Shire Development Research Articles

Safety and efficacy of multimatrix mesalamine in paediatric patients with mild-to-moderate ulcerative colitis: a phase 3, randomised, double-blind study

Previous studies have demonstrated the tolerability and efficacy of multimatrix mesalamine in inducing and maintaining remission in adults with mild-to-moderate ulcerative colitis (UC). We evaluated the safety and efficacy of low-dose and high-dose once-daily multimatrix mesalamine in children and adolescents with mild-to-moderate UC or those in remission. This prospective, randomised, parallel-group, phase 3 study (8-week double-blind acute [DBA] phase; 26-week double-blind maintenance [DBM] phase; and an additional 8-week, open-label acute [OLA] phase) was conducted in 33 sites across North America, Europe, and the Middle East between December 12, 2014, and November 28, 2018. Eligible patients aged 5-17 years and weighing 18-90kg were randomised 1:1 to either low (900-2400mg) or high (1800-4800mg) oral doses of multimatrix mesalamine once daily, stratified by body weight. Interactive response technology was used for randomisation. The primary efficacy outcome was to estimate the clinical response of multimatrix mesalamine (two doses) in different weight groups. Efficacy and safety analyses were conducted in the safety analysis set (Clinicaltrials.gov: NCT02093663; Study completed). Overall, 107 patients were randomised into the DBA (n=54) or DBM phase (n=88; directly or after completing the double-blind or OLA phases); the overall safety analysis set included 105 patients. In the DBA phase, the high-dose group (n=17; 65.4%) achieved a higher clinical response rate than the low-dose (n=10; 37.0%) group; difference 28.3% (95% CI: 2.5-54.2; p=0.039), odds ratio (OR) 3.21 (95% CI: 1.04-9.88). In the DBM phase at Week 26, similar proportions of patients maintained clinical response in the low-dose (n=23; 54.8%) and high-dose (n=24; 53.3%) groups: OR 0.99 (0.42-2.34); p=0.981. Overall, 246 treatment-emergent adverse events (TEAEs) were reported in 73 patients (69.5%); 23 TEAEs in 14 patients (13.3%) were considered related to the study drug. No treatment-related deaths were reported. Our findings suggested that the benefit-risk ratio of once-daily multimatrix mesalamine in paediatric patients was favourable and comparable with that reported in adults with mild-to-moderate UC. Shire Development LLC, a Takeda company.

A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States.

Research describing patient experience and outcomes with extended half-life recombinant factor VIII (EHL rFVIII) outside of clinical trials is limited. Real-world rFVIII consumption studies, when people with hemophilia A (PWHA) switch from standard half-life (SHL) to EHL rFVIII, may help payers and clinicians make more informed treatment choices. To conduct a retrospective, observational, U.S.-based analysis to describe clinical and demographic profiles of PWHA who switched to prophylactic rurioctocog alfa pegol. Data were obtained from PWHA treated by 38 prescribers across 21 states using specialty pharmacy database case report forms, electronic medical records, and direct communication with providers, PWHA, or their guardians. Assessments included disease severity, pain severity, number and location of target joints, prior HA therapy, reasons for switching, treatment duration, dosing frequency, adherence, and annualized bleeding rates (ABRs) before and after switching to rurioctocog alfa pegol from SHL or another EHL rFVIII. Data were collected from 56 PWHA. The mean age was 26 years (range = 5-88); median age was 24 years (interquartile range = 14-34); 20% were aged < 12 years; and 89% (50/56) had severe HA. All PWHA had ≥ 12 months of rFVIII treatment before switching to rurioctocog alfa pegol. The population had a mean 1.8 target joints. Baseline subjective pain assessment was mild to moderate for 68% (38/56) of respondents. Before receiving rurioctocog alfa pegol, most PWHA received antihemophilic factor (recombinant) for prophylaxis (73%, 41/56) or breakthrough bleeding (59%, 33/56). Mean dosing frequency for prior prophylaxis was 2.8 per week for SHL rFVIII and 1.8 per week for EHL rFVIII, and 2.2 per week for all PWHA after switching to rurioctocog alfa pegol prophylaxis. The median time on rurioctocog alfa pegol prophylaxis was 12.0 months versus 80.8 months on previous SHL rFVIII and 13.5 months on previous EHL rFVIII. Mean ABRs on prior prophylaxis were 5.9 for SHL rFVIII (n = 35) and 4.7 for EHL rFVIII (n = 3). After switching to rurioctocog alfa pegol, the overall mean ABR reduced by 71% (5.8 to 1.7, P < 0.001) and 20/56 PWHA had no bleeding events. There was also a 20.9% reduction in the mean days per week of factor administration (P < 0.001) after switching to prophylactic rurioctocog alfa pegol. For 47 PWHA who switched from SHL rFVIII, their weekly dose decreased from 109.8 to 100.6 IU per kg with rurioctocog alfa pegol (P = 0.094). The proportion of PWHA with good/complete treatment adherence increased from 68% (38/56) on any prior rFVIII to 80% (45/56) on rurioctocog alfa pegol. The most common reason PWHA switched to rurioctocog alfa pegol was to reduce treatment infusions. Switching from either an SHL or EHL rFVIII to rurioctocog alfa pegol is associated with fewer bleeding episodes owing to more effective prophylaxis and improved adherence. Those who switched from an SHL rFVIII reported reduced factor consumption with rurioctocog alfa pegol. This long-acting factor is an important additional option for the care of PWHA. This study was funded by Shire Development LLC, a Takeda company, Lexington, MA. Trio Health was involved in study design and acquisition, analysis, and interpretation of data and was funded by Shire Development LLC, a Takeda company. Aledort serves on the data and safety monitoring boards of Baxalta U.S. Inc., a Takeda company, and Octapharma; is chair of the scientific advisory board of Kedrion; and receives consultancy fees and honoraria from Baxalta U.S. Inc., a Takeda company. Milligan is an employee of Trio Health and reports research support from AbbVie, Gilead, Merck, Sanofi, and ViiV, unrelated to this study. Watt is an employee of Shire International GmbH, a Takeda company, and owns stock in the company. Booth was an employee of Baxalta U.S. Inc., a Takeda company, at the time of this study and owns stock in the company. Data from this study were presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; April 23-28, 2018; Boston, MA; SETH (2018) Sociedad Espanola de Trombosis y Hemostasia-XXXIV Congreso Nacional; October 11-13, 2018; Grenada, Espana; and Blood 2018 Annual Scientific Meeting; October 21-24, 2018; Brisbane, Australia.

