BID Group Research Articles

Pharmacokinetics and tolerability of probucol after multiple oral administrations in healthy volunteers

Probucol is indicated for primary hyperlipidemia and for hypercholesterolemia with hypertriglyceridemia. The objective of this study was to evaluate the tolerability and pharmacokinetics of probucol by multiple oral administration in healthy Korean male subjects. This study was conducted by a randomized, openlabel, three-treatment, parallel-group design. A total of 30 subjects were randomly assigned to 1 of the 3 treatment groups were administered probucol orally at 250 mg once daily (QD) after breakfast (250 mg/d), at 500 mg once daily after breakfast (500 mg/d), or at 250 mg twice a day (b.i.d) after breakfast and dinner (500 mg/d) for 14 days. Serial samples of blood were collected and plasma drug concentrations were determined using liquid chromatography-tandem mass spectrometry (LC/MS/MS). For tolerability assessment, measurement of vital signs and electrocardiograms (ECG), clinical laboratory tests and physical examinations were performed. At Day 13, the mean of the AUC(24h) of probucol was 123,800 µg × h/l in the 250 mg QD group, 198,500 µg × h/l in the 500 mg QD group, and 244,700 µg × h/l in the 250 mg BID group. The mean accumulation index for AUC(24h) (ratio of AUC(24h) for Day 13 to that for Day 1) was 2.5 in the 250 mg QD group, 2.85 in the 500 mg QD group, and 4.21 in the 250 mg b.i.d. group. No clinically significant changes in ECG, including QTc prolongation were observed during the study period. All adverse events were mild and no clinically significant changes were observed in any other tolerability assessment, thus confirming tolerability for all regimens tested. This study provided data on the pharmacokinetics and tolerability of probucol by multiple oral administrations in healthy male volunteers.

Efficacy and Safety of Prandial Premixed Therapy Using Insulin Lispro Mix 50/50 3 Times Daily Compared With Progressive Titration of Insulin Lispro Mix 75/25 or Biphasic Insulin Aspart 70/30 Twice Daily in Patients With Type 2 Diabetes Mellitus: A Randomized, 16-Week, Open-Label Study

Background Prandial premixed therapy 3 times daily has been proposed recently for type 2 diabetes mellitus (T2DM) patients who fail to achieve glycemic control with commonly used premixed insulin analogs, insulin lispro mix 75/25 (LM75/25) and biphasic insulin aspart 70/30 (BIAsp70/30) BID. Objective The aim of this work was to compare the efficacy and safety of 3-times daily insulin lispro mix 50/50 (TID group) with progressive titration of twice-daily LM75/25 or BIAsp70/30 (BID group) administered along with metformin in T2DM patients. Methods This was an open-label, 16-week, multicenter, randomized, parallel trial. End point glycosylated hemoglobin (HbA 1c) was the primary efficacy measure; HbA 1c reduction from baseline to end point, percentage of patients reaching target HbA 1c (<7.0% and ≤6.5%), postprandial blood glucose (BG), and BG excursions after lunch were secondary measures. Safety was evaluated by collecting adverse events. Results A total of 302 patients with mean (SD) age 57.7 (9.27) years, diabetes duration 11.2 (6.47) years, HbA 1c 8.5% (1.23), fasting BG 184.0 (53.04) mg/dL, body weight 86.8 (14.79) kg, body mass index 31.7 (4.23) kg/m 2, and daily insulin dose ∼48 IU were randomized. No significant difference was observed in end point HbA 1c between the 2 groups. Seven-point BG profiles showed lower fasting and postbreakfast BG in the BID group but lower postlunch BG in the TID group. Daily insulin dose change was similar in both groups, with more weight gain in the TID group ( P = 0.0009). Overall hypoglycemic rates were similar in both groups, but nocturnal hypoglycemia was more frequent in the BID group ( P = 0.0063). Conclusions In patients with T2DM who have not achieved adequate glycemic control with LM75/25 and BiAsp70/30 BID plus metformin and who are not candidates for basal bolus therapy, switching either to treatment with LM50/50 TID or to progressive titration of premix insulin analogs BID did not produce sufficient evidence of a difference of overall glycemic control between the 2 treatment groups. Short study duration and less intensive dose adjustments might have contributed to these results.

