A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial.

BACKGROUND: Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. In highly regulated markets, there are currently no approved biosimilars of pegfilgrastim. Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare proposed biosimilar LA-EP2006 with reference pegfilgrastim (Neulasta, Amgen) in early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy. METHODS: A total of 308 patients were randomized to LA-EP2006 or reference pegfilgrastim. Each patient received TAC (intravenous docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2)) on day 1 of each cycle, for six or more cycles. Pegfilgrastim (LA-EP2006 or reference) was given subcutaneously (6 mg in 0.6 mL) on day 2 of each cycle. The primary endpoint was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with an absolute neutrophil count <0.5 × 10(9)/L), with equivalence confirmed if 90% and 95% confidence intervals (CIs) were within a 1-day margin. RESULTS: Baseline characteristics were well balanced. DSN was equivalent between groups at mean ± SD 1.36 ± 1.13 (LA-EP2006, n = 155) and 1.19 ± 0.98 (reference, n = 153) in cycle 1. With a treatment difference (reference minus LA-EP2006) of -0.16 days (90% CI -0.36 to 0.04; 95% CI -0.40 to 0.08), LA-EP2006 was equivalent to reference pegfilgrastim. Secondary efficacy parameters were similar between groups during cycle 1 and across cycles. Safety profiles were also similar between groups. No neutralizing antibodies against pegfilgrastim, filgrastim, or polyethylene glycol were detected. CONCLUSION: LA-EP2006 and reference pegfilgrastim were therapeutically equivalent and comparable regarding efficacy and safety in the prevention of neutropenia in patients with early-stage breast cancer receiving TAC. IMPLICATIONS FOR PRACTICE: The granulocyte colony-stimulating factor pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. Biosimilars are biologics with similar quality, safety, and efficacy to a reference product that may increase the affordability of treatment compared with their reference compounds. There are currently no approved biosimilars of pegfilgrastim in highly regulated markets. No previous phase III studies have been performed with LA-EP2006. PROTECT-2 was conducted to confirm the similarity of the proposed biosimilar LA-EP2006 to pegfilgrastim. Biosimilar pegfilgrastim (LA-EP2006) may benefit oncology patients by offering increased access to biological treatments that may improve clinical outcomes. This means that patients could potentially be treated prophylactically with biologics rather than only after complications have occurred.

Healthy donor hematopoietic stem cell mobilization with biosimilar granulocyte-colony-stimulating factor: safety, efficacy, and graft performance.

BACKGROUND: Biosimilar granulocyte-colony-stimulating factors (G-CSFs) have been available in the European Union since 2008, and Sandoz' biosimilar filgrastim was approved in the United States in March 2015 for all of the reference product's indications except acute radiation syndrome. Biosimilar G-CSFs have been largely embraced by the medical community, except for some reservations about healthy-donor stem cell mobilization, for which use outside of clinical studies was cautioned against by some members of the scientific community. STUDY DESIGN AND METHODS: In a two-center safety surveillance study (National Clinical Trial NCT01766934), 245 healthy volunteer stem cell donors were enrolled. Of 244 donors who began mobilization with twice-daily Sandoz biosimilar filgrastim, 242 received a full (n = 241) or partial (n = 1) course of G-CSF and underwent apheresis. Efficacy and safety were assessed and are reported here. RESULTS: Biosimilar filgrastim was accompanied by the typical G-CSF class-related adverse effects of expected frequency and severity. Median mobilization for CD34-positive stem cells was 97/µL (range, 20-347/µL); after one apheresis (91%) or two aphereses (9%) from all but three donors (1.2%), cell doses in excess of the typical 4 × 106 CD34-positive cells/kg of the recipient had been collected (range, 3-52 × 106 /kg). Biochemical and hematologic alterations were consistent with previous reports; all had normalized by the first follow-up 1 month after mobilization. Stem cell products engrafted with typical probability and kinetics for G-CSF-mobilized stem cell products. CONCLUSION: These data support the use of biosimilar filgrastim for healthy-donor stem cell mobilization as safe and effective.

Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer.

AIM: This randomized, double-blind trial compared proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer (PROTECT-1). PATIENTS & METHODS: Women (≥18 years) were randomized to receive LA-EP2006 (n = 159) or reference (n = 157) pegfilgrastim (Neulasta(®), Amgen) for ≤6 cycles of (neo)-adjuvant TAC chemotherapy. Primary end point was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 10(9)/l) with equivalence confirmed if 90% and 95% CIs were within a ±1 day margin. RESULTS: For DSN, LA-EP2006 was equivalent to reference (difference: 0.07 days; 90% CI: -0.09-0.23; 95% CI: -0.12-0.26). CONCLUSION: LA-EP2006 and reference pegfilgrastim showed no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving chemotherapy.

Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study.

BACKGROUND: Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. METHODS: PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and "off" time. RESULTS: Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in "off" time were observed. The majority (71/88; 81%) improved on PGIC. CONCLUSIONS: Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012.

Incorporating Prior Data in Quantitative Benefit-Risk Assessments: Case Study of a Bayesian Method.

BACKGROUND: Multiple criteria decision analysis (MCDA) and stochastic multi-criteria acceptability analysis (SMAA) in their current implementation cannot incorporate prior or external information on benefits and risks. We demonstrate how to incorporate prior data using a Bayesian mixture model approach while conducting quantitative benefit-risk assessments (qBRA) for medical products. METHODS: We implemented MCDA and SMAA in a Bayesian framework. To incorporate information from a prior study, we use mixture priors on each benefit and risk attribute that mixes information from a previous study with a vague prior distribution. The degree of borrowing is varied using a mixing proportion parameter. RESULTS: A demonstration case study for qBRA using the supplementary New Drug Application (sNDA) filing for Rivaroxaban for the indication of reduction in the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD) was used to illustrate the method. Net utility scores, obtained from the randomized controlled trial data to support the sNDA, from the MCDA for Rivaraxoban and comparator were 0.48 and 0.56, respectively, with Rivaroxaban being the preferred alternative only 33% of the time. We show that with only 30% borrowing from a previous RCT, the MCDA and SMAA results are favorable for Rivaroxaban, accounting for the seemingly aberrant results on all-cause death in the trial data used to support the sNDA. CONCLUSION: Our method to formally incorporate prior data in MCDA and SMAA is easy to use and interpret. Software in the form of an RShiny App is available here: https://sai-dharmarajan.shinyapps.io/BayesianMCDA_SMAA/ .

Design and Execution of Sustainable Decentralized Clinical Trials.

The decentralized clinical trial (DCT) approach is increasingly recognized as a means to accelerate the development of potential therapeutic interventions. DCTs have a crucial advantage over traditional clinical trials: patients are monitored in their environment using technology (e.g., wearables), that capture data as they continue in daily life. This narrative review outlines a gap analysis focused on the frameworks and guidance from expert working groups and regulatory agencies for the design and execution of DCTs. Eight DCT elements guided the analysis and summarized the frameworks and guidance: (1) suitability, (2) protocol, (3) investigational medicinal product (IMP) supply, (4) investigators and health care providers, (5) safety, (6) regulatory and ethics, (7) data and technology, and (8) engagement, communication, and advocacy. Based on the gap analysis, two key takeaways were identified: (1) a need for a comprehensive sustainability assessment of each DCT element; and (2) current frameworks and guidance provide recommendations on social sustainability and some on economic sustainability. DCTs are an essential evolution in healthcare research; however, more guidance related to a comprehensive assessment of designing and executing sustainable DCTs is needed. This is especially the case for environmental sustainability, including, for example, carbon footprint and disposal of IMPs and sensors.

Platform trials to evaluate the benefit-risk of COVID-19 therapeutics: Successes, learnings, and recommendations for future pandemics.

