REAL-WORLD EFFECTIVENESS AND SAFETY OF RANIBIZUMAB TREATMENT IN PATIENTS WITH AND WITHOUT POLYPOIDAL CHOROIDAL VASCULOPATHY: Twelve-Month Results From the LUMINOUS Study.

PURPOSE: To evaluate the real-world effectiveness and safety of intravitreal ranibizumab 0.5 mg in treatment-naive patients with and without polypoidal choroidal vasculopathy (PCV). METHODS: Assessment of neovascular age-related macular degeneration patients with or without PCV after 12 months of ranibizumab treatment during the LUMINOUS study. Outcome measures were visual acuity and central retinal thickness changes from baseline and the rate of ocular adverse events. RESULTS: At baseline, 572 and 5,644 patients were diagnosed with and without PCV, respectively. The mean visual acuity gain from baseline at Month 12 in the PCV and non-PCV groups was +5.0 and +3.0 letters, respectively; these gains were achieved with a mean of 4.4 and 5.1 ranibizumab injections. Eighty percent of PCV patients and 72.2% of non-PCV patients who had baseline visual acuity ≥73 letters maintained this level of vision at Month 12; 20.6% and 17.9% of patients with baseline visual acuity <73 letters achieved visual acuity ≥73 letters in these groups. Greater reductions in central retinal thickness from baseline were also observed for the PCV group versus the non-PCV group. The rate of serious ocular adverse events was 0.7% (PCV group) and 0.9% (non-PCV group). CONCLUSION: LUMINOUS confirms the effectiveness and safety of ranibizumab in treatment-naive patients with PCV.

RANIBIZUMAB TREATMENT IN TREATMENT-NAIVE NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Results From LUMINOUS, a Global Real-World Study.

PURPOSE: To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in treatment-naive patients with neovascular age-related macular degeneration enrolled in LUMINOUS study. METHODS: This 5-year, prospective, multicenter, observational study recruited 30,138 adult patients (treatment-naive or previously treated with ranibizumab or other ocular treatments) who were treated according to the local ranibizumab label. RESULTS: Six thousand two hundred and forty-one treatment-naive neovascular age-related macular degeneration patients were recruited. Baseline (BL) demographics were, mean (SD) age 75.0 (10.2) years, 54.9% females, and 66.5% Caucasian. The mean (SD) visual acuity (VA; letters) gain at 1 year was 3.1 (16.51) (n = 3,379; BLVA, 51.9 letters [Snellen: 20/92]) with a mean (SD) of 5.0 (2.7) injections and 8.8 (3.3) monitoring visits. Presented by injection frequencies <3 (n = 537), 3 to 6 (n = 1,924), and >6 (n = 918), visual acuity gains were 1.6 (14.93), 3.3 (16.57), and 3.7 (17.21) letters, respectively. Stratified by BLVA <23 (n = 382), 23 to <39 (n = 559), 39 to <60 (n = 929), 60 to <74 (n = 994), and ≥74 (n = 515), visual acuity change was 12.6 (20.63), 6.7 (17.88), 3.6 (16.41), 0.3 (13.83), and -3.0 (11.82) letters, respectively. The incidence of ocular/nonocular adverse events was 8.2%/12.8% and serious adverse events were 0.9%/7.4%, respectively. CONCLUSION: These results demonstrate the effectiveness and safety of ranibizumab in treatment-naive neovascular age-related macular degeneration patients.

Functional versus functional and anatomical criteria-guided ranibizumab treatment in patients with neovascular age-related macular degeneration - results from the randomized, phase IIIb OCTAVE study.

BACKGROUND: To evaluate the efficacy and safety of two individualized ranibizumab retreatment schemes in neovascular age-related macular degeneration. METHODS: Patients (N = 671) were randomized (1:1) to receive three initial monthly ranibizumab 0.5 mg injections, then retreatment guided by either best-corrected visual acuity (BCVA) loss (Group I) or BCVA loss and/or signs of disease activity on optical coherence tomography (OCT; Group II). The study was terminated prematurely and the decision to discontinue the study was made by the sponsor. Efficacy analyses were performed on patients who completed 12 months of the originally planned 24-month study. Safety analyses are presented for all safety analyzable patients. RESULTS: Of 671 randomized patients, 305 completed 12 months of the study. For the 12-month completers, baseline mean (standard deviation) BCVA and reading-center evaluated central subfield thickness (CSFT) were comparable [Group I: 60.9 (13.10) letters and 517.7(201.79) µm; Group II: 60.2 (12.21) letters and 515.3 (198.37) µm]. The change from baseline at Month 12 in BCVA was 6.7 (13.48) letters in Group I and 8.3 (13.53) letters in Group II and the change in CSFT was - 161.3 (163.48) µm and - 175.3 (170.45) µm, respectively. The mean number of ranibizumab injections was 8.2 in Group I and 8.4 in Group II. CONCLUSION: Ranibizumab treatment resulted in visual and anatomic gains at 12 months for both retreatment strategies, with a trend in favor of OCT-guided vs BCVA loss guided retreatment. No new safety signals were seen. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT01780935). Registered 31 January 2013.

Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration: Results with Ranibizumab from the TREND Study.

PURPOSE: To evaluate the efficacy and safety of ranibizumab 0.5 mg treat-and-extend (T&E) versus monthly regimens in patients with neovascular age-related macular degeneration (nAMD) from the TReat and extEND (TREND) study. DESIGN: A 12-month phase 3b visual acuity (VA) assessor-masked, multicenter, randomized, interventional study. PARTICIPANTS: Six hundred fifty patients. METHODS: Treatment-naïve nAMD patients (age, ≥50 years) were randomized 1:1 to receive either a ranibizumab 0.5 mg T&E (n = 323) or monthly (n = 327) regimen. MAIN OUTCOMES MEASURES: The primary objective was to show noninferiority of ranibizumab 0.5 mg T&E versus monthly regimen, as assessed by the change in best-corrected VA (BCVA) from baseline to the end of the study. Secondary objectives included change in retinal central subfield thickness (CSFT) from baseline to the end of study, treatment exposure, and safety. RESULTS: Overall, 89.8% (T&E) and 90.2% (monthly) of patients completed the study. Patient demographic and baseline characteristics were well balanced between the 2 treatment groups. The T&E regimen was noninferior (P < 0.001) to the monthly regimen, with a least squares mean BCVA change from baseline of 6.2 versus 8.1 letters to the end of study, respectively. In both treatment groups, most BCVA improvements occurred during the first 6 months and were maintained until the end of the study. The mean change in CSFT from baseline to the end of study was -169.2 µm and -173.3 µm in the T&E and monthly groups, respectively. Fewer injections were required in patients receiving the T&E (8.7) versus monthly (11.1) regimen, with mean number of postbaseline visits of 8.9 and 11.2, respectively. Types and rates of adverse events were comparable between the treatment groups. CONCLUSIONS: Ranibizumab 0.5 mg administered according to a T&E regimen was statistically noninferior and clinically comparable with a monthly regimen in improving VA from baseline to the end of study. No new safety signals for ranibizumab were identified.

LONG-TERM OUTCOMES OF RANIBIZUMAB TREATMENT OF MYOPIC CHOROIDAL NEOVASCULARIZATION IN EAST-ASIAN PATIENTS FROM THE RADIANCE STUDY.

PURPOSE: To evaluate long-term efficacy and safety of ranibizumab for treatment of myopic choroidal neovascularization (mCNV) in clinical practice. METHODS: Noninterventional, retrospective cohort study of East-Asian patients previously treated with ranibizumab during the RADIANCE trial. Forty-one patients who completed the RADIANCE trial were followed-up for up to 48 months (post-RADIANCE observation period). Outcome measures were best-corrected visual acuity changes from baseline (assessed at RADIANCE trial initiation), mCNV recurrences, and ocular adverse events. RESULTS: Mean visual gain from baseline best-corrected visual acuity (56.5 ± 12.1 letters) (20/80) was significant at 12 months (+14.3 ± 11.4 letters, n = 40, P < 0.0001), 24 months (+10.4 ± 22.3 letters, n = 31, P = 0.0143), 30 months (+11.0 ± 22.4 letters, n = 29, P = 0.0134), 42 months (+12.9 ± 20.9 letters, n = 25, P = 0.0051), and 48 months (+16.3 ± 18.7, n = 16, P = 0.0034). Of the 16 patients who completed 48 months of follow-up, 63% gained ≥10 letters and 13% lost ≥10 letters. Over the post-RADIANCE observation period, 83% of patients required no further treatment for mCNV, 10% experienced mCNV recurrences, and 12% experienced a nonserious ocular adverse event. Patients who required additional treatment for mCNV received a mean of 5.0 (SD 5.9, range 1.0-18.0) ranibizumab injections. CONCLUSION: Best-corrected visual acuity gained at the end of the RADIANCE trial was sustained over additional 36 months of follow-up. Few patients required further treatment and no new safety concerns were observed.