A Design-Around Solution for a MMX-Based Tablet Drug Comprising Mesalazine—A Lesson from Shire Development, LLC v. Watson Pharmaceuticals, Inc.

This article explores Shire Development, LLC v. Watson Pharmaceuticals, Inc., 848 F.3d 981 (Fed. Cir. 2017) and illustrates some implications for designing around a MMX-based tablet drug, Lialda. T...

Growth and sexual maturation in a 2-year, open-label clinical study of lisdexamfetamine dimesylate in children and adolescents with ADHD

IntroductionIndividuals with attention-deficit/hyperactivity disorder (ADHD) may require long-term medication.ObjectivesTo measure growth and sexual maturation of children and adolescents with ADHD receiving lisdexamfetamine dimesylate (LDX) in a 2-year trial (SPD489-404).AimsTo investigate the impact of long-term LDX treatment on growth and maturation.MethodsParticipants (6–17 years) received dose-optimized, open-label LDX (30–70 mg/day) for 104 weeks. Weight, height and BMI z-scores were derived using the Centers for Disease Control and Prevention norms [1]. Sexual maturation was assessed using the Tanner scale (participant-rated as closest to their stage of development based on standardized drawings).ResultsOf 314 enrolled participants, 191 (60.8%) completed the study. Mean z-scores at baseline and last on-treatment assessment (LOTA) were 0.53 (standard deviation, 0.963) and 0.02 (1.032) for weight, 0.61 (1.124) and 0.37 (1.131) for height, and 0.32 (0.935) and–0.27 (1.052) for BMI. In general, z-scores shifted lower over the first 36 weeks and then stabilized. At LOTA, most participants remained at their baseline Tanner stage or shifted higher, based on development of hair (males, 95.5%; females, 92.1%) or genitalia/breasts (males, 94.7%; females, 98.4%).ConclusionsConsistent with previous studies of stimulants used to treat ADHD [2], z-scores for weight, height and BMI decreased, mostly in the first year, then stabilized. No clinically concerning trends of LDX treatment on sexual maturation or the onset of puberty were observed.Disclosure of interestStudy funded by Shire Development LLC.Dr Isabel Hernández Otero (Alicia Koplowitz Foundation, Eli Lilly, Forest, Janssen-Cilag, Junta de Andalucia, Roche, Shire, Shire Pharmaceuticals Iberica S.L., and Sunovion).

Health-related quality of life and work productivity of adults with ADHD: A UK web-based survey

IntroductionEuropean data on health-related quality of life (HRQoL) in adults with attention deficit/hyperactivity disorder (ADHD) in the general population is sparse.Aims and objectivesTo report HRQoL in UK adults with ADHD.MethodsUK residents aged 18–55 years with a diagnosis of adult ADHD completed an online, cross-sectional survey including questions on disease history, the EuroQol Five Dimensions questionnaire with five-levels (EQ-5D-5L) and the Work productivity and activity impairment questionnaire: general health (WPAI:GH). ADHD symptom severity was assessed by telephone using ADHD rating scale version IV with adult prompts (ADHD-RS-IV).ResultsThe survey was completed by 233 participants (65.2% women; 77.3% white British), mean age 32.6 years (standard deviation [SD] 9.5), mean ADHD-RS-IV total score 43.46 (SD 7.88). Their mean EQ-5D-5L utility score of 0.74 (SD 0.21) was lower than the UK population norm of 0.86 (SD 0.23).[1] WPAI:GH scores indicated that health problems resulted in impairments of 32.04% in work productivity and 45.79% in regular daily activities. Regression analyses adjusting for gender, age and comorbidities demonstrated associations between EQ-5D-5L utility scores and gender (men had lower scores, P &lt; 0.001), work impairment due to health problems (increasing impairment was associated with lower scores, P = 0.005) and age (for each additional year of age, scores decreased by 0.007, P = 0.010).ConclusionsThese results highlight the impact on health utility, work productivity and regular daily activities, and add to the description of the disease burden of adult ADHD in the UK.This study was funded by Shire Development LLC.Disclosure of interestKings College London research support account for Asherson received honoraria for consultancy to Shire, Eli-Lilly and Novartis educational/research awards from Shire, Lilly, Novartis, Vifor Pharma, GW Pharma and QbTech speaker at sponsored events for Shire, Lilly and Novartis.