BACKGROUND: In response to the COVID-19 global pandemic, multiple platform trials were initiated to accelerate evidence generation of potential therapeutic interventions. Given a rapidly evolving and dynamic pandemic, platform trials have a key advantage over traditional randomized trials: multiple interventions can be investigated under a master protocol sharing a common infrastructure. METHODS: This paper focuses on nine platform trials that were instrumental in advancing care in COVID-19 in the hospital and community setting. A semi-structured qualitative interview was conducted with the principal investigators and lead statisticians of these trials. Information from the interviews and public sources were tabulated and summarized across trials, and recommendations for best practice for the next health crisis are provided. RESULTS: Based on the information gathered takeaways were identified as 1) the existence of some aspect of trial design or conduct (e.g., existing network of investigators or colleagues, infrastructure for data capture and relevant statistical expertise) was a key success factor; 2) the choice of treatments (e.g., repurposed drugs) had major impact on the trials as did the choice of primary endpoint; and 3) the lack of coordination across trials was flagged as an area for improvement. CONCLUSION: These trials deployed during the COVID-19 pandemic demonstrate how to achieve both speed and quality of evidence generation regarding clinical benefit (or not) of existing therapies to treat new pathogens in a pandemic setting. As a group, these trials identified treatments that worked, and many that did not, in a matter of months.

A New Comprehensive Approach to Assess the Probability of Success of Development Programs Before Pivotal Trials.

The point at which clinical development programs transition from early phase to pivotal trials is a critical milestone. Substantial uncertainty about the outcome of pivotal trials may remain even after seeing positive early phase data, and companies may need to make difficult prioritization decisions for their portfolio. The probability of success (PoS) of a program, a single number expressed as a percentage reflecting the multitude of risks that may influence the final program outcome, is a key decision-making tool. Despite its importance, companies often rely on crude industry benchmarks that may be "adjusted" by experts based on undocumented criteria and which are typically misaligned with the definition of success used to drive commercial forecasts, leading to overly optimistic expected net present value calculations. We developed a new framework to assess the PoS of a program before pivotal trials begin. Our definition of success encompasses the successful outcome of pivotal trials, regulatory approval and meeting the requirements for market access as outlined in the target product profile. The proposed approach is organized in four steps and uses an innovative Bayesian approach to synthesize all relevant evidence. The new PoS framework is systematic and transparent. It will help organizations to make more informed decisions. In this paper, we outline the rationale and elaborate on the structure of the proposed framework, provide examples, and discuss the benefits and challenges associated with its adoption.

Academic outcomes in Asian children aged 8-11 years with attention-deficit/hyperactivity disorder treated with atomoxetine hydrochloride.

OBJECTIVE: To investigate the relationship between changes in attention-deficit/hyperactivity disorder (ADHD) core symptoms and changes in academic outcome of Asian children treated with atomoxetine. METHODS: This open-label study enrolled patients aged 8-11 years with DSM-IV-TR-defined ADHD, who were naïve to ADHD medications and met the symptomatic severity threshold of 1.5 standard deviations above the age and gender norm for the ADHDRS-IV-Parent:Inv (ADHDRS) total score. Data collection occurred for 24 weeks and included academic outcome, measured by the school grade average (SGA). RESULTS: Of 228 patients enrolled from China (n = 82), Taiwan (n = 76), and Korea (n = 70), 77.2% completed the study. Statistically significant (P < 0.001) baseline to last observation improvements in ADHDRS and SGA scores were observed. However, no linear correlation between change in ADHDRS total score and SGA (-0.083, P = 0.293) was observed. CONCLUSIONS: Despite significant independent improvements in core ADHD symptoms and academic grades over 24 weeks, the mean improvements observed in these measures did not appear to be correlated.

Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice.