Apathy in Neurodegenerative Diseases: Recommendations on the Design of Clinical Trials.

Apathy is a common feature of neurodegenerative disorders but is difficult to study in a clinical trial setting due to practical and conceptual barriers. Principal challenges include a paucity of data regarding apathy in these disorders, an absence of established diagnostic criteria, the presence of confounding factors (eg, coexisting depression), use of concomitant medications, and an absence of a gold-standard apathy assessment scale. Based on a literature search and ongoing collaboration among the authors, we present recommendations for the design of future clinical trials of apathy, suggesting Alzheimer disease and Parkinson disease as models with relevance across a wider array of neuropsychiatric disorders. Recommendations address clarification of the targeted study population (apathy diagnosis and severity at baseline), confounding factors (mood/cognition, behavior, and treatment), outcome measures, study duration, use of comparators and considerations around environment, and the role of the caregiver and patient assent. This review contributes to the search for an optimal approach to study treatment of apathy in neuropsychiatric disorders.

Effectiveness and optimization of low-sodium oxybate in participants with narcolepsy switching from a high-sodium oxybate: data from the SEGUE study.

STUDY OBJECTIVES: Low-sodium oxybate (LXB; calcium, magnesium, potassium, and sodium oxybates; Xywav) contains the same active moiety as high-sodium oxybates (sodium oxybate [SXB; Xyrem] and fixed-dose sodium oxybate [Lumryz]), with 92% less sodium, and is approved in the US for treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy, and idiopathic hypersomnia in adults. Patients with narcolepsy have increased cardiovascular risk relative to people without narcolepsy. LXB's lower sodium content is recognized by the US FDA in the narcolepsy population as clinically meaningful in reducing cardiovascular morbidity compared with high-sodium oxybates. The Substitution of Equal Grams of Uninterrupted Xyrem to Xywav (SEGUE) study (NCT04794491) examined the transition experience of patients with narcolepsy switching from SXB to LXB. METHODS: Eligible participants were aged 18 to 80 years with narcolepsy type 1 or 2 on a stable SXB dose/regimen. After 2 weeks, participants transitioned gram-per-gram to LXB for 6 weeks, with opportunity for subsequent titration. Assessments included the Epworth Sleepiness Scale (ESS), Patient Global Impression of Change (PGIc), ease of switching medication scale (EOSMS), and forced preference questionnaire (FPQ). RESULTS: The study enrolled 62 participants at baseline; 60 transitioned to LXB and 54 completed the study. At baseline and end of the LXB intervention/early discontinuation, respectively, mean total doses were 8.0 and 8.0 g/night; mean ESS scores were 9.4 and 8.8. Most participants reported improvement (45%) or no change (48%) in narcolepsy symptoms on the PGIc, reported the transition to LXB was "easy" (easy, extremely easy, not difficult at all; 93%) on the EOSMS, and preferred LXB compared with SXB (79%) on the FPQ, most commonly due to the lower sodium content. CONCLUSIONS: Most participants switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition process was easy. Effectiveness of oxybate treatment was maintained on LXB, and most participants preferred LXB to SXB. No new safety or tolerability issues were identified. CLINICALTRIALREGISTRATION: Registry: ClinicalTrials.gov; Name: An Interventional Safety Switch Study (Segue Study) of XYWAV in Narcolepsy; URL: https://classic.clinicaltrials.gov/ct2/show/NCT04794491; Identifier: NCT04794491.

Dosing and transition characteristics in people with narcolepsy transitioning from sodium oxybate to low-sodium oxybate: Data from the real-world TENOR study.

OBJECTIVE: The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study assessed the real-world experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92 % less sodium than SXB). METHODS: TENOR is a patient-centric, prospective, observational, virtual-format study. Eligible participants included US adults with narcolepsy transitioning from SXB to LXB (±7 days from LXB initiation). Longitudinal data were collected from baseline (taking SXB) through 21 weeks post-transition. RESULTS: TENOR included 85 participants with narcolepsy (type 1, n = 45; type 2, n = 40). Mean (SD) age was 40.3 (13.0) years; the majority (73 %) were female and White (87 %). At study completion, wake-promoting agents were the most common concomitant medications (47 %). Mean (SD) SXB treatment duration was 57.8 (52.1) months; 96 % took SXB twice nightly. After transitioning, 97 % continued on twice-nightly regimens. Mean (SD) dose of both total nightly SXB (n = 85) and baseline LXB (n = 84) was 7.7 (1.5) g; SXB-LXB dose conversions at baseline were gram-for-gram in 87 % of participants. The mean final total nightly dose of LXB was 7.9 g. The most common participant-reported reasons for transitioning included lower sodium content for improved long-term health (93 %), physician recommendation (47 %), to avoid cardiovascular issues (39 %), to avoid side effects (31 %), and to improve control of narcolepsy symptoms (18 %). CONCLUSION: Most participants transitioned from SXB to LXB using a gram-for-gram strategy. The most commonly cited reason for transition was long-term health benefits due to lower sodium.

