Three Times Daily Research Articles

Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis.

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.).

ACID BASE, ION DISORDERS, LITHISASIS

Introduction and Aims: Hyperkalaemia is a risk factor for mortality in patients with cardiovascular disease and chronic kidney disease (CKD) (Goyal, 2012; Torlen, 2012) and limits use of renin-angiotensin-aldosterone system inhibitors (RAASi) in these patients. Sodium (or calcium) polystyrene sulfonate (SPS/CPS) has uncertain efficacy and has been associated with substantial adverse events, as well as poor gastrointestinal tolerability, and hence is suboptimal for acute use and unsuitable for chronic use (Harel, 2013; Sterns, 2010). Therefore, there is a need for a hyperkalaemia treatment that rapidly reduces serum potassium (K+) and is safe and well tolerated in these patients. ZS-9, a nonabsorbed cation exchanger designed to specifically entrap excess K +, significantly reduced K+ vs placebo over 48 hr with excellent tolerability in patients with CKD (Ash, 2013). We report acute-phase efficacy in a Phase 3 trial of ZS-9 in patients with hyperkalemia. Methods: Patients (N=753) with serum K+ 5.0-6.5 mmol/L were randomised (1:1:1:1:1) to ZS-9 (1.25g, 2.5g, 5g or 10g) or placebo given three times daily (TID) with meals for 48 hr (acute phase), after which those with K+ ≤4.9 mmol/L (n=542) were re-randomised to ZS-9 or placebo once daily for Day 3-15. Serum K+ was measured at baseline and at predefined intervals, including 1, 4, 24, and 48 hr after the first dose. The acute-phase primary efficacy endpoint was the rate of K+ change over the first 48 hr, using longitudinal modeling to account for all post-baseline data. Results:Mean K+ at baseline was 5.3 mmol/L. Substantial percentages of patients had CKD (60%), a history of heart failure (40%), or diabetes (60%) or were on RAASi therapy (67%). ZS-9 demonstrated significant dose-dependent reductions in K+; the acute-phase primary efficacy endpoint was met for ZS-9 2.5g (p=0.0009), 5g (p<0.0001) and 10g TID (p<0.0001; Fig. 1). There was a significant decrease in K+ by -0.11 mmol/L with ZS-9 10g vs an increase of +0.01 mmol/L with placebo (p=0.009) 1 hr after the first dose. At 48 hr K+ fell by -0.73 mmol/L with 10g TID vs -0.25 mmol/L with placebo (p<0.001); other significant reductions vs placebo are shown in Fig 2. Rates of all adverse events (AEs) and gastrointestinal AEs were not significantly different in the ZS-9 and placebo groups. Conclusions: ZS-9 produced significant dose-dependent reductions in K+ when given TID for 48 hr, with an AE profile similar to placebo. The significant reduction in serum K+ 1 hr after the first ZS-9 10g dose further suggests that ZS-9 is effective in removing K+ from the small intestine fluid, where it is in equilibrium with blood levels. ZS-9 may address an important unmet clinical need by rapidly correcting hyperkalaemia in high-risk patients, many of whom require RAASi for end-organ protection. SP321 PHASE 3, MULTICENTER, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALOF ZS-9: SUBGROUP ANALYSIS STRATIFIED BY BASELINE SERUM POTASSIUM LEVELS

Lower-dose diclofenac capsules developed using solumatrix fine particle technology result in clinically meaningful improvements in pain in a phase 3 study of patients with osteoarthritis

Lower-dose diclofenac capsules developed using solumatrix fine particle technology result in clinically meaningful improvements in pain in a phase 3 study of patients with osteoarthritis

Once versus three times daily dosing of oral budesonide for active Crohn's disease: A double-blind, double-dummy, randomised trial