The National Research Council (NRC) Expert Panel Report on Prevention and Treatment of Missing Data in Clinical Trials highlighted the need for clearly defining objectives and estimands. That report sparked considerable discussion and literature on estimands and how to choose them. Importantly, consideration moved beyond missing data to include all postrandomization events that have implications for estimating quantities of interest (intercurrent events, aka ICEs). The ICH E9(R1) draft addendum builds on that research to outline key principles in choosing estimands for clinical trials, primarily with focus on confirmatory trials. This paper provides additional insights, perspectives, details, and examples to help put ICH E9(R1) into practice. Specific areas of focus include how the perspectives of different stakeholders influence the choice of estimands; the role of randomization and the intention-to-treat principle; defining the causal effects of a clearly defined treatment regimen, along with the implications this has for trial design and the generalizability of conclusions; detailed discussion of strategies for handling ICEs along with their implications and assumptions; estimands for safety objectives, time-to-event endpoints, early-phase and one-arm trials, and quality of life endpoints; and realistic examples of the thought process involved in defining estimands in specific clinical contexts.

Defining Efficacy Estimands in Clinical Trials: Examples Illustrating ICH E9(R1) Guidelines.

This paper provides examples of defining estimands in real-world scenarios following ICH E9(R1) guidelines. Detailed discussions on choosing the estimands and estimators can be found in our companion papers. Three scenarios of increasing complexity are illustrated. The first example is a proof-of-concept trial in major depressive disorder where the estimand is chosen to support the sponsor decision on whether to continue development. The second and third examples are confirmatory trials in severe asthma and rheumatoid arthritis respectively. We discuss the intercurrent events expected during each trial and how they can be handled so as to be consistent with the study objectives. The estimands discussed in these examples are not the only acceptable choices for their respective scenarios. The intent is to illustrate the key concepts rather than focus on specific choices. Emphasis is placed on following a study development process where estimands link the study objectives with data collection and analysis in a coherent manner, thereby avoiding disconnect between objectives, estimands, and analyses.

Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics.

BACKGROUND: Biosimilars provide safety, purity, and potency similar to those of a reference biologic product. METHODS: An array of protein analytical techniques was used to compare the physicochemical properties of proposed biosimilar filgrastim (EP2006), US-approved originator filgrastim, and EU-approved originator filgrastim. Biological characterization involved surface plasmon resonance spectroscopy analyses and in vitro proliferation assays. A randomized, double-blind, two-way crossover, phase I study in healthy volunteers assessed the pharmacodynamics, pharmacokinetics, and safety profiles of EP2006 and US-approved originator filgrastim (administered as a single subcutaneous 10 µg/kg injection). RESULTS: EP2006 and originator filgrastim (US and EU approved) were highly similar with respect to primary, secondary, and tertiary protein structures; mass, size, purity, charge, and hydrophobicity. No differences in receptor binding affinity were observed, and all samples demonstrated similar in vitro bioactivity. In the phase I study, no statistically significant differences between EP2006 and US-approved originator filgrastim were noted in pharmacodynamic or pharmacokinetic parameters, and all confidence intervals were within the equivalence boundaries. The two products had similar safety profiles. CONCLUSION: These studies provide robust evidence of the structural and functional similarity between the proposed biosimilar filgrastim (EP2006) and the US-approved originator filgrastim.

Pharmacokinetics, Safety and Bioequivalence of Levetiracetam Intravenous Infusion and Oral Tablets in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: Levetiracetam is available in China as adjunctive oral therapy for partial-onset seizures. This study was conducted to evaluate the bioequivalence between single-dose intravenous infusion and oral levetiracetam 1500 mg (Part A), and to assess the pharmacokinetics of multiple-dose intravenous infusion at the same dose (Part B) in healthy Chinese subjects. METHODS: Part A was an open-label, crossover comparison (intravenous vs. oral), while Part B was a double-blind, parallel-group study of intravenous levetiracetam versus intravenous placebo administered for 5 days. RESULTS: Bioequivalence was demonstrated between the 45-min intravenous infusion and oral tablets, with geometric mean area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC(∞)) 492.3 and 506.8 µg·h/mL, and geometric mean maximum concentration (Cmax) 65.12 and 55.93 µg/mL for intravenous infusion and oral dosing, respectively. Linear pharmacokinetics were demonstrated (geometric least-squares mean AUC during the dosing interval τ at steady state (AUC(τ,ss)) 475.6 µg·h/mL; geometric least-squares mean AUC(∞) after single dose 501.7 µg·h/mL; linearity factor = 0.948). Geometric mean Cmax (77.44 µg/mL) and AUC(τ,ss) (475.6 µg·h/mL) of intravenous infusion levetiracetam 1500 mg after multiple doses were within the expected range, based on their respective single-dose values and the terminal half-life of levetiracetam after a single dose (7.13 h). A theoretical accumulation of approximately 40% would be expected after multiple doses, which is consistent with the calculated accumulation of 18.0 and 43.5% (Rmax and R(AUC), respectively). CONCLUSIONS: Intravenous infusion of levetiracetam is bioequivalent to oral levetiracetam in healthy Chinese subjects and is a suitable alternative for levetiracetam administration in patients who are temporarily unable to take their medication orally.