Implications of Oxybate Dosing Regimen for Sleep, Sleep Architecture, and Disrupted Nighttime Sleep in Patients with Narcolepsy: A Commentary.

Narcolepsy is associated with disrupted nighttime sleep (DNS). Sodium oxybate (SXB; Xyrem®), administered twice nightly, is indicated for the treatment of cataplexy and excessive daytime sleepiness in patients 7 years or older with narcolepsy. Recently, low-sodium oxybate (LXB, Xywav®; for people 7 years of age and older), which contains 92% less sodium than SXB and is dosed twice nightly, and sodium oxybate for extended release (SXB-ER; Lumryz™; for adults), which contains equal sodium to SXB and is dosed once nightly, have also been approved to treat cataplexy or excessive daytime sleepiness in narcolepsy. This paper reviews the evidence regarding the overall impact of oxybate administration, and impact of different oxybate dosing regimens (once nightly, SXB-ER; twice nightly, SXB), on DNS in narcolepsy utilizing polysomnographic data from five clinical trials (three assessing SXB in adults [referred to here as SXB trials 1, 2, and 3], one assessing SXB in children [referred to as the pediatric SXB trial], and one assessing SXB-ER in adults [REST-ON]). Both once-nightly and twice-nightly oxybate regimens similarly improved symptoms of DNS. Regardless of dosing regimen, people with narcolepsy treated with oxybate experience roughly 42-53 arousals and 9-38 awakenings each night, with one of these awakenings on twice-nightly oxybate being due to the second dosing requirement in studies of SXB. Additionally, for SXB, but not SXB-ER, polysomnographic data has been analyzed by half of the night, demonstrating a greater positive impact on sleep architecture in the second half of the night, which might be related to its nonlinear pharmacokinetic profile. We conclude that while once-nightly and twice-nightly oxybate dosing regimens differ in their pharmacokinetic profiles, both improve DNS in patients with narcolepsy to a similar degree.

Narcolepsy causes daytime sleepiness and difficulty sleeping (commonly called disrupted nighttime sleep). Sodium oxybate (Xyrem^®) and low-sodium oxybate (Xywav^®, which contains 92% less sodium than sodium oxybate), are taken twice nightly in patients with narcolepsy. Sodium oxybate for extended release (Lumryz™), which contains as much sodium as sodium oxybate, is taken once per night. All three medications improve narcolepsy symptoms and have the same active ingredient. It is important to understand how well they improve nighttime sleep.This review examined results of five clinical studies looking at disrupted nighttime sleep in people with narcolepsy: three of twice-nightly sodium oxybate in adults (called SXB trials 1, 2, and 3 here), one of twice-nightly sodium oxybate in children (called the pediatric SXB trial here), and one of once-nightly sodium oxybate for extended release in adults (called REST-ON here). No studies specifically investigated disrupted nighttime sleep with twice-nightly low-sodium oxybate in people with narcolepsy. Although the trial designs for these studies were different, both twice-nightly and once-nightly oxybate medications improved sleep similarly, and neither eliminated arousals or awakenings. Certain aspects of sleep improved more during the second half of the night in SXB trials 1 and 3 compared with the first half of the night. Both once-nightly and twice-nightly oxybate medications similarly improve nighttime sleep in people with narcolepsy. Twice-nightly oxybate may be particularly helpful in improving sleep in the second half of the night.

Impairment in Functioning and Quality of Life in Patients with Idiopathic Hypersomnia: The Real World Idiopathic Hypersomnia Outcomes Study (ARISE).