BackgroundOral budesonide 9mg/day represents first-line treatment of mild-to-moderately active ileocolonic Crohn's disease. However, there is no precise recommendation for budesonide dosing due to lack of comparative data. A once-daily (OD) 9mg dose may improve adherence and thereby efficacy. MethodsAn eight-week, double-blind, double-dummy randomised trial compared budesonide 9mg OD versus 3mg three-times daily (TID) in patients with mild-to-moderately active ileocolonic Crohn's disease. Primary endpoint was clinical remission defined as CDAI <150 at week 8 (last observation carried forward). ResultsThe final intent-to-treat population comprised 471 patients (238 [9mg OD], 233 [3mg TID]). The confirmatory population for the primary endpoint analysis was the interim per protocol population (n=377; 188 [9mg OD], 189 [3mg TID]), in which the primary endpoint was statistically non-inferior with budesonide 9mg OD versus 3mg TID. Clinical remission was achieved in 71.3% versus 75.1%, a difference of −3.9% (95% CI [−14.6%; 6.4%]; p=0.020 for non-inferiority). The mean (SD) time to remission was 21.9 (13.8) days versus 21.4 (14.6) days with budesonide 9mg OD versus 3mg TID, respectively. In a subpopulation of 122 patients with baseline SES-CD ulcer score ≥1, complete mucosal healing occurred in 32.8% (21/64) on 9mg OD and 41.4% (24/58) on 3mg TID; deep remission (mucosal healing and clinical remission) was observed in 26.6% (17/64) and 32.8% (19/58) of patients, respectively. Treatment-emergent suspected adverse drug reactions were reported in 4.6% of 9mg OD and 4.7% of 3mg TID patients. ConclusionsBudesonide at the recommended dose of 9mg/day can be administered OD without impaired efficacy and safety compared to 3mg TID dosing in mild-to-moderately active Crohn's disease.

Prevention of Recurrent Ischemic Priapism with Ketoconazole: Evolution of a Treatment Protocol and Patient Outcomes

The management of recurrent ischemic priapism (RIP) is not clearly defined. Ketoconazole (KTZ) is used to treat RIP and produces a temporary hypogonadal state to suppress sleep-related erections (SREs), which often evolve into episodes of ischemic priapism in this population. We review our experience to prevent RIP using KTZ and present our outcomes using a decreased dose regimen. A retrospective chart review and phone survey of 17 patients with RIP was performed. KTZ inhibits adrenal and gonadal testosterone production with a half-life of 8 hours. By suppressing testosterone levels, SREs are interrupted. We compared our previous protocol of three times daily (TID) KTZ dosing with prednisone for 6 months with our current regimen of initiating KTZ 200 mg TID with prednisone 5 mg daily for 2 weeks and then tapering to KTZ 200 mg nightly for 6 months. The primary outcome was the prevention of RIP using KTZ. Secondary outcomes included side effects secondary to KTZ use and patient satisfaction. All men experienced daily or almost daily episodes of prolonged, painful erections prior to starting KTZ. The mean number of emergency room (ER) visits per patient prior to starting KTZ was 6.5. No patient required an ER visit for RIP while on KTZ. Sixteen of 17 patients (94%) had complete resolution of priapism while on KTZ with effects noted immediately after starting therapy and no reported sexual side effects attributed to KTZ. One man stopped therapy after 4 days because of nausea/vomiting. Fourteen of 16 men eventually discontinued KTZ after a median duration of 7 months. Twenty-nine percent reported no recurrent priapic episodes after discontinuing. A total of 78.6% had partial or complete resolution of symptoms persisting after KTZ was discontinued with a mean post-treatment follow-up of 36.7 months. No reliable effective preventative therapy has been identified for RIP. In our relatively sizable single-center experience, KTZ appears to be a reasonably effective, safe, and inexpensive treatment to prevent RIP while preserving sexual function. We now recommend our tapered dose regimen listed above. After 6 months, we recommend stopping the medication as we have found a majority of patients will not need to resume nightly KTZ.

How should propranolol be initiated for infantile hemangiomas: Inpatient versus outpatient?

How should propranolol be initiated for infantile hemangiomas: Inpatient versus outpatient?

Acute intermittent porphyria with psychiatric manifestations: A case report

The porphyrias are a group of eight genetic disorders of heme biosynthesis that result from the deficient activity of a certain enzyme in the biosynthesis pathway. These disorders are separated by symptom manifestation and classified as acute porphyrias and cutaneous porphyrias. One of the acute porphyrias, acute intermittent porphyria (AIP), is caused by a prophobilinogen deaminase deficiency and usually presents as abdominal pain, nausea, constipation, and confusion.