Switch from oral pramipexole or ropinirole to rotigotine transdermal system in advanced Parkinson's disease: an open-label study.

OBJECTIVE: Investigate safety, feasibility and efficacy of switching therapy in patients with advanced-stage Parkinson's disease (PD) inadequately controlled with pramipexole (≤ 3.5 mg/day) or ropinirole (≤ 14 mg/day) to rotigotine transdermal system (≤ 14 mg/24 h; dose adjustments ≤ 16 mg/24 h permitted). METHODS: PD0009 (ClinicalTrials.gov: NCT01711866) was an open-label study in patients with advanced-stage PD receiving levodopa, and experiencing sleep disturbance or early-morning motor impairment. Pramipexole/ropinirole was switched to equivalent dose rotigotine overnight or in two stages. During the 4-week treatment period rotigotine dose adjustments were permitted (up to 16 mg/24 h). Primary variable: Clinical Global Impressions (CGI) item 4: side effects (assessing safety) at end of treatment. RESULTS: 79/87 (91%) patients completed the study; 2 (2%) withdrew due to adverse events (AEs). Most (84; 97%) had CGI item 4 score < 3 indicating switch did not interfere with functioning; three experienced drug-related AEs interfering with functioning (score = 3). 62% patients improved on Patient Global Impression of Change, assessing effectiveness. AEs occurring ≥ 5%: application site pruritus (10%), application site erythema (7%), dizziness (7%), dyskinesia (7%), erythema (6%), pruritus (6%). Unified Parkinson's Disease Rating Scale II and III, Parkinson's Disease Sleep Scale-2 and Pittsburgh Sleep Quality Index were unchanged. Numerical improvements in 'off' time, awakenings and nocturias were observed. CONCLUSIONS: Switch from pramipexole or ropinirole to rotigotine (up to 14 mg/24 h) was feasible and possibly associated with some benefit.

Association between painful physical symptoms and clinical outcomes in Chinese patients with major depressive disorder: a three-month observational study.

BACKGROUND: Painful physical symptoms (PPS) may present as a component of major depressive disorder (MDD). Their effect in Chinese patients has not been investigated. This analysis reports the changes in disease severity, treatment patterns, quality of life and outcomes in a Chinese cohort according to the presence (PPS+) or absence (PPS-) of painful physical symptoms. METHODS: A subgroup of Chinese patients from a large observational 3-month study of patients from Asian countries and regions of China were classified using the modified Somatic Symptom Inventory (SSI) as PPS+ (mean score >or= 2) or PPS- (mean score < 2). Depression severity was assessed with the Clinical Global Impression of Severity (CGI-S) scale and 17-item Hamilton depression rating scale (HAMD(17)). Pain severity was measured using a visual analogue scale (VAS), while the EuroQoL (EQ-5D) assessed patient well-being. Antidepressants were compared with regard to their efficacy. RESULTS: Of the 299 Chinese patients enrolled in the study, 105 were classified as PPS+ (73/105, 70% women). At baseline, PPS+ patients reported greater pain severity (VAS, mean (SD): 49.56 (26.49) vs. 16.60 (20.99) for PPS-, P < 0.01), were more depressed (HAMD(17), mean (SD): 25.32 (5.47) vs. 23.33 (5.24) for PPS-, P = 0.002) and had poorer quality of life (EQ-5D Health State, mean (SD): 38.48 (22.38) vs. 49.57 (18.54) for PPS-, P < 0.001). PPS+ patients showed less overall improvement in depressive symptom severity (HAMD(17), change from baseline (95%CI): -17.38 (-18.65, -16.12) vs. -19.20 (-20.05, -18.35) for PPS-, P = 0.032; CGI-S, change from baseline (95%CI): -2.85 (-3.11, -2.58) vs. -3.20 (-3.38, -3.02) for PPS-, P = 0.044). CONCLUSIONS: PPS were less frequent than expected compared with previous studies of Asian populations. PPS+ were associated with greater MDD severity and less improvement than PPS- when antidepressants were given.