Measurement of Adherence to Brimonidine Therapy for Glaucoma Using Electronic Monitoring

To assess the patient adherence and behavior with brimonidine twice daily (bid) or 3 times daily (tid) in patients used to topical glaucoma medication. Seventy-five patients with glaucoma or ocular hypertension were enrolled in a prospective, observational cohort study. Consenting patients were randomly assigned to brimonidine bid or tid and received conventional brimonidine eye drops with attached electronic monitoring devices for 4 weeks. Patients were not explicitly informed on the compliance monitoring. The study was completed by 67 patients (89%). In 65 patients (97%), at least 1 dosing interval exceeded 24 hours. The mean adherence rates were better in the brimonidine bid group (72 ± 19% vs. 62 ± 16%, P=0.04), although dosing frequency was higher in the tid group (1.9 ± 0.5 vs. 1.4 ± 0.4 per day; P<0.001). On average medication coverage was 70% for the bid group and 67% for the tid group; 19 patients (28%) had a coverage rate above 75%, 42 patients (63%) 50% to 75%, and 6 (9%) below 50%. Patients with normal-tension glaucoma had lower coverage rates than patients with primary open-angle glaucoma and ocular hypertension (P<0.05). Data also showed that on average 20% of the glaucoma medication was wasted owing to inefficient drug delivery by using more than 1 drop per dosing. Individual adherence with brimonidine was highly variable and pharmacologically insufficient for more than two-third of the patients. Special attention should be paid to compliance of patients with normal-tension glaucoma. Our findings underline the need to improve individual adherence and drug delivery in topical glaucoma therapy.

A clinical study on treating lumbar disc herniation with different electroacupuncture dose

Objective The therapeutic effectiveness of different electroacupuncture dose on lumbar disc herniation was studied. Methods 200 cases with lumbar disc herniation, who were also diagnosed of blood stasis and qi stagnation, and obstruction of collaterals by TCM syndrome differentiation, were randomly divided into a control group and a treatment group (100/group) by tail number of cases. Both groups were cured with electroacupuncture, while receiving treatments of Qd, 20 minutes/time in the control group; Bid, 20minutes/time in the treatment group. Effects were analyzed after the treatment(35days/course). Results After treatment, control-markedly rate was 91％ in the treatment group, and 68％ in the control group; There was significant difference of control- markedly rate between the two groups (Z=-3.5480, P＜0.05). According to the analysis of the symptoms and signs: low back pain (0.65±0.03) score, tender point (1.12±0.11) score, lumbar activity (0.75±0.12) score, dysbasia ( 1.01 ±0.06) score, straight leg raising test (0.37±0.12) score,radioactive pain in the legs (0.61 ±0.09) score, strengthening test (0.29±0.08) score, toe strength (0.29±0.09)score in the control group, those improvements of both groups existed obvious statistical difference (P＜0.05).There was also significant difference of average effective time between the two groups (P＜0.01) [ (3.86±2.106)d in the treatment group, (5.12±3.125)d in the control group]. Conclusion Electroacupuncture Bid group was superior to electroacupuncture Qd group for treating lumbar disc herniation. Key words: Electroacupuncture; Different acupuncture dose; Lumbar disc herniation

Efficacy and safety of intrapatient dose escalation of sorafenib as first-line treatment for metastatic renal cell carcinoma (mRCC).