Neuroradiological efficacy of oral BG-12 for relapsing–/INS;remitting multiple sclerosis (RRMS): Integrated analysis of the Phase 3 DEFINE and CONFIRM studies

Neuroradiological efficacy of oral BG-12 for relapsing–/INS;remitting multiple sclerosis (RRMS): Integrated analysis of the Phase 3 DEFINE and CONFIRM studies

Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease

ObjectiveIPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients. MethodsThis was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopa-naïve patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39). ResultsAll IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P < 0.0001). The mean improvement in UPDRS Parts II + III at 30 weeks compared to baseline was 11.7, 12.9, and 14.9 points for the three dosages and 0.6 points for placebo (P < 0.0001, all dosages). PDQ-39 total scores improved with IPX066 (P ≤ 0.034, all dosages). The most commonly reported adverse events with IPX066 included nausea, dizziness, and headache. No unexpected drug-related serious adverse events were reported. ConclusionIPX066 provided significant clinical benefits at the three dosages tested compared to placebo and was well tolerated in levodopa-naive PD patients. Of the dosages tested, IPX066 145 mg TID appeared to provide the best overall balance between efficacy and safety.

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the DEFINE study

In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium-enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68% [hazard ratio 0.32 (95% confidence interval (CI) 0.16-0.62)] to 26% [0.74 (0.51-1.09)] and from 66% [0.34 (0.23-0.50)] to 25% [0.75 (0.42-1.36)] with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the CONFIRM study

In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics.

Responsiveness of a Tri-Component Endpoint in Non-Constipation Irritable Bowel Syndrome: Pooled Results from Two Phase 3 Trials, TARGET 1 and TARGET 2

Purpose: Current FDA guidance suggests the use of a composite endpoint that includes two primary symptoms of IBS with diarrhea (IBS-D): abdominal pain and stool consistency. Because this endpoint may not capture otherwise unmeasured GI symptoms such as urgency and bloating, which may be important to patients with IBS-D, we sought to evaluate the responsiveness of a tri-component endpoint that includes daily assessment of abdominal pain and stool consistency as recommended by the FDA guidance as well as daily assessment of global IBS symptoms. Methods: Patients with mild-to-moderate non-constipation IBS (N=1260) were randomized to rifaximin 550 mg three times daily (TID) or placebo for two weeks and evaluated for 10 weeks post treatment. The primary results of these trials have been previously published. Patients rated daily IBS symptom severity for global IBS symptoms and IBS-related abdominal pain using a 7-point scale (0=not at all - 6=a very great deal). Stool consistency was rated using a 5-point scale (1=very hard-5=watery). The proposed tri-component endpoint defines the weekly responders as patients who reported ≥30% improvement from baseline in abdominal pain, had ≥50% improvement in the number of days in a week with stool consistency of loose or watery compared with baseline, and had ≥1 point improvement in weekly average score of daily global IBS symptoms. Responsiveness (ability to detect change) was assessed (Wilcoxon rank-sum test) by comparing the change from baseline in each daily question between weekly responder and non-responder. Spearman rank correlation coefficients were calculated to assess the correlations among weekly responders and daily measures of efficacy. Results: For each study and the combined data, the responders defined by the tri-component endpoint had significantly greater improvements in all daily IBS symptom severity measures than non-responders at each week during the course of the study, demonstrating it was a responsive endpoint. The tricomponent endpoint also demonstrated evidence for convergent validity as it consistently correlated with all daily IBS symptom severity measures at each week during the course of the study based on a Spearman's correlation of 0.40 or greater with other daily symptom severity measures. Conclusion: The tri-component endpoint, which adds a global assessment of IBS symptoms to the FDA's guidance endpoint, is a responsive endpoint that correlates with all daily IBS symptoms. Further study with this endpoint is warranted in patients with IBS-D. Disclosure: Salix Pharmaceuticals, Inc. provided all study drug and research funding for these studies. Dr. Lembo - Consultant and Speaker: Salix Pharmaceuticals, Inc.; Dr. Pimentel - Consultant, Speaker, and Investigator: Salix Pharmaceuticals, Inc.; Dr. Yu - Employee and Stockholder: Salix Pharmaceuticals, Inc.; Dr. Paterson - Employee and Stockholder: Salix Pharmaceuticals, Inc.; Dr. Bortey - Employee and Stockholder: Salix Pharmaceuticals, Inc.; and Dr. Forbes - Employee and Stockholder: Salix Pharmaceuticals, Inc. This research was supported by an industry grant from Salix Pharmaceuticals, Inc.