Factors associated with weight gain during olanzapine treatment in patients with schizophrenia or bipolar disorder: results from a six-month prospective, multinational, observational study.

The aim of this 6-month observational study was to examine which clinical, eating- and lifestyle-related factors were associated with weight gain in patients initiating or switching to oral olanzapine for the treatment of schizophrenia or bipolar mania. A total of 622 outpatients in four countries (China, Mexico, Romania, Taiwan) were assessed at monthly intervals for up to 6 months. Mixed model repeated-measures analysis, adjusted for baseline weight, was used to identify which factors were associated with weight gain during olanzapine therapy. After 6 months of therapy, the LS mean weight change was +4.1 kg and 43.9% of the patients had significant (> or = 7%) weight gain. Early significant weight gain after 2 months of therapy occurred in 23.4% of the patients and these patients gained significantly more weight overall. Ten factors were associated with weight gain during 6 months of olanzapine therapy in an exploratory multivariate analysis: country, housing conditions, stronger appetite, excessive amount of food needed to feel full, eating until uncomfortably full, thoughts preoccupied with food, meal location, increased meal frequency, evening snack consumption, and a lower amount of vigorous exercise. These results indicate that the influence of environmental, eating- and lifestyle-related factors should be considered when assessing weight gain during olanzapine therapy.

Association between Painful Physical Symptoms and Clinical Outcomes in Korean Patients with Major Depressive Disorder: A Three-Month Observational Study.

OBJECTIVE: This paper aims to examine the association between painful physical symptoms (PPS) and major depressive disorder (MDD) in a naturalistic clinical practice setting within a Korean population. METHODS: Patients with acute MDD that joined a multicountry, observational, three-month study in six Asian countries and regions were classified as PPS+ (mean score >/=2) and PPS- (mean score <2) using the modified Somatic Symptom Inventory. In this analysis, we report the results from the Korean subset, where depression severity was assessed using the Clinical Global Impression of Severity (CGI-S) scale and 17-item Hamilton Depression Rating Scale (HAMD(17)). Pain severity was measured using a visual analogue scale (VAS), while the EuroQoL (EQ-5D) assessed patient well-being. RESULTS: Of 198 patients, 45.96% (91/198) of patients were classified as PPS+, of which 78.02% (71/91) were women. PPS+ patients had significantly more severe depression at baseline {CGI-S score, mean [standard deviation (SD)], PPS+: 5.09 [0.79]; PPS-: 4.63 [0.76]; p<0.001; HAMD(17) total score, mean [SD], PPS+: 24.34 [5.24]; PPS-: 20.76 [5.12]; p<0.001} and poorer quality of life [EQ-5D overall health state, mean (SD), PPS+: 39.37 (20.52); PPS-: 51.27 [20.78]; p<0.001] than PPS- patients. Both groups improved significantly (p<0.001) in depression and pain severity outcomes, as well as quality of life by endpoint, but no significant within-group baseline-to-endpoint change wase observed. CONCLUSION: The frequency of PPS was common in Korean patients with MDD, and was associated with more severe depression, poorer quality of life, and a trend towards poorer clinical outcome.