Antihyperlipidemic Medication Treatment Patterns and Statin Adherence Among Patients with ASCVD in a Managed Care Plan After Release of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol.

The American College of Cardiology (ACC) and American Heart Association (AHA) released a new blood cholesterol treatment guideline in November 2013. It is unknown how the new recommendations have affected cholesterol medication use and adherence in a commercial health plan. To evaluate the effect of the 2013 guideline release on antihyperlipidemic treatment patterns and statin adherence in patients with atherosclerotic cardiovascular disease (ASCVD) compared with a historical control group. This study was a historical cohort analysis of adult patients (aged 21-75 years) with clinical ASCVD enrolled in a SelectHealth commercial health plan. Patients were included in the guideline implementation cohort if they had a medical claim with an ICD-9-CM diagnosis of ASCVD in the year before the November 2013 ACC/AHA guideline release. The index date was defined as the first outpatient medical claim with an ICD-9-CM for ASCVD in the first 6 months after the guideline was released. Patients were required to have continuous enrollment for ≥ 1 year before and after the index date. These same criteria were applied to patients exactly 4 years earlier to identify a historical control group. Patients meeting these criteria formed the antihyperlipidemic treatment patterns cohort. Of these, patients who also had ≥1 pharmacy claim for a statin in the 1-year pre- and post-index periods were included in the statin adherence cohort. Antihyperlipidemic treatment patterns were assessed using pharmacy claims for antihyperlipidemic medications in the 1-year pre- and post-index periods. Antihyperlipidemic medication claims were classified as a nonstatin cholesterol medication, low-intensity statin, moderate-intensity statin, or high-intensity statin. To address differences in pre-index antihyperlipidemic medications between the guideline implementation and historical control groups, patients were randomly matched 1:1 based on pre-index classification in a post hoc analysis. Post-index antihyperlipidemic classifications were compared between groups using a Stuart-Maxwell test. The change in mean statin adherence (proportion of days covered [PDC]) was compared within and between groups using paired and independent t-tests, respectively. The proportion of adherent patients (PDC ≥ 0.80) in the pre- and post-index periods was compared between groups using a chi-square test. A multivariable logistic regression was used to compare the likelihood of being adherent in the post-index period while controlling for pre-index adherence and other potential confounders. A total of 7,818 adult members with ASCVD in the index period and 1 year before the index period were identified. Of those, 1,841 patients met the criteria to be included in the analysis, and 1,526 patients were matched on antihyperlipidemic classification and included in the antihyperlipidemic treatment patterns analysis. Baseline characteristics were similar, although the guideline implementation group was younger (58.3 vs. 60.5 years, P < 0.001), and more were male (74.8% vs. 71.3%, P = 0.106) than the historical control group. In the matched cohort, there was a significant difference in the post-index antihyperlipidemic classification (P < 0.001), which appeared to be a result of the difference in nonstatin cholesterol medications (guideline 6.9% vs. historical 13.0%) and high-intensity statins (guideline 23.7% vs. historical 16.3%). Of the 1,841 patients in the antihyperlipidemic treatment patterns cohort, 919 patients met inclusion criteria for the statin adherence analysis. Although PDC decreased over time in both groups, significantly more patients in the guideline implementation group were adherent in the post-index period than the historical control group (66.5% vs. 57.3%, respectively; P = 0.005). Additionally, patients in the guideline implementation group were more likely than the historical control to be adherent in the post-index period when adjusting for potential confounders (OR = 1.49, 95% CI = 1.10-2.03; P = 0.011). Since the release of the updated ACC/AHA treatment guideline, more commercial health plan patients with ASCVD used high-intensity statins and fewer used nonstatin cholesterol medications than historical controls. Additionally, since the guideline release, more patients are adherent to statin therapy than historical controls. This study provides managed care organizations with valuable information regarding the effect of the 2013 ACC/AHA guideline. No outside funding or services were received for this work. Outside of the current study, Bellows has received research funding from Biogen Idec, Regeneron Pharmaceuticals, Myriad Genetic Laboratories, Shire Development, and Bristol-Myers Squibb and an honorariam from Avanir Pharmaceuticals. Voelker received summer intern support from Pfizer and the AMCP Foundation during the time of this study. The remaining authors have nothing to disclose. All authors contributed to study concept and design and to the revision of the manuscript. Bellows, Olsen, and Voelker collected the data, assisted by Wander; data interpretation was performed primarily by Bellows, along with Olsen and Voelker and assisted by Wander. The manuscript was primarily written by Bellows, along with the other authors.

Post HOC Analyses of the Efficacy of Lisdexamfetamine Dimesylate in Adults Previously Treated with Attention Deficit/hyperactivity Disorder Medication.