4609^ Background: Previous data of intrapatient dose-escalated sorafenib in mRCC suggest that doses up to 800 mg bid were manageable with enhanced activity in terms of PFS and responses compared to the standard dose of 400 mg bid. This phase II study was conducted to investigate these earlier findings. Methods: Main eligibility criteria were metastatic and/or unresectable clear cell RCC; at least one measurable lesion, ECOG PS 0/1, MSKCC score good or intermediate, no prior systemic anticancer therapy. Patients (pts) were to receive sorafenib 400 mg bid for 4 weeks, then 600 mg bid for 4 weeks and 800 mg bid from month 3 to 6+, with response evaluated at 6 months. The primary endpoint was response rate (best overall response) within the first 6 months of treatment (≥4 months of treatment at the highest tolerated dose for all pts). Results: Of the 83 enrolled pts (65% male) who received ≥ one dose of sorafenib (safety population); 16 withdrew due to grade 1/2 toxicities and 67 had ≥ one post-baseline assessment (ITT population). Dose escalation per protocol was tolerated by 18 pts; all achieved clinical benefit (9-PR; 9-SD). The other 49 pts had dose escalations and reductions as tolerated throughout the study. Results for the ITT population and subgroups taking 400, 600, or 800 mg bid for the longest time while on study are shown (Table). Median age in the 400, 600, and 800 mg bid groups was 64.5, 58.5, and 57 years, respectively; other baseline characteristics were comparable. No clinically relevant differences in the severity or frequency of side effects were seen across the 3 groups. Conclusions: In the majority of pts dose escalation per protocol was not feasible. Pts in whom the sorafenib dose could be escalated above 400 mg bid appeared to have greater clinical benefit. 400 mg bid (n=25) 600 mg bid (n=12) 800 mg bid (n=20) ITT population (n=67)* Partial response n (%) 1 (4) 2 (16.7) 7 (35) 12 (17.9) Stable disease n (%) 15 (60) 10 (83.3) 13 (65) 46 (68.7) Clinical benefit (PR+SD) n (%) 16 (64) 12 (100) 20 (100) 58 (86.6) Median PFS mo (95% CI) 3.7 (1.8-9.5) 7.4 (6.3-12) 8.5 (5.6-14.9) 7.4 (6.3-9.7) PFS rate at 12 months % 18.7 33.3 46.4 35.9 * The dose for the longest time on treatment was 200 mg/day for 3 pts and 400 mg/day for 7 pts.

Phase I, dose-finding study of monotherapy with AZD8931, an inhibitor of ErbB1, 2, and 3 signaling, in patients (pts) with advanced solid tumors.

3097 Background: AZD8931 is an oral, equipotent inhibitor of ErbB1, ErbB2 and ErbB3 receptor signaling. Methods: This open-label, multiple ascending (standard 3+3 design) dose cohort study (NCT00637039) determined the safety, tolerability, and PK of AZD8931. Pts received a single oral dose of AZD8931 followed by a 4-day observation and then AZD8931 bid for 21 consecutive days (continuation post day 21 was optional). Results: 28 pts (mean age 56 years) received AZD8931 (n=5, 40 mg bid; n=8, 80 mg bid; n=6, 160 mg bid; n=6, 240 mg bid; n=3, 300 mg bid); 21 had metastatic disease and 27 had received prior cancer therapy. The most common primary tumors were ovary (n=8) and breast (n=5). The 21-day repeat-dosing period was completed by 22 pts and 9 remained on treatment after this period. Median duration of exposure to AZD8931 was 22 days (range 7–140). DLTs were identified in 1/6 pts in the 240 mg bid cohort (Grade [Gr] 3 rash) and in 2/2 evaluable pts in the 300 mg bid cohort (Gr 3 and Gr 4 diarrhea). Skin and subcutaneous tissue disorders and GI disorders were the most common system organ class AEs. In the 40 mg bid group cohort all skin-type AEs (n=5) were mild (Gr 1). AZD8931 demonstrated rapid absorption (median tmax was 1–3 h), was well distributed, had moderate to high clearance and terminal t½ of 11 h. Following continuous bid dosing, steady state was achieved by day 2, accumulation was ~1.5-fold and no time-dependent changes in PK were observed. Exposure increased proportionally with dose up to 160 mg; for single doses >160 mg, exposure increased slightly greater than proportionally with dose. Of 21 pts evaluable for response at day 21, 12 had stable disease and 9 had disease progression. Conclusions: The MTD of AZD8931 determined from tolerability data during the DLT period was 240 mg bid. However, more long-term data are needed to define a dose of AZD8931 suitable for chronic treatment. AZD8931 dose (n) 40 mg bid (5) 80 mg bid (8) 160 mg bid (6) 240 mg bid (6) 300 mg bid (3) Total (28) Patients with an AE considered related to study treatment, n Any grade 5 8 6 6 3 28 Grade ≥3 1 3 3 4 3 14 SAE 0 0 0 0 1 1 Most frequent grade ≥3 skin-related and GI AEs, n Diarrhea 1 0 2 2 2 7 Acne-type rash 0 3 0 1 0 4 Skin exfoliation 0 1 0 1 0 2 Ascites 0 1 1 0 0 2