Purpose: Idiopathic hypersomnia is a debilitating neurologic sleep disorder characterized by excessive daytime sleepiness, sleep inertia, and prolonged sleep. Its impact on patients' quality of life and daily functioning has not been fully elucidated. The Real World Idiopathic Hypersomnia Outcomes Study (ARISE) evaluated the daily functioning, relationships, cognition, emotional well-being, and productivity/employment of participants with idiopathic hypersomnia. Patients and Methods: ARISE was a US-based virtual cross-sectional survey comprising multiple patient-reported outcome measures (Functional Outcomes of Sleep Questionnaire, short version [FOSQ-10], Quality of Life in Neurological Disorders [Neuro-QoL] Social Roles and Stigma domains, British Columbia Cognitive Complaints Inventory [BC-CCI], Patient Health Questionnaire [PHQ-9], and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem [WPAI:SHP]). Participants were adults 21-65 years of age with idiopathic hypersomnia. Data were analyzed for all participants and for subgroups with/without long sleep time (LST; self-reported sleep ≥11 hours in 24 hours). Results: Of 75 participants enrolled, most were female (81.3%) and the mean (SD) age was 34.1 (10.7) years. Participants' scores on the FOSQ-10 (mean [SD] score: 10.7 [2.8]) and the Neuro-QoL Social Roles (43.4 [4.2]) and Stigma (57.3 [5.9]) domains reflected impairments in daily functioning and quality of life. More than half of participants reported moderate to severe cognitive complaints (BC-CCI; 62.7%) and moderate to severe depressive symptoms (PHQ-9; 66.7%). Scores on the WPAI:SHP showed substantial impairments in absenteeism, presenteeism, overall work productivity, and overall regular daily activity (mean percent [SD]: 12.3 [23.6], 47.6 [22.7], 51.4 [24.7], and 64.0 [21.9], respectively). These considerable impairments were found in participants with and without LST. Conclusion: ARISE participants with idiopathic hypersomnia demonstrated poor quality of life and impaired functioning across multiple symptom domains.

Symptom Severity and Treatment Satisfaction in Patients with Idiopathic Hypersomnia: The Real World Idiopathic Hypersomnia Outcomes Study (ARISE).

Objective: Idiopathic hypersomnia is a debilitating sleep disorder characterized by excessive daytime sleepiness, sleep inertia, and prolonged sleep duration. The patient burden of idiopathic hypersomnia is poorly understood. The Real World Idiopathic Hypersomnia Outcomes Study (ARISE) evaluated symptoms and treatment effectiveness/satisfaction in participants with idiopathic hypersomnia. Methods: ARISE was a United States-based virtual cross-sectional survey. Participants were adults 21-65 years of age with idiopathic hypersomnia recruited from social media, the Hypersomnia Foundation website, and a patient panel. Self-assessments included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Treatment Satisfaction Questionnaire for Medication, version II (TSQM-vII), and additional treatment questions. Data were analyzed for all participants and for subgroups with/without long sleep time (LST; ≥11 hours in 24 hours). Results: Of 75 participants enrolled, most were female (81.3%). The mean (SD) age was 34.1 (10.7) years and 49% had LST. Most participants took off-label prescription medications (89.3%) and/or used other measures (93.3%) to manage their symptoms. The mean (SD) ESS score was 14.5 (3.5) and the mean IHSS score was 35.2 (7.6). Treatment satisfaction was low (mean [SD] TSQM-vII score: overall, 61.9 [21.2]; with LST, 57.9 [21.4]; without LST, 66.7 [20.3]), primarily driven by dissatisfaction with treatment effectiveness. The most common classes of prescription medications used were stimulants (61.3%), wake-promoting agents (28.0%), and antidepressants (18.7%); non-prescription measures used to manage symptoms included caffeine (73.3%), planned naps (34.7%), and individual accommodations (32.0%). Conclusion: Overall, participants with idiopathic hypersomnia, with or without LST, had substantial symptom burden despite most of the study population taking off-label medications and using nonprescription measures to manage symptoms.

Effectiveness and tolerability in people with narcolepsy transitioning from sodium oxybate to low-sodium oxybate: Data from the real-world TENOR study.

OBJECTIVES: The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study was conducted to provide real-world insight into the experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92% less sodium than SXB). METHODS: TENOR is a patient-centric, prospective, observational, virtual-format study. Participants were adults with narcolepsy (type 1 or 2) who were transitioning from SXB to LXB treatment (±7 days from LXB initiation). Effectiveness and tolerability data were collected online from baseline (taking SXB) through 21 weeks (taking LXB) via daily and weekly diaries and questionnaires, including the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and the British Columbia Cognitive Complaints Inventory (BC-CCI). RESULTS: TENOR participants (N = 85) were 73% female with a mean (SD) age of 40.3 (13.0) years. Mean (SD) ESS scores decreased numerically throughout the transition from SXB to LXB (baseline: 9.9 [5.2]; week 21: 7.5 [4.7]), with 59.5% and 75.0% of participants having scores in the normal range (≤10) at baseline and week 21, respectively. Mean (SD) FOSQ-10 scores (baseline: 14.4 [3.4]; week 21: 15.2 [3.2]) and BC-CCI scores (baseline: 6.1 [4.4]; week 21: 5.0 [4.3]) also remained stable. The most common symptoms related to tolerability reported by participants at baseline were sleep inertia, hyperhidrosis, and dizziness (45.2%, 40.5%, and 27.4%, respectively), which decreased in prevalence by week 21 (33.8%, 13.2%, and 8.8%, respectively). CONCLUSIONS: Findings from TENOR confirm maintenance of effectiveness and tolerability when transitioning from SXB to LXB treatment.