Introduction Symptoms of attention-deficit/hyperactivity disorder (ADHD) appear in childhood, but often persist into adulthood. The prodrug lisdexamfetamine dimesylate (LDX) is an effective once-daily treatment for the symptoms of ADHD in children, adolescent and adults. Objectives To evaluate post hoc the impact of ADHD medication history on the efficacy of LDX in adults. Methods In this phase 4, double-blind, dose-optimized study, patients aged 18–55 with ADHD and impaired executive function were randomized (1:1) to LDX or placebo for 10 weeks. Patients well controlled on current ADHD medication with acceptable tolerability were ineligible. Self-reported, lifetime ADHD medication histories were recorded at screening. Investigator-rated ADHD Rating Scale IV with adult prompts (ADHD-RS-IV-Adult) was a secondary efficacy measure. Primary efficacy and safety outcomes have been published (J Clin Psychiatry 2013;74:694–702). Results Baseline characteristics were similar across treatment arms and previous ADHD medication subgroups. Differences between LDX and placebo in mean change from baseline to endpoint in ADHD-RS-IV-Adult total score were observed in the overall study population (n=154; –11.1 [95% confidence interval: –14.96, –7.32]; effect size, 0.9), treatment-naive patients (n=80; –11.4 [–16.81, –5.96]; 0.9) and patients previously treated with: any ADHD medication (n=74; –10.9 [–16.50, –5.30]; 0.9), methylphenidate (n=40; –9.9 [–17.44, –2.45]; 0.9), amfetamine (n=38; –13.8 [–20.86, –6.75]; 1.3) and atomoxetine (n=21; –8.4 [–21.97, +5.26]; 0.6). Conclusion In these post hoc analyses, the response to LDX was similar in the overall study population and subgroups of patients categorized by ADHD medication history. Study funded by Shire Development LLC.

P394 Pooled clinical trial analysis of MMX mesalazine safety: Focus on 4.8 g/d dose long-term exposure

Background: Mesalazine (5-aminosalicylic acid) is standard first-line treatment for mild-to-moderate ulcerative colitis (UC), and has been studied for the treatment of diverticulitis (DV). Although there is some evidence of improved efficacy in induction of remission in UC with high-dose treatment, data are limited on the safety of long-term high-dose mesalazine treatment. This analysis examines the safety profile of highdose (4.8 g/d) MMX mesalazine administered for 2 years to patients with DV, pooled from 2 studies. Methods: Two Phase 3, randomized, double-blind, placebocontrolled, multicenter studies (PREVENT1, NCT00545740; PREVENT2, NCT00545103; sponsor, Shire Development LLC) evaluated the efficacy and safety of 3 dose regimens of oncedaily MMX mesalazine (1.2 g, 2.4 g, or 4.8 g) versus placebo in the prevention of recurrent DV in adult patients over a period of 104 wks. Results: A total of 1,182 total patients were enrolled in PREVENT1 and PREVENT2, and 301 were randomized to receive 4.8 g/d MMX mesalazine. Of these, 299 were administered 1 dose of MMX mesalazine (mean [SD] age, 55.6 [11.9] y; 46.8% male). Mean (SD) treatment exposure was 64.4 (42.7)wks. Among patients who received 1 dose of MMX mesalazine, 211 (70.6%) reported 1 treatment-emergent adverse event (TEAE; 1006 events reported); 59 (19.7%) patients experienced only mild TEAEs, 114 (38.1%) experienced TEAEs with a maximum severity of moderate, and 38 (12.7%) experienced severe TEAEs. Serious TEAEs were reported by 32 (10.7%) patients (38 events). A total of 51 (17.1%) patients experienced TEAEs determined to be related to study treatment (102 events), and 4 (1.3%) patients reported serious TEAEs related to study treatment (4 events). A total of 36 (12.0%) patients experienced TEAEs that led to withdrawal from their respective studies. The most frequently reported TEAEs (>5%) were abdominal pain (11.0%), diarrhoea (10.0%), headache (9.3%), back pain (6.3%), urinary tract infection (6.0%), nausea (5.3%), and upper respiratory tract infection (5.3%). Conclusions: Pooled analysis of adverse event data from longterm exposure to MMX mesalazine 4.8 g/d in patients with a history of DV showed that high-dose MMX mesalazine was welltolerated for 2 years.

Reply to L. Reale et al. “More and better should be done to guarantee evidence-based management of ADHD in children across Europe”

Dear Editor We appreciate the interest shown by L. Reale et al. in our recent publication on the management of ADHD in children across Europe [1]. We fully agree with the authors that patients should be managed according to the best available levels of both evidence and treatment, and indeed, this was the motivation for undertaking our study to examine the similarities and differences in real-world management of ADHD in Europe. We acknowledge the limitations of a retrospective study design and clearly discuss these in our paper. The imbalances observed within and between countries demonstrate that a clear, consistent approach to diagnosis and treatment of ADHD is lacking. The use of tools other than DSM-IV or ICD 9/10 for diagnosis in clinical practice highlights the need for diagnostic methods to be standardized across Europe, as the physicians sampled in this study have, in general, large practices and many years of experience. With regard to starting therapy, data on up to five previous treatments were collected in the study, working back from the time of chart abstraction. Only seven patients in our sample (about 1 %) had five or more lines of treatment, so we believe that our data set does include starting therapy information in the majority (99 %) of the study population. As we note in our paper, it is not possible to ascertain whether medication was optimally titrated, which is why we consider that it is important to evaluate further the treatment data in subsequent research studies. In our view, this research, along with other published studies [2], highlights the fact that evidence-based interventions are not always applied by treating physicians, and that, for example, prevalence rates of diagnosed ADHD patients may easily be influenced by the use of different diagnostic tools. Reale et al. also comment that as “only 34.5 % of patients were being treated with combination therapy in accordance with National Institute for Health and Care Excellence (NICE) guidelines [3], only 30.8 % of patients would be expected to show ‘complete symptom control’.” As they have already noted, our study data were collected in 2009 and relate to patients first diagnosed between 2004 and 2007, prior to the publication of the current NICE guidelines, so we would not necessarily expect participating physicians to be following this guidance. It must also be accepted that whilst NICE guidelines provide the expert opinion of optimal ways to support individuals with ADHD, they certainly do not suggest that using these methods will result in “complete symptom control” for all. Our data show a snapshot of current treatment practice at the time of chart abstraction, in a real-world setting. More patients than shown in this snapshot will have received combination therapy at some point during their treatment Debanjali Mitra: affiliation at the time this workwas done and the original article was published P. Hodgkins (*) : J. Setyawan Shire Development, LLC, Wayne, PA, USA e-mail: phodgkins@shire.com