Once-a-Day Administration of Everolimus Is Safe in De Novo Renal Transplant Recipients: 1-Year Results of a Pilot Study

Introduction The half-life of everolimus is approximately 28 hours, but everolimus is generally administered twice a day. The aim of this prospective, single-center, exploratory study was to compare the efficacy and safety of a once a day everolimus (OD) with the standard twice a day administration regimen (BID) as immunosuppressive therapy in renal transplantation. Methods Forty-one de novo renal transplant recipients prospectively assigned to OD ( n = 21) or BID ( n = 20) treatment were followed for 1 year. In the OD group, everolimus was orally administered targeting a trough blood level of 2 to 5 ng/mL. In the BID group, everolimus was given twice a day targeting a trough blood level of 3 to 12 ng/mL. All patients also received induction with basiliximab and low-dose calcineurin inhibitor immunosuppression. Results At 1 year follow-up patient and graft survivals were 100%. The intention-to-treat analysis showed similar renal function between the two regimens: serum creatinine values for OD 1.54 ± 0.6 versus BID 1.48 ± 0.53 mg/dL ( P = NS). Also the occurrence of acute rejection episodes was not significantly different: 4.8% in the OD versus 15% in the BID group, ( P = NS). The median trough blood levels were significantly lower among the OD group: OD 4.5 versus BID 7.2 ng/mL ( P < .001). Discussion This study demonstrated that once a day administration of everolimus achieved excellent patient and graft survival and good renal function without an increased incidence of acute rejection episodes.

Chronic renal insufficiency is associated with high on-treatment platelet reactivity

Although Asian people are believed to be more susceptible to bleeding on currently recommended dose of ticagrelor, there is limited evidence supporting low-dose ticagrelor. We prospectively randomized patients receiving dual antiplatelet therapy with aspirin and clopidogrel into 3 groups; aspirin plus clopidogrel 75 mg versus aspirin plus ticagrelor 90 mg once daily versus aspirin plus ticagrelor 45 mg twice daily. Platelet function assessments were conducted using VerifyNow P2Y12 assay at baseline and 28 days after randomization. No differences in baseline P2Y12 reaction unit (PRU) values were observed among the 3 groups. PRU values at the end of the treatment periods were significantly lower in low-dose ticagrelor (90 mg QD group, 98.6 ± 73.4 and 45 mg BID group, 65.5 ± 58.8) compared with clopidogrel (221.2 ± 50.1, both p <0.001). There was no significant difference in PRU values between 2 groups of low-dose ticagrelor (p = 0.208). The rates of high on-treatment platelet reactivity were significantly lower in low-dose ticagrelor compared with clopidogrel, whereas clopidogrel showed higher rate of optimal on-treatment platelet reactivity than ticagrelor 45 mg BID. However, similar rate of optimal on-treatment platelet reactivity was observed in clopidogrel and ticagrelor 90 mg QD. In conclusion, low-dose ticagrelor treatment, either with 90 mg QD or 45 mg BID, was associated with a more potent antiplatelet effect compared with clopidogrel treatment and once daily dose provided similar antiplatelet effect but favorable effect on optimal platelet inhibition compared with twice daily dose.

Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial†

Oltipraz, a cancer chemopreventive agent, has an anticirrhotic effect in animals. A phase II trial was designed to investigate the preliminary efficacy of oltipraz therapy in liver fibrosis or cirrhosis. Of 83 patients who were randomized to receive placebo, oltipraz 60 mg bid or oltipraz 90 mg qd for 24 weeks, 68 completed the study without any major protocol violation. Pre- and post-treatment liver biopsies, and blood fibrosis markers were assessed. Twenty-four weeks of oltipraz treatment showed no significant differences in the proportions of patients showing an improvement in histological outcomes, including Ishak fibrosis score. In the oltipraz 60 mg bid group, there was a trend of decreases in hepatic collagen area and plasma transforming growth factor-β1 (TGF-β1, a blood fibrosis marker) levels from baseline to week 24. In the per-protocol population (n = 68), decreases in plasma TGF-β1 correlated with those in the Ishak fibrosis score, suggesting that circulating TGF-β1 serves a possible indicator for fibrosis treatment. No significant differences in liver histological outcomes were seen among the three treatment groups in this 24-week pilot study. Our finding indicates an association between TGF-β1 repression and improvement in the histological index of fibrosis.