Adjunctive long-acting risperidone in patients with bipolar disorder who relapse frequently and have active mood symptoms.

BACKGROUND: The objective of this exploratory analysis was to characterize efficacy and onset of action of a 3-month treatment period with risperidone long-acting injection (RLAI), adjunctive to an individual's treatment regimen, in subjects with symptomatic bipolar disorder who relapsed frequently and had significant symptoms of mania and/or depression. METHODS: Subjects with bipolar disorder with ≥4 mood episodes in the past 12 months entered the open-label stabilization phase preceding a placebo-controlled, double-blind study. Subjects with significant depressive or manic/mixed symptoms at baseline were analyzed. Significant depressive symptoms were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) ≥16 and Young Mania Rating Scale (YMRS) < 16; manic/mixed symptoms were YMRS ≥16 with any MADRS score. Subjects received open-label RLAI (25-50 mg every 2 weeks) for 16 weeks, adjunctive to a subject's individualized treatment for bipolar disorder (mood stabilizers, antidepressants, and/or anxiolytics). Clinical status was evaluated with the Clinical Global Impressions of Bipolar Disorder-Severity (CGI-BP-S) scale and changes on the MADRS and YMRS scales. Within-group changes were evaluated using paired t tests; categorical differences were assessed using Fisher exact test. No adjustment was made for multiplicity. RESULTS: 162 subjects who relapsed frequently met criteria for significant mood symptoms at open-label baseline; 59/162 (36.4%) had depressive symptoms, 103/162 (63.6%) had manic/mixed symptoms. Most subjects (89.5%) were receiving ≥1 medication for bipolar disorder before enrollment. Significant improvements were observed for the total population on the CGI-BP-S, MADRS, and YMRS scales (p < .001 vs. baseline, all variables). Eighty-two (53.3%) subjects achieved remission at the week 16 LOCF end point. The subpopulation with depressive symptoms at open-label baseline experienced significant improvement on the CGI-BP-S and MADRS scales (p < .001 vs. baseline, all variables). Subjects with manic/mixed symptoms at baseline had significant improvements on the CGI-BP-S and YMRS scales (p < .001 vs. baseline, all variables). No unexpected tolerability findings were observed. CONCLUSIONS: Exploratory analysis of changes in overall clinical status and depression/mania symptoms in subjects with symptomatic bipolar disorder who relapse frequently showed improvements in each of these areas after treatment with RLAI, adjunctive to a subject's individualized treatment. Prospective controlled studies are needed to confirm these findings.

Resource utilization in patients with schizophrenia who initiated risperidone long-acting therapy: results from the Schizophrenia Outcomes Utilization Relapse and Clinical Evaluation (SOURCE).

BACKGROUND: Schizophrenia is a chronic mental health disorder associated with increased hospital admissions and excessive utilization of outpatient services and long-term care. This analysis examined health care resource utilization from a 24-month observational study of patients with schizophrenia initiated on risperidone long-acting therapy (RLAT). METHODS: Schizophrenia Outcomes Utilization Relapse and Clinical Evaluation (SOURCE) was a 24-month observational study designed to examine real-world treatment outcomes by prospectively following patients with schizophrenia initiated on RLAT. At baseline visit, prior hospitalization and ER visit dates were obtained for the previous 12 months and subsequent hospitalization visit dates were obtained at 3-month visits, if available. The health care resource utilization outcomes measures observed in this analysis were hospitalizations for any reason, psychiatric-related hospitalizations, and emergency room (ER) visits. Incidence density analysis was used to assess pre-event and postevent rates per person-year (PY). RESULTS: The primary medical resource utilization analysis included 435 patients who had a baseline visit, ≥1 postbaseline visits after RLAT initiation, and valid hospitalization dates. The number of hospitalizations and ER visits per PY declined significantly (p < .0001) after initiation with RLAT. A 41% decrease (difference of -0.29 hospitalizations per PY [95% CI: -0.39 to -0.18] from baseline) in hospitalizations for any reason, a 56% decrease (a difference of -0.35 hospitalizations per PY [95% CI: -0.44 to -0.26] from baseline) in psychiatric-related hospitalizations, and a 40% decrease (-0.26 hospitalizations per PY [95% CI: -0.44 to -0.10] from baseline) in ER visits were observed after the baseline period. The percentage of psychiatric-related hospitalizations decreased significantly after RLAT initiation, and patients had fewer inpatient hospitalizations and ER visits (all p < .0001). CONCLUSION: The results suggest that treatment with RLAT may result in decreased hospitalizations for patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00246194.