Pharmacokinetics of Coadministered Guanfacine Extended Release and Lisdexamfetamine Dimesylate

BackgroundIn clinical practice, α2-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug–drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.ObjectiveThe primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.Study DesignThis was an open-label, randomized, three-period crossover, DDI study.SettingThe study was conducted in a single clinical research center.ParticipantsForty-two healthy adults were randomized in this study.InterventionsSubjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.Main Outcome MeasuresBlood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90 % confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration–time curve extrapolated to infinity (AUC0–∞) and maximum plasma concentration (C max) falling within the bioequivalence reference interval (0.80–1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).ResultsForty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0–∞ and C max of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90 % CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for C max the upper bound of the 90 % CI exceeded the standard range for bioequivalence by 7 %. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9 % of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3 %) and headache (7.5, 4.9, and 7.3 %) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.ConclusionsIn healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.

957 – Post hoc comparison of the efficacy of lisdexamfetamine dimesylate and osmotic-release oral system methlyphenidate in children and adolescents with adhd

Introduction In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) were more effective than placebo in improving core symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Objectives and aims To compare post hoc the efficacy of LDX and OROS-MPH in study SPD489-325. Methods This 7-week, randomized, double-blind, parallel-group, dose-optimized, placebo-controlled trial enrolled patients aged 6-17 years with ADHD of at least moderate severity. Patients were randomized (1:1:1) to receive a once-daily dose of LDX (30, 50, 70 mg/day), OROS-MPH (18, 36, 54 mg/day) or placebo. Efficacy was assessed using the ADHD Rating Scale version IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Endpoint was defined as the last ontherapy treatment visit with a valid assessment. Results The full analysis set comprised 317 patients (LDX, n=104; placebo, n=106; OROS-MPH, n=107). The difference between LDX and OROS-MPH in least squares mean change (95% confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of LDX (-5.6 [-8.4, -2.7]; p Conclusions This post hoc analysis indicated that LDX is significantly more effective than OROS-MPH in improving core symptoms and global functioning in children and adolescents with ADHD. Supported by: Funding from Shire Development LLC.

958 – Efficacy of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: effect of age, sex and baseline disease severity

Introduction In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) was more effective than placebo in improving symptoms and global functioning in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Objectives and aims To evaluate the impact of age, sex and baseline disease severity on efficacy outcomes in SPD489- 325. Methods This 7-week, double-blind, parallel-group, dose-optimized study enrolled patients aged 6-17 years with ADHD. Patients were randomized (1:1:1) to once-daily LDX (30, 50 or 70mg/day), osmotic-release oral system methylphenidate (OROS-MPH; 18, 36 or 54mg/day) or placebo. Efficacy outcomes were analysed in patients dichotomized by age (6-12 years [n=229] or 13-17 years [n=88]), sex (male [n=255] or female [n=62]) and baseline ADHD Rating Scale version IV (ADHD-RSIV) total score (28-41 [n=161] or 42-54 [n=152]). Endpoint was the last on-treatment visit with a valid assessment. Results At endpoint, differences (active-placebo) in least-squares mean changes from baseline in ADHD-RS-IV total scores were statistically significant in all age, sex and ADHD-RS-IV total score subgroups for LDX (p Conclusions LDX showed greater efficacy than placebo in children and adolescents with ADHD, regardless of their age, sex or baseline disease severity. Supported by: Funding from Shire Development LLC.

Comparison of Pharmacokinetic Parameters of Anagrelide in Healthy Japanese and Caucasian Volunteers

