) scores ≥24 (0-6 scale). Six-week effect sizes were calculated. Efficacy onset, pharmacokinetics, discontinuations, weight gain, and extrapyramidal symptoms were also assessed. RESULTS: At 6 weeks, mean BPRS scores decreased by 14 to 15 points for olanzapine LAI (405 mg/4 weeks, 210 or 300 mg/2 weeks), by 8 to 16 for oral olanzapine (10 ± 2.5 or 15 ± 2.5 mg/day), and by 12 to 13 for haloperidol (15 ± 5 mg/day). For those same dose groups, effect sizes vs. placebo for the BPRS were 0.7 to 0.8 for olanzapine LAI, 0.5 to 0.7 for oral olanzapine, and 0.6 for haloperidol. The first statistically significant separation from placebo on the BPRS occurred at 3 days for the olanzapine LAI groups and at 1 week for oral olanzapine and haloperidol (15 ± 5 mg/day) in oral study 1 although as late as week 6 for the 10-mg/day olanzapine dose in oral study 3. Olanzapine concentrations were similar across studies. Weight gain ≥7% of baseline occurred in up to 35% of olanzapine LAI and oral patients versus up to 12% of haloperidol and placebo patients. Extrapyramidal symptoms were lowest in the olanzapine LAI groups and significantly greater in the haloperidol groups. No post-injection delirium/sedation syndrome events occurred in the olanzapine LAI study. CONCLUSIONS: Patients treated acutely with olanzapine LAI showed a similar pattern of improvement to that seen historically with oral olanzapine. With the exception of injection-related adverse events, the efficacy and tolerability profile of olanzapine LAI is similar to oral olanzapine. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00088478; ClinicalStudyResults.org ID; URL: http://www.clinicalstudyresults.org/: 917, 978, 982, and 5984.

Reductions in acute medication use and healthcare resource utilization in patients with chronic migraine: a secondary analysis of a phase 3, randomized, double-blind, placebo-controlled study of galcanezumab with open-label extension (REGAIN).

AIMS: To analyze secondary objectives of the REGAIN study related to acute headache medication use and healthcare resource utilization (HCRU) in patients with chronic migraine treated with galcanezumab, a monoclonal antibody to calcitonin gene-related peptide. METHODS: Adults with chronic migraine (N = 1,113) were randomized (2:1:1) and treated with double-blind monthly injections of placebo, galcanezumab-120 mg, or galcanenzumab-240 mg for 3 months, followed by a 9-month open-label extension with 120 or 240 mg/month galcanezumab. Headache and medication information was collected by daily eDiary. HCRU was reported for the 6 months before randomization, monthly thereafter, and converted to rate per 100-patient-years. RESULTS: At baseline, 63-64% of patients met criteria for acute headache medication overuse. At Month 3, incidence of headache medication overuse in the galcanezumab groups (33% and 33%) was significantly lower than in the placebo group (46%, both p < .001) and was 16% and 23% in the previous-galcanezumab groups at Month 12. From a baseline of 14.5 to 15.5, reduction in mean number of monthly migraine headache days with acute headache medication use was also significantly greater in the galcanezumab groups at Month 3 (-4.2 and -4.9) than in placebo (-2.6, both p < .001), with reductions of -6.8 and -7.6 in the previous-galcanezumab groups at Month 12. Migraine-specific HCRU rates decreased for all groups, with no significant between-group differences at Month 3. At Month 12, in the two previous-galcanezumab groups, emergency room visits decreased by 58% and 75%, hospital admissions by 100%, and healthcare professional visits by 54% and 67%. LIMITATIONS: Only 3 months of double-blind, placebo-controlled data, a longer HCRU recall period for baseline than postbaseline, and patients receiving care in the clinical trial itself, may limit generalizability. CONCLUSIONS: Treatment with galcanezumab resulted in significant reductions in headache medication overuse and migraine headache days requiring acute medication use, with notable reductions in migraine-specific HCRU.

Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study.