Assessment of effectiveness measures in patients with schizophrenia initiated on risperidone long-acting therapy: the SOURCE study results.

BACKGROUND: To evaluate effectiveness outcomes in a real-world setting in patients with schizophrenia initiating risperidone long-acting therapy (RLAT). METHODS: This was a 24-month, multicenter, prospective, longitudinal, observational study in patients with schizophrenia who were initiated on RLAT. Physicians could change treatment during the study as clinically warranted. Data were collected at baseline and subsequently every 3 months up to 24 months. Effectiveness outcomes included changes in illness severity as measured by Clinical Global Impression-Severity (CGI-S) scale; functional scores as measured by Personal and Social Performance (PSP) scale, Global Assessment of Functioning (GAF), and Strauss-Carpenter Levels of Functioning (LOF); and health status (Medical Outcomes Survey Short Form-36 [SF-36]). Life-table methodology was used to estimate the cumulative probability of relapse over time. Adverse events were evaluated for safety. RESULTS: 532 patients were enrolled in the study; 209 (39.3%) completed the 24-month study and 305 (57.3%) had at least 12 months of follow-up data. The mean (SD) age of patients was 42.3 (12.8) years. Most patients were male (66.4%) and either Caucasian (60.3%) or African American (23.7%). All changes in CGI-S from baseline at each subsequent 3-month follow-up visit were statistically significant (p < .0001), indicating improvement in disease severity. Improvements were also noted for the PSP, GAF, and total LOF, indicating improvement in daily functioning and health outcome. CONCLUSIONS: Patients with schizophrenia who were initiated on RLAT demonstrated improvements in measures of effectiveness within 3 months, which persisted over 24 months. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00246194.

Effectiveness of injectable risperidone long-acting therapy for schizophrenia: data from the US, Spain, Australia, and Belgium.

BACKGROUND: Because wide variations in mental health care utilization exist throughout the world, determining long-term effectiveness of psychotropic medications in a real-world setting would be beneficial to physicians and patients. The purpose of this analysis was to describe the effectiveness of injectable risperidone long-acting therapy (RLAT) for schizophrenia across countries. METHODS: This was a pragmatic analysis of data from two prospective observational studies conducted in the US (Schizophrenia Outcomes Utilization Relapse and Clinical Evaluation [SOURCE]; ClinicalTrials.gov registration number for the SOURCE study: NCT00246194) and Spain, Australia, and Belgium (electronic Schizophrenia Treatment Adherence Registry [eSTAR]). Two separate analyses were performed to assess clinical improvement during the study and estimate psychiatric hospitalization rates before and after RLAT initiation. Clinical improvement was evaluated using the Clinical Global Impressions-Severity (CGI-S) and Global Assessment of Functioning (GAF) scales, and change from baseline was evaluated using paired t tests. Psychiatric hospitalization rates were analyzed using incidence densities, and the bootstrap resampling method was used to examine differences between the pre-baseline and post-baseline periods. RESULTS: The initial sample comprised 3,069 patients (US, n = 532; Spain, n = 1,345; Australia, n = 784; and Belgium, n = 408). In all, 24 months of study participation, completed by 39.3% (n = 209), 62.7% (n = 843), 45.8% (n = 359), and 64.2% (n = 262) of patients from the US, Spain, Australia, and Belgium, respectively, were included in the clinical analysis. Improvements compared with baseline were observed on both clinical assessments across countries (P < 0.001 at all post-baseline visits). The mean improvement was approximately 1 point on the CGI-S and 15 points on the GAF. A total of 435 (81.8%), 1,339 (99.6%), 734 (93.6%), and 393 (96.3%) patients from the US, Spain, Australia, and Belgium, respectively, had ≥1 post-baseline visit and were included in the analysis of psychiatric hospitalization rates. Hospitalization rates decreased significantly in all countries regardless of hospitalization status at RLAT initiation (P < 0.0001) and decreased significantly in the US and Spain (P < 0.0001) when the analysis was limited to outpatients only. CONCLUSIONS: RLAT in patients with schizophrenia was associated with improvements in clinical and functional outcomes and decreased hospitalization rates in the US, Spain, Australia, and Belgium, despite differences in health care delivery systems.