AbstractAbstract 5066 Aim:Currently, it is not fully elucidated how ethnicity influences the pharmacokinetic (PK) profile of anagrelide. The aim of this retrospective analysis was to compare the PK profile of anagrelide in healthy Japanese and Caucasian volunteers. Methods:Retrospective analyses were conducted on two phase I studies with anagrelide: a study of healthy Japanese volunteers (study A) and healthy Caucasian volunteers (study B). In study A, healthy males received anagrelide (0. 5, 1. 0 or 2. 0 mg) or placebo under fasted or fed conditions. In study B, healthy volunteers received a single 1. 0 mg dose under fasted conditions. PK analysis of anagrelide was conducted as part of these original studies. The calculated PK parameters were maximum plasma concentration (Cmax), time for Cmax (tmax), area under plasma concentration from time zero to time infinity (AUC0-inf) and terminal-phase disposition half-life (t1/2). Results:PK data for healthy Japanese males (n=6) aged 20–35 years, with a body weight of 50–80 kg and receiving 1. 0 mg anagrelide in study A were compared with PK data for healthy Caucasian volunteers (n=10, 8 male and 2 female) aged 40–69 years, with a body weight of 56–100 kg and receiving 1. 0 mg anagrelide in study B. Single-dose PK parameters under fasted conditions across both studies are shown in the Table for anagrelide and its metabolite 2-amino-5, 6-dichloro-3, 4-dihydroquinazilone (RL603).TableSingle-dose PK parameters (mean ± SD) in healthy Japanese (n=6) and Caucasian (n=10) volunteers receiving anagrelide, 1 mg fasted administrationAnalyte/PopulationCmax (ng/mL)tmax (h)AUC0-inf (ng·h/mL)t1/2 (h)AnagrelideJapanese4.86±2.401.25±0.6112.82±5.431.42±0.51Caucasian4.88±2.151.15±0.6311.30±3.731.35±0.21RL603Japanese8.55±1.183.00±1.1073.25±13.855.86±0.98Caucasian1.64±0.402.10±0.5718.20±3.866.84±1.58Compared with Caucasian volunteers, healthy Japanese volunteers exhibited similar Cmax, and slightly higher AUC0-inf for anagrelide. In contrast, Cmax and AUC0-inf for the inactive metabolite RL603 were considerably higher in Japanese volunteers. Five adverse events (AEs) were reported in 3 volunteers in study A and 9 AEs in 3 volunteers in study B: 5 and 3 AEs, respectively, were considered possibly related to treatment. The most commonly reported AEs were headache and nausea. No serious AEs were observed during either study. Discussion:The PK analyses conducted on volunteers receiving a single 1 mg dose showed that under fasted conditions anagrelide was rapidly absorbed with similar Cmax and tmax between Japanese and Caucasian volunteers. The slightly higher AUC0-inf of anagrelide in Japanese volunteers may be an artefact of the high inter-subject variability, which is common with drugs such as anagrelide that exhibit extensive pre-systemic metabolism. It remains unclear as to why Japanese volunteers had higher RL603 Cmax and AUC0-inf values than Caucasian individuals.Analyses of PK data from studies of patients with essential thrombocythaemia (ET) (Okamoto et al, manuscript in preparation; Besses et al, Int J Clin Pharmacol Ther, 2012, manuscript in press) noted that compared with non-Japanese patients, Japanese patients also had slightly higher Cmax (2. 81±0. 99 vs 5. 88±4. 58 ng/mL) and AUC (6. 8±2. 4 vs 16. 3±6. 5 ng·h/mL) for anagrelide. Overall, across both ethnic groups, patients with ET had higher anagrelide exposures than healthy volunteers. However, within the Japanese population, Cmax and AUC0-inf values were only slightly higher in patients with ET than in volunteers, which may suggest that the PK exposures of anagrelide did not differ substantially between these Japanese cohorts. Conclusion:Anagrelide exhibits high inter- and intra-subject variability, which makes it difficult to compare PK exposures in studies with small populations. The PK data across all these studies indicate that the first-pass metabolism of anagrelide may be marginally lower in the Japanese population than in Caucasian individuals; however these differences do not translate to different clinical outcomes with respect to the observed treatment-related AEs associated with anagrelide therapy. Despite the small differences observed in metabolism of anagrelide, it is well tolerated in Japanese populations and ethnicity-specific dosing regimens are not required. Disclosures:Kanakura:Shire: Consultancy. Hodgson:Shire Pharmaceutical Development Ltd: Employment. Troy:Shire Development, LLC: Employment. Abhyankar:Shire Pharmaceuticals: Employment. Smith:Shire Pharmaceuticals: Employment. Besses:Shire: Honoraria; Novartis: Honoraria.

The Effect of Ulcerative Colitis (UC) Remission Status After Induction With MMX® Mesalamine on Long-Term Maintenance Therapy Outcomes (MOMENTUM Study): Induction Phase Results Presidential Poster

Purpose: 5-aminosalicylic acid therapy is the mainstay of treatment for mildly-to-moderately active UC. However, data are lacking for long-term outcomes with maintenance therapy and transitions from induction phase to maintenance phase. Methods: This is an open-label, prospective study evaluating 12-month results in UC patients who achieved complete (clinical and endoscopic) or partial remission after 8 weeks of induction therapy with MMX® mesalamine (NCT01124149). Adults with active mild-to-moderate UC (acute flare or newly diagnosed with modified UC Disease Activity Index [UC-DAI] total score 4-10, endoscopy score ≥1, and Physician's Global Assessment ≤2) received 8 weeks of MMX mesalamine 4.8 g/d QD during acute treatment. Those patients who achieved complete remission (modified UC-DAI ≤1; rectal bleeding and stool frequency scores of 0; ≥1-point reduction in endoscopy score) or partial remission (modified UC-DAI ≤3; combined stool frequency and rectal bleeding score ≤1; not in complete remission) at Week 8 continue to receive maintenance MMX mesalamine 2.4 g/d QD for 12 months (ongoing portion of the study). The primary endpoint is the percentage of patients in complete remission after 12 months of maintenance. Here we report results from the 8-week induction phase. Results: This pre-determined interim data cut included 672 patients, of whom 666 are included in the efficacy/safety population. The induction phase was completed by 610 patients and 467 entered the maintenance phase; 664 (99.7%) had histology compatible with UC. At Week 3, symptom improvement (≥1-point reduction from baseline) was observed in 43.1%, 38.9%, and 26.3% of patients for rectal bleeding, stool frequency, or both, respectively; at Week 8, these proportions increased to 63.4%, 62.2%, and 48.0%, respectively. Complete or partial remission was achieved by 27.9% and 42.2% of patients at Week 8, and complete mucosal healing (endoscopic subscore of 0) was achieved by 33.3%. Mean ± SD UC-DAI score decreased by 4.3 ± 2.24 points after the 8-week induction phase. The most common treatment-emergent adverse events during the induction phase were inefficacy of drug (6.5%), headache (1.8%), and fever (1.8%). Conclusion: This is the largest study of MMX mesalamine for mild to moderate UC and the 8 week induction results demonstrated a majority with partial or complete remission, and 33% with normal endoscopy (subscore of 0). There were no new safety signals. Unique to this study design is the enrollment of all patients during a flare with follow-through to maintenance phase (to be reported later). Disclosure: David T. Rubin - Financial Support for Research: Abbott, Elan, Warner Chilcott, Prometheus, Shire Development LLC; Lecture Fee(s): Merck; Consultancy: Abbott, Janssen, UCB, Elan, Shire, Exagen, Prometheus, Takeda. Geert D'Haens - Financial Support for Research: Abbott Laboratories, Jansen Biologics, Given Imaging, MSD, DrFalk Pharma, Photopill, Shire Development LLC; Lecture Fee(s): Abbott Laboratories, Tillotts, Tramedico, Ferring, MSD, UCB, Norgine, Shire; Consultancy: Abbott Laboratories, Actogenix, Centocor, Cosmo, Engene, Ferring Pharmaceuticals, GlaxoSmithKline, Jansen Biologics, Millenium Pharmaceuticals, MSD, Novonordisk, PDL Biopharma, Pfizer, SetPoint, Shire, Takeda, Teva, UCB Susi Inglis. Elizabeth Magee - Employees: Shire Pharmaceutical Development Ltd. Dory Solomon - Employee: Shire Development LLC. This research was supported by an industry grant. This study was funded by Shire Development LLC, Wayne, PA, USA.