BACKGROUND: Galcanezumab, a monoclonal antibody to calcitonin gene-related peptide, was found to be safe and efficacious for the preventive treatment of chronic migraine based on the randomized, placebo-controlled double-blind period of the REGAIN study. Long-term safety and efficacy were assessed in an open-label extension. METHODS: Patients 18-65 years old with chronic migraine completing the 3-month double-blind period of REGAIN could enter a 9-month open-label extension (OLE; months 4-12). Upon entering the OLE, patients received a 240-mg galcanezumab loading dose, then 120 mg at the next month, with flexible dosing thereafter (120 or 240 mg/month). The primary efficacy measure was the mean change in the number of monthly migraine headache days from double-blind baseline to month 12. Other endpoints included response rates (based on percent reduction in monthly migraine headache days from double-blind baseline to month 12), safety and tolerability. RESULTS: Of patients who completed double-blind treatment, 1022 (99%) entered the OLE, with 81% completing month 12. From a baseline of 19.4 monthly migraine headache days at the beginning of the double-blind period, patients at month 12 in the previous placebo, 120-mg, and 240-mg galcanezumab groups had a mean change of -8.5, -9.0, and -8.0, respectively (SE = 0.43 to 0.55, within-group p's < .001). At month 12, the percentage of patients with ≥50% response was 57%, 57%, and 53%, respectively. Percentage with ≥75% response was 32%, 31%, and 30%, respectively. Percentage with 100% response was 8%, 6%, and 6%, respectively. There were no significant new safety findings during the open-label period. The incidence of discontinuation from the OLE due to adverse events was 5%. CONCLUSION: Galcanezumab was effective, safe, and well-tolerated, with high adherence, for up to 12 months of treatment in patients with chronic migraine. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02614261; www.clinicaltrials.gov/ct2/show/NCT02614261.

Early response predicts subsequent response to olanzapine long-acting injection in a randomized, double-blind clinical trial of treatment for schizophrenia.

BACKGROUND: In patients with schizophrenia, early non-response to oral antipsychotic therapy robustly predicts subsequent non-response to continued treatment with the same medication. This study assessed whether early response predicted later response when using a long-acting injection (LAI) antipsychotic. METHODS: Data were taken from an 8-week, randomized, double-blind, placebo-controlled study of olanzapine LAI in acutely ill patients with schizophrenia (n = 233). Early response was defined as ≥ 30% improvement from baseline to Week 4 in Positive and Negative Syndrome Scale (PANSS0-6) Total score. Subsequent response was defined as ≥ 40% baseline-to-endpoint improvement in PANSS0-6 Total score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy were calculated. Clinical and functional outcomes were compared between Early Responders and Early Non-responders. RESULTS: Early response/non-response to olanzapine LAI predicted later response/non-response with high sensitivity (85%), specificity (72%), PPV (78%), NPV (80%), and overall accuracy (79%). Compared to Early Non-responders, Early Responders had significantly greater improvement in PANSS0-6 Total scores at all time points and greater baseline-to-endpoint improvement in PANSS subscale scores, Quality of Life Scale scores, and Short Form-36 Health Survey scores (all p ≤ .01). Among Early Non-responders, 20% demonstrated response by Week 8. Patients who lacked early improvement (at Week 4) in Negative Symptoms and Disorganized Thoughts were more likely to continue being non-responders at Week 8. CONCLUSIONS: Among acutely ill patients with schizophrenia, early response predicted subsequent response to olanzapine LAI. Early Responders experienced significantly better clinical and functional outcomes than Early Non-responders. Findings are consistent with previous research on oral antipsychotics. CLINICAL TRIALS REGISTRY: F1D-MC-HGJZ: Comparison of Intramuscular Olanzapine Depot With Placebo in the Treatment of Patients With Schizophrenia http://clinicaltrials.gov/ct2/show/NCT00088478?term=olanzapine+depot&rank=3Registry identifier - NCT00088478.

Comparison of metabolic changes in patients with schizophrenia during randomized treatment with intramuscular olanzapine long-acting injection versus oral olanzapine.

Metabolic changes were examined in patients with schizophrenia during treatment with either oral olanzapine or olanzapine long-acting injection (LAI). Data were collected from patients who had been stabilized on oral olanzapine (10, 15, or 20 mg/day) for ≥4 weeks and then randomized to either continued olanzapine oral treatment (n = 322) or LAI (n = 599; 150 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) for up to 24 weeks. Mean and categorical changes in metabolic parameters were analyzed. Mean changes in weight, glucose, and most lipids were generally not significantly different between treatment groups. Weight changes over time followed similar patterns and were not significantly different at endpoint between the two treatment-formulation groups. Low-density lipoprotein cholesterol decreased significantly less among olanzapine LAI-treated patients. Percentages of patients with potentially clinically significant changes in blood glucose and lipid concentrations were similar for the two treatments. Percentages of patients experiencing adverse events related to weight, diabetes, or dyslipidemia were also not significantly different between treatments. Metabolic changes in patients with schizophrenia appeared generally similar during treatment with oral olanzapine or olanzapine LAI.

Galcanezumab in Patients with Multiple Previous Migraine Preventive Medication Category Failures: Results from the Open-Label Period of the CONQUER Trial.