Effectiveness and safety of ranibizumab 0.5 mg in treatment-naïve patients with diabetic macular edema: Results from the real-world global LUMINOUS study.

PURPOSE: To assess the one-year effectiveness and safety of ranibizumab 0.5 mg in treatment- naïve patients with diabetic macular edema (DME) enrolled in the real-world LUMINOUS study. PATIENTS AND METHODS: A 5-year, prospective, observational, open-label, global study which recruited 30,138 patients across all approved indications. Consenting patients (≥18 years) who were treatment-naïve or previously treated with ranibizumab or other ocular treatments were treated as per the local ranibizumab label. Here, we present the change in visual acuity (VA) (Early Treatment Diabetic Retinopathy Study letter score; primary treated eye) at Year 1, as well as the change in VA based on injection frequencies (≤4 and ≥5), treatment exposure, and the overall adverse events (AEs) and serious AEs (SAEs) in treatment-naïve DME patients. RESULTS: Of the 4,710 DME patients enrolled in the study, 1,063 were treatment-naïve. At baseline, mean age was 64.5 years, 54.7% were male, and 69.2% were white. At 1 year, mean VA letter score improved by +3.5 (n = 502) from a baseline of 57.7 with a mean of 4.5 injections. Presented by injection frequencies ≤4 and ≥5, VA letter score gains were 0.5 (n = 264) and 6.9 (n = 238) from baseline letter scores of 56.6 and 59.0, respectively. Over 5 years, the incidence of ocular/non-ocular AEs and SAEs was 7.2%/10.1% and 0.3%/5.8%, respectively. No endophthalmitis cases were reported. CONCLUSIONS: The LUMINOUS study included patients with DME with more diverse baseline characteristics than those in randomized clinical trials. The 1-year data showed improvement in VA with low number of injections in treatment- naïve patients with DME. Greater VA gains were observed in patients who received ≥5 injections. No new safety findings were identified. LUMINOUS confirms the effectiveness and safety of ranibizumab for the treatment of patients with DME in a real-world clinical practice.

A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently.

OBJECTIVE: No large controlled trials have evaluated adjunctive maintenance treatment with long-acting injectable antipsychotics in patients with bipolar disorder. This study assessed whether adjunctive maintenance treatment with risperidone long-acting therapy (RLAT), added to treatment-as-usual (TAU) medications for bipolar disorder, delays relapse in patients with bipolar disorder type I. METHODS: This study included patients with bipolar disorder type I with > or = four mood episodes in the 12 months prior to study entry. Following a 16-week, open-label stabilization phase with RLAT plus TAU, remitted patients entered a 52-week, double-blind, placebo-controlled, relapse-prevention phase. Randomized patients continued treatment with adjunctive RLAT (25-50 mg every two weeks) plus TAU (n = 65) or switched to adjunctive placebo injection plus TAU (n = 59). The primary outcome measure was time to relapse to any mood episode. RESULTS: Of 240 enrolled patients, 124 entered double-blind treatment. Time to relapse was longer in patients receiving adjunctive RLAT (p = 0.010). Relapse rates were 23.1% (n = 15) with adjunctive RLAT versus 45.8% (n = 27) with adjunctive placebo; relative relapse risk was 2.3-fold higher with adjunctive placebo (p = 0.011). Completion rates were: adjunctive RLAT, 60.0% (n = 39) and adjunctive placebo, 42.4% (n = 25; p = 0.050). Adverse event (AE)-related discontinuations were 4.6% (n = 3) and 1.7% (n = 1), respectively. Common AEs (adjunctive RLAT versus adjunctive placebo) were: tremor (24.6% versus 10.2%), insomnia (20.0% versus 18.6%), muscle rigidity (12.3% versus 5.1%), weight increased (6.2% versus 1.7%), and hypokinesia (7.7% versus 0.0%). CONCLUSIONS: Adjunctive RLAT significantly delayed time to relapse in patients with bipolar disorder type I who relapse frequently. Safety and tolerability of RLAT were generally consistent with that previously observed.