A Comparison of Atomoxetine Administered as Once Versus Twice Daily Dosing on the School and Home Functioning of Children with Attention-Deficit/Hyperactivity Disorder

This secondary analysis examined the efficacy and tolerability of atomoxetine (ATX) dosed once (QD) versus twice (BID) daily in 55 children aged 6-12 with attention-deficit/hyperactivity disorder (ADHD). The original 8-week trial was designed to assess the benefits of adding behavioral therapy to ATX. In it, all subjects were treated openly with ATX, with 50% randomly assigned to additional behavioral treatments. Every subject was started on QD dosing with a target dose of 1.2 mg/kg per day. A switch to BID dosing was allowed at study midpoint to improve tolerability and efficacy. Subjects not responding to ATX at midpoint were also given the option of 0.6 mg/kg dose increase. ADHD and oppositional defiant disorder (ODD) symptoms, global functioning, side effects, and classroom performance were measured weekly. There were 22 subjects (40%) who switched to BID dosing at midpoint (mean dose = 1.56 mg/kg per day) with the other 33 remaining on QD dosing (mean dose = 1.33 mg/kg per day). The BID group did not display any improvement in parent-rated ODD symptoms during the first 4 weeks of the study on QD dosing, but there was a significant improvement seen after the addition of the second ATX dose (p < 0.05). However, BID dosing was not associated with differential rates of change for parent-rated ADHD symptoms or impairment, teacher ratings, or other measures of classroom functioning. BID dosing was associated with decreased rates of stomachaches (p < 0.05) but more persistent appetite loss than QD dosing. The degree of improvement observed during the first half of the study in ratings of global impairment and ODD but not ADHD symptoms predicted a switch to BID dosing at midpoint (p < 0.05). The addition of an afternoon dose of ATX was associated with improved control of ODD symptoms at home, with no change in school functioning.

Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy

Background Cyclophilin inhibitors have shown activity against a variety of viruses, including HCV. NIM811, a novel, non-immunosuppressive cyclophilin inhibitor was studied in ascending doses in a randomized, double-blind, placebo-controlled 14-day trial in genotype 1 HCV patients. Doses of 10 up to 600 mg were given orally once or twice daily as monotherapy (9:3 randomization of NIM811:placebo). 600 mg or placebo bid for 14 days was then co-administered with pegylated interferon alpha (PEG-IFN-α) administered on days 1 and 8 to genotype 1 relapsers. Results NIM811 was well tolerated at all doses. Although lack of antiviral effect was noted in the monotherapy arms, liver transaminase normalization occurred at doses over 75 mg. Mild, clinically non-significant elevations of bilirubin, and significant declines in platelet numbers were observed in the 400 and 600 mg bid groups. In the combination group, the mean HCV RNA decline was 2.85 log, compared to a 0.56 log in the PEG-IFN alone arm. The mean ALT (alanine transaminase) declined significantly by day 14 in the combination, but was unchanged in the PEG-IFN alone group. In the combination therapy group, the mean platelets were 203 × 10 9/L at baseline and fell to 105 × 10 9/L by day 14; for patients treated with PEG-IFN the values were 177 × 10 9/L and 139 × 10 9/L. There was a significant increase in bilirubin, although this did not reach clinically concerning levels. There were no severe or serious adverse events. The pharmacokinetics in both monotherapy and combination arms were dose linear and not affected by PEG-INF. Conclusion NIM811 monotherapy resulted in a normalization of liver transaminases in the absence of significant virological response. The combination of NIM811 and pegylated interferon alpha showed significant antiviral activity compared