P-339 - Effect of lisdexamfetamine dimesylate on functional impairment in children and adolescents with attention-deficit/hyperactivity disorder

Lisdexamfetamine dimesylate (LDX) is the first long-acting, prodrug stimulant, and is approved in the USA, Canada and Brazil for the treatment of attention-deficit/hyperactivity disorder (ADHD). To evaluate the effect of LDX on functional impairment in patients with ADHD, using the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P). A randomized, double-blind, placebo-controlled trial of an optimized daily dose of LDX was conducted in children and adolescents (6–17 years) with ADHD in Europe. A 4-week dose-optimization period was followed by 3-weeks of dose-maintenance. The WFIRS-P was completed at baseline, day 28 and endpoint. A decrease from baseline indicated an improvement in functional outcomes. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment arm. Of 336 randomized patients, 317 were included in the full analysis set and 196 completed the study. Baseline mean (SD) WFIRS-P total scores were similar across treatment groups: LDX, 1.01 (0.45); placebo, 1.10 (0.46); OROS-MPH, 1.07 (0.44). The least squares (LS) mean decrease (95% confidence intervals) in WFIRS-P total score from baseline to endpoint was statistically significantly greater with LDX than with placebo (difference of −0.3 [−0.4, −0.2], p < 0.001), with an effect size of 0.924 for LDX. The difference in LS mean change from baseline to endpoint between OROS-MPH and placebo was −0.2 (−0.3, −0.1; p < 0.001) in favour of OROS-MPH (effect size, 0.772). LDX was more effective than placebo in improving functional impairments in children and adolescents with ADHD. By funding from Shire Development Inc.

P-257 - The negative impact of attention deficit hyperactivity disorder on adult daily life: results of the european lifetime impairment survey

Introduction Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder in childhood (estimated global prevalence 3–5%). ADHD symptoms and impairments frequently continue into adulthood, but data on lifelong impact are limited. Objectives The Lifetime Impairment Survey aimed to evaluate the extent of lifetime impairment of individuals with ADHD in six European countries. We analysed the responses obtained from adults with/without ADHD regarding their current situation. Methods The survey was developed by a committee of ADHD specialists and implemented by a market research organization. Participants were recruited from a database of 487,533 volunteers, and answered questions on ADHD diagnosis and current experiences. Survey items were combined into scales/scores evaluating different areas of impairment. Mean scale scores for ADHD and controls were compared. Cross-country comparisons of impairment scales were also performed. Results A total of 629 adults with ADHD and 736 controls participated. ADHD was diagnosed after a median of 22 months and after consulting a median of two physicians. Impairments reported by adults with ADHD were significantly greater (p Conclusions Compared with controls, the impairments reported by adults with ADHD suggest a continued impact of the condition on both personal and professional life; no substantial cross-cultural differences were observed. Study supported By Shire Development Inc.