INTRODUCTION: Results from the open-label extension of the phase 3b CONQUER trial are presented to evaluate the effectiveness and safety of galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide, for up to 6 months in patients with multiple prior migraine preventive treatment failures. METHODS: Patients were 18-75 years old with episodic or chronic migraine and 2-4 standard-of-care migraine preventive medication category failures. After 3 months of randomized treatment with galcanezumab (120 mg/month with 240 mg loading dose; n = 232) or placebo (n = 230), patients entered a 3-month open-label extension (120 mg/month galcanezumab with a blinded 240 mg loading dose for previous-placebo patients). Primary efficacy measure was mean change from double-blind baseline in monthly migraine headache days. RESULTS: A total of 432/449 patients (96%) who entered open-label treatment completed the study. Mean change in monthly migraine headache days in the total population, which was - 1.3 for placebo and - 4.4 for galcanezumab patients at the end of double-blind treatment (p < 0.001), was - 5.2 and - 5.6, respectively, at the end of open-label treatment with galcanezumab. Among patients with episodic migraine, mean change in monthly migraine headache days had been - 0.6 for placebo and - 2.8 for galcanezumab after double-blind treatment (p < 0.001) and was - 4.5 and - 3.8, respectively, after open-label treatment. Among patients with chronic migraine, mean change in monthly migraine headache days had been - 2.5 for placebo and - 6.6 for galcanezumab after double-blind treatment (p < 0.001) and was - 6.5 and - 8.2, respectively, after open-label treatment. Adverse events were similar to those observed during double-blind placebo treatment. Review of data in elderly patients (65-75 years of age) indicated that galcanezumab was well tolerated in this age group, with no safety issues identified. CONCLUSIONS: Galcanezumab was effective and safe during open-label treatment in patients who had experienced failures of previous migraine preventives. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03559257.

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases.

BACKGROUND: An advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI. METHODS: Safety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors. RESULTS: Based on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified. CONCLUSIONS: Post-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism.

BACKGROUND: Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur. METHODS: Healthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media. RESULTS: Injection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue. CONCLUSIONS: Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial.

BACKGROUND: Many patients who require migraine preventive treatment have not been able to tolerate or have not responded to multiple previous preventive medications. We aimed to assess the safety and efficacy of galcanezumab, an antibody to calcitonin gene-related peptide, in patients with migraine who had not benefited from preventive medications from two to four categories. METHODS: CONQUER was a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial done at 64 sites (hospitals, clinics, or research centres) in 12 countries (Belgium, Canada, Czech Republic, France, Germany, Hungary, Japan, the Netherlands, South Korea, Spain, the UK, and the USA). Patients were 18-75 years of age, with episodic or chronic migraine, with migraine onset before the age of 50 years, who had a documented failure of preventive medications from two to four drug categories in the past 10 years owing to lack of efficacy or tolerability, or both. Patients were randomised 1:1 to receive subcutaneous placebo or galcanezumab 120 mg per month (with a 240 mg loading dose administered as two 120 mg injections) for 3 months. For masking purposes, patients receiving placebo also received two injections during the first dosing visit. Randomisation was done by a computer-generated random sequence by means of an interactive web-response system stratified by country and migraine frequency (low frequency episodic migraine, four to fewer than eight migraine headache days per month; high frequency episodic migraine, eight to 14 migraine headache days per month and fewer than 15 headache days per month; chronic migraine, at least eight migraine headache days per month and at least 15 headache days per month). The primary endpoint was the overall mean change from baseline in number of monthly migraine headache days during the 3-month treatment period in all patients who were randomly assigned and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03559257, and is now completed. FINDINGS: Between Sept 10, 2018, and March 21, 2019, 462 participants with episodic (269 [58%]) or chronic (193 [42%]) migraine were randomly assigned and received at least one injection with placebo (n=230) or galcanezumab (n=232). Galcanezumab-treated patients had significantly greater reduction in migraine headache days versus placebo across months 1-3. The galcanezumab group had on average 4·1 fewer monthly migraine headache days compared with baseline (13·4), while the placebo group had on average 1·0 fewer than at baseline (13·0; between-group difference -3·1 [95% CI -3·9 to -2·3]; p<0·0001; effect size=0·72). Types and number of treatment-emergent adverse events were similar between galcanezumab and placebo. Treatment-emergent adverse events were reported in 122 (53%) of 230 patients in the placebo group and 119 (51%) of 232 patients in the galcanezumab group. There were four serious adverse events during the study, two (1%) reported in the placebo group and two (1%) reported in the galcanezumab group. INTERPRETATION: Galcanezumab was superior to placebo in the preventive treatment of migraine and was safe and well tolerated in patients for whom multiple previous standard-of-care preventive treatments had failed. Galcanezumab might represent an important treatment option for patients who have not benefited from or tolerated previous standard-of-care treatments. FUNDING: Eli Lilly.