Effects of BG-12 on Magnetization Transfer Ratio in Whole Brain and Normal-Appearing Brain Tissue: Findings from the DEFINE Study (S11.004)

Objective: To report the BG-12 effects on magnetization transfer ratio (MTR) in the Phase 3 DEFINE study. Background Brain MTR measurements are considered to be sensitive to changes in myelin and axonal content, with increases reflecting higher concentrations of myelin and axons. DEFINE examined MTR changes with BG-12 treatment in the magnetic resonance imaging cohort. Design/Methods: DEFINE was a randomized, double-blind, placebo-controlled study evaluating BG-12 over 2 years in relapsing-remitting multiple sclerosis (RRMS). Patients aged 18-55 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale score of 0.0-5.0 were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). MTR was analyzed in whole brain (WB) and normal-appearing brain tissue (NABT) at baseline, 1, and 2 years. Results: MTR analysis included 392 patients. In WB, mean percentage change from baseline at 2 years in median MTR was -0.386% in the placebo group versus 0.129% ( P =0.0027) and 0.096% ( P =0.0051) with BID and TID, respectively, indicating significant increases relative to placebo. In NABT, mean percentage change from baseline at 2 years in median MTR was -0.392% with placebo versus 0.190% ( P =0.0006) and 0.115% ( P =0.0029) with BG-12 BID and TID, respectively. The post hoc analysis performed on patients with no new/enlarging T2 lesions (N=147) demonstrated decreased WB MTR with placebo (mean percentage change, -0.379%), but increased WB MTR with the BG-12 BID (mean percentage change, 0.286%; P =0.0293) and TID (mean percentage change, 0.170%; P =0.0538) groups at 2 years. Likewise, MTR in NABT decreased in the placebo group (mean percentage change, -0.312%) and increased in the BID (mean percentage change, 0.314%; P =0.0285) and TID (mean percentage change, 0.171%; P =0.0644) groups at 2 years. Conclusions: DEFINE MTR results demonstrate increased brain MTR in BG-12-treated patients, potentially reflecting protective effects leading to increased myelin and axonal content. Supported by: Biogen Idec Inc. Disclosure: Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Ms. Yang has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

BG-12 Increases the Proportion of Patients Free of Clinical and Radiologic Disease Activity in Relapsing-Remitting Multiple Sclerosis: Findings from the DEFINE Study (PD5.005)

Objective: To evaluate the impact of BG-12 (dimethyl fumarate) on the proportion of patients with relapsing-remitting multiple sclerosis (RRMS) who were free of clinical or magnetic resonance imaging (MRI) disease activity in the Phase 3 DEFINE study. Background DEFINE was a 2-year randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of BG-12 in patients with RRMS. In DEFINE, BG-12 significantly reduced clinical relapses, disability progression, and MRI measures of disease activity. Design/Methods: Patients aged 18-55 years with a diagnosis of RRMS and an Expanded Disability Status Scale (EDSS) score of 0.0-5.0 were included in the study. Patients were randomly assigned 1:1:1 to placebo, BG-12 240 mg twice daily (BID) or three times daily (TID). In the current analysis, absence of disease activity over 2 years was analyzed as follows: clinical (no relapses or EDSS progression), radiologic (no new or newly enlarging T2 lesions and gadolinium-enhancing lesions), and overall (no clinical and radiologic disease activity). Analyses of disease-free measures were performed on the MRI cohort using a chi-square test and logistic regression model. Results: The analysis included 469 patients with MRI measures. The proportion of disease-free patients over 2 years was significantly higher in both BG-12 treatment groups versus placebo: clinical (BID 63% and TID 59% vs placebo 39%; P P P Conclusions: Findings from this subset analysis of DEFINE indicate that BG-12 demonstrated a significant treatment effect on clinical, radiologic, and overall disease-free activity compared with placebo over 2 years in patients with RRMS. Supported by: Biogen Idec Inc. Disclosure: Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Sheikh has received personal compensation for activities with Biogen Idec as an employee. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Effect of BG-12 in Subgroups of Patients with Relapsing-Remitting Multiple Sclerosis: Findings from the DEFINE Study (P01.130)

Objective: To assess the efficacy of BG-12 in subgroups of patients from the Phase 3 DEFINE study. Background BG-12 is an experimental oral treatment for relapsing-remitting multiple sclerosis (RRMS) that may have anti-inflammatory and neuroprotective effects via the Nrf2 pathway. DEFINE, a randomized, double-blind, placebo-controlled, multicenter study evaluating BG-12 over 2 years in patients with RRMS, showed significant reductions in clinical relapses, accumulation of disability progression, and disease activity on magnetic resonance imaging scans. Design/Methods: Patients 18-55 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale score of 0.0-5.0 were randomized to placebo, BG-12 240 mg twice daily (BID), or BG-12 240 mg three times daily (TID). Subgroup analyses were based on baseline demographic and disease characteristics, including age, relapses in year prior to study entry (≤1 versus ≥2 relapses), prior MS treatment (yes/no), baseline EDSS score (≤ or >2.0), and others. Effects of BG-12 on primary efficacy endpoint and secondary clinical endpoints at 2 years were evaluated. Results: Both doses of BG-12 demonstrated consistent benefits on relapse and disability progression across all subgroups over 2 years. For instance, in patients who had ≤1 relapse in the year prior to study entry, the hazard ratio (HR [95% CI]) for risk of relapse over 2 years was 0.52 [0.38-0.71] for BG-12 BID and 0.51 [0.37-0.70] for BG-12 TID, representing reductions relative to placebo of 48% and 49%, respectively, whereas in patients who had ≥2 relapses in the year prior to study entry, reductions were 49% (0.51 [0.34-0.77]) and 51% (0.49 [0.32-0.74]). Likewise, both BG-12 doses demonstrated positive benefits on annualized relapse rate and disability progression regardless of the number of relapse in the year prior to study entry. Conclusions: BG-12 treatment resulted in reduction of clinical activity across RRMS patients with varied demographic and disease subgroups. Supported by: Biogen Idec Inc. Disclosure: Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. O9Gorman has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Clinical Efficacy of BG-12 in Relapsing-Remitting Multiple Sclerosis (RRMS): Data from the Phase 3 CONFIRM Study (S01.003)

Objective: To describe the efficacy of BG-12 (dimethyl fumarate) in patients with RRMS in the Phase 3 CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis) study. Background BG-12 demonstrated significant reductions in the proportion of patients relapsed, annualized relapse rate (ARR), and disability progression versus placebo in RRMS patients in DEFINE, the first of two Phase 3 studies. Design/Methods: CONFIRM was a multicenter, randomized, placebo-controlled, reference comparator study that evaluated the efficacy and safety of BG-12 over 2 years in RRMS patients. Patients (18–55 years) with a diagnosis of RRMS per McDonald criteria and an Expanded Disability Status Scale (EDSS) score of 0.0–5.0 were enrolled. CONFIRM evaluated BG-12 240 mg twice (BID) and three times daily (TID) versus placebo and included an active reference comparator arm with subcutaneous glatiramer acetate (GA) 20 mg/day. The primary endpoint was ARR at 2 years. Secondary clinical endpoints included the proportion of patients who relapsed and disability progression as measured by EDSS at 2 years. Results: A total of 1417 patients received treatment. Baseline demographic and clinical characteristics were similar across treatment groups. BG-12 BID (n=359) and TID (n=345) significantly reduced ARR by 44% (p Conclusions: Efficacy results from CONFIRM further support those from DEFINE and suggest that BG-12 has the potential to be a valuable treatment option for RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Fox has received personal compensation for activities with Avanir, Biogen Idec, EMD Serono, and Novartis. Dr. Fox has received research support from Biogen Idec and Genentech, Inc. Dr. Miller has received personal compensation for activities with UCL Institute of Neurology, Biogen Idec, GlaxoSmithKline, and Bayer Schering Pharma. Dr. Miller has received personal compensation in an editorial capacity for Journal of Neurology. Dr. Miller has received research support from GlaxoSmithKline, Biogen Idec, and Novartis. Dr. Phillips has received personal compensation for activities with Avanir, Biogen Idec, Genzyme, Novartis, and Teva as a speaker or consultant.Dr. Phillips has received research support from Biogen Idec and Roche. Dr. Kita has received personal compensation for activities with Biogen Idec as a speaker. Dr. Kita has received research support from Biogen Idec. Dr. Hutchinson has received personal compensation for activities with Biogen Idec as a speaker. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Ms. Yang has received personal compensation for activities with Biogen Idec as an employee. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Viglietta has received personal compensation for activities with Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Effects of BG-12 on Quality of Life in Patients with Relapsing-Remitting Multiple Sclerosis: Findings from the DEFINE Study (P07.102)

Objective: To report the impact of BG-12 on patient quality of life (QoL) after 2 years9 treatment in the Phase 3 DEFINE study. Background In DEFINE, a randomized, double-blind, placebo-controlled, multicenter study that evaluated the efficacy and safety of BG-12 over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), BG-12 significantly reduced clinical relapses, disability progression, and magnetic resonance imaging measures of disease activity. Design/Methods: Patients aged 18-55 years with RRMS (McDonald criteria) and Expanded Disability Status Scale score of 0.0-5.0 were eligible for enrollment. Patients were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). A Short Form (SF)-36 questionnaire measured patients9 health status and health-related QoL on 8 multi-item 100-point scales at baseline and 6, 12, and 24 months; higher scores indicated higher QoL. These scores were used to calculate the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Results: Overall, 1234 patients enrolled and received study treatment. At 2 years, patients reported higher mean SF-36 PCS scores with BG-12 BID (43.4) and TID (44.2) versus placebo (41.9; P Conclusions: Together with the significant effects on clinical measures (reduced relapse risk, annualized relapse rate, and disability progression), the demonstrated benefits on patient-reported health-related QoL further supports a potential role for BG-12 as a valuable oral treatment option in RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Agarwal has received personal compensation for activities with Biogen Idec Inc as an employee. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Kong has received personal compensation for activities with Biogen Idec as an employee. Dr. Sheikh has received personal compensation for activities with Biogen Idec as an employee. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Effect of BG-12 on Brain Atrophy and Lesions Volume: MRI Results from the DEFINE Study during First and Second Year of Treatment (IN3-2.002)

Objective: To report results of BG-12 on tertiary magnetic resonance imaging (MRI)-related outcomes from the Phase 3 DEFINE study. Background BG-12 is an experimental oral treatment for relapsing-remitting multiple sclerosis (RRMS) that may have anti-inflammatory and neuroprotective effects via the Nrf2 pathway. DEFINE, a randomized, double-blind, placebo-controlled study evaluating BG-12 over 2 years in RRMS patients, showed significant reductions in clinical relapses, accumulation of disability progression, and number of lesions on brain MRI images. Design/Methods: Patients aged 18-55 years with RRMS (McDonald criteria) and EDSS score of 0.0-5.0 were enrolled. Patients were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). A subset of patients from 76 sites had MRI scans at baseline, 24 weeks, 1 year, and 2 years. Tertiary endpoints included brain atrophy from 6 months to 2 years measured using the SIENA method and the volume of T2, gadolinium-enhancing (Gd+), and T1 hypointense lesions at 1 and 2 years. Results: The MRI intent-to-treat cohort comprised 540 patients. The median percent whole brain volume change from 6 months to 2 years was -0.660% in placebo compared with -0.460% and -0.550% in the BG-12 BID and TID groups, respectively, representing reductions of 30% (P=0.0214) and 17% (P=0.2478) versus placebo. Over 2 years, the median percent change of T2 hyperintense lesion volume from baseline was 20.1% with placebo versus -6.2% (P Conclusions: Results of the MRI analysis of the DEFINE study demonstrate reduced brain atrophy and lesion volume compared with placebo and supports BG-129s potential as an effective oral treatment for RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin

BI 207127 is a potent non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor in vitro. In this double-blind, placebo-controlled study, 57 HCV genotype (GT)-1 patients (n=27 treatment-naïve [TN]; n=30 treatment-experienced [TE]) with compensated liver disease were randomised for 28-day treatment with 400, 600, or 800 mg BI 207127 three times daily (TID) or placebo (only TN) in combination with peginterferon alfa 2a and ribavirin (PegIFN/RBV). Plasma HCV RNA was measured by Roche COBAS TaqMan assay. HCV RNA decreased in a dose-dependent manner with little difference between 600 mg (TN 5.6 log(10), TE 4.2 log(10)) and 800 mg (TN 5.4 log(10), TE 4.5 log(10)). Rapid virological response (RVR; HCV RNA <15 IU/ml) at day 28 occurred in 11/19 TN and 4/30 TE patients treated with BI 207127. GT-1b patients had stronger reductions in HCV RNA than GT-1a (RVR: TN 64% vs. 43%; TE 33% vs. 5%). There were no breakthroughs (HCV RNA rebound >1 log(10) from nadir) in the TN groups, whereas 3/30 TE patients experienced breakthrough due to P495-mutations. Gastrointestinal adverse events (AEs) and rash were the major AEs and most frequent at higher doses. One and four patients discontinued due to AEs in the 600 and 800 mg groups, respectively. Overall, tolerability was good and better at 600 mg than 800 mg. BI 207127 in combination with PegIFN/RBV demonstrated strong antiviral activity with a favourable safety and tolerability profile. The best benefit/risk ratio was observed at 600 mg.

Pharmacokinetics of Different Dosing Strategies of Oral Posaconazole in Patients with Compromised Gastrointestinal Function and Who Are at High Risk for Invasive Fungal Infection

The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these "poor absorbers" on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.