Cost of Illness and Comorbidities in Adults Diagnosed With Attention-Deficit/Hyperactivity Disorder

This retrospective study assessed the cost of illness and medical and psychiatric comorbidities in adults with attention-deficit/hyperactivity disorder (ADHD) compared with adults without ADHD (matched 1:3) and adults with depression (1:1). Individuals with depression were included as a benchmark against which the burden of ADHD could be measured. Measures of health care and employment-related costs were compared to generate estimates of medical expenditures, workplace absences, and comorbidities in adults with ADHD (using ICD-9-CM codes) who were enrolled in employer-sponsored health plans throughout 2006. Individuals with ADHD (31,752) were matched with 95,256 non-ADHD controls. The majority of individuals with ADHD (n = 29,965) were also matched with an equal number of individuals with a depression diagnosis (using ICD-9-CM codes). In this adult population with ADHD enrolled in an employer-sponsored health plan, medical and psychiatric comorbidities were the primary drivers of health care utilization and cost. Of note, depression was significantly prevalent among those with ADHD compared to matched non-ADHD controls (14% vs 3.2%; P ≤ .0001). Subgroup analysis demonstrated that ADHD patients with depression had a significantly higher number of medical and other psychiatric comorbid illnesses including diabetes, hypertension, asthma, irritable bowel syndrome, bipolar disorder, anxiety, alcohol abuse, and substance abuse compared to those with ADHD alone (P ≤ .0001). Patients with ADHD incurred higher total annual health care expenditures than control subjects ($4,306 vs $2,418); approximately 15% of costs were paid by the patient. The total annual costs associated with productivity losses were also higher (driven by differences in short-term disability costs) in the ADHD group compared with controls ($4,403 vs $4,209). Medical and psychiatric comorbidities were primary drivers of the direct health care cost associated with ADHD in adult patients. The present study demonstrated that the total costs of ADHD among adults are doubled when indirect costs associated with workplace productivity losses are included.

P01-296-Comparison of the burden of illness for adults with adhd across seven countries: a qualitative study

IntroductionAround 65% of children with ADHD continue to be impaired by symptoms in adulthood. Nevertheless, ADHD in adults is often poorly understood and misdiagnosed globally, notably in Europe. Furthermore, few data are available comparing the experiences of adult patients with ADHD from different geographical regions.ObjectivesTo examine the symptoms and impairments associated with ADHD in adults from the patient's perspective and to better understand how culture, country of residence and different ADHD management approaches can impact on the experiences of adults with the condition.MethodsData were obtained from focus groups in the USA, Canada, UK, The Netherlands, Italy, France and Germany. Patients participated in semi-structured interviews using a series of open-ended questions relating to medical history, life experience, daily impacts of ADHD and psychological and social issues. Transcripts of the interviews were analysed based on grounded theory qualitative data analysis methodology.ResultsData from 14 focus groups representing 103 adults with ADHD (mean age 36, 47% female) were analysed. Reported impacts were consistent across focus groups with respect to the participants’ history of diagnosis, symptoms, medication use, childhood experiences, and psychological and social issues as adults, regardless of country of residence, culture, treatment patterns or health care systems. Minimal differences were reported with respect to the perception of ADHD, treatment options and costs of care. This poster will focus on European results.ConclusionThe burden of illness and impacts of ADHD in adults are largely independent of culture or country of residence.Supported by Shire Development, Inc.

P01-574 - Long-term outcomes of ADHD: Global and regional study publication trends

IntroductionAs awareness of ADHD has increased throughout the world, interest has grown beyond the constellation of ADHD symptoms, including long-term effects and impact on people's lives.ObjectivesTo examine the consequences of childhood ADHD and the relevance of these outcomes in different world regions.AimsThis analysis examined the publication trends of studies of long-term outcomes of ADHD over time and among world regions.MethodsStudy identification followed Cochrane guidelines. Twelve databases were searched for reports published in English 1980–2010. Limiting criteria were designed to maximize study inclusion while maintaining a high level of study rigor: the studies were to(1)be peer-reviewed,(2)be primary study reports,(3)include a comparator group or baseline, and(4)report outcome results measured for a mean of 8 years (prospective studies, range of all studies was 6 months-40 years) after the start of the study, in late adolescence, or adulthood.The fully-defined electronic search yielded 4615 citations, which were then reviewed manually based on the titles and abstracts, yielding a final of 371 studies.ResultsStudy publication trends analysed included: publication year, country and world region of origin, outcome types, and study types. In general, the numbers of studies published per year globally has increased substantially (from 2 in 1980 to more than 40/year in 2007 and 2008) with differences observed between Europe and North America.ConclusionsAnalysis of publication trends can provide insight into outcomes of ADHD and the focus of specific world regions.Supported by Shire Development Inc.

P01-278 - Consortium for the lifespan examination of ADHD registry (Clear): An update on methodology and recruitment

IntroductionADHD is often unrecognised and untreated, particularly in Europe. There is a need for improved understanding of ADHD in adults and its impact on patients across the lifespan. Registries allow for multiple real-world comparisons based on assessment of patients that are typically excluded from clinical studies. Data describing the cost, burden and consequences of ADHD are essential to inform clinicians, regulatory agencies, payers and patients about the condition.ObjectivesTo address the gaps in our current understanding of the care and cost of treating adult patients with ADHD by documenting real-life experiences.MethodsA prospective, longitudinal, observational study of adults &gt; 18 years with ADHD, designed to follow 2500 patients in the USA, UK, Germany, The Netherlands and Canada for a minimum of 5 years.In year one, patients will be asked questions regarding:the impact of childhood diagnosis and/or treatment on adult ADHD, long- and short-term treatment patterns and their consequences, differences between ADHD treatments, the relationship between disease severity and compliance with treatment, increased tendency to risk behaviour/substance abuse, costs.In subsequent years, topics may be expanded to include the transition into adulthood and healthcare access for young adults.ResultsTen sites are currently recruiting, with 45 patients enrolled up to 7 October 2010. Challenges associated with initiating a global registry in North America and Europe will be discussed.ConclusionData generated from CLEAR will help improve the global understanding of the longitudinal impact of ADHD.Supported by Shire Development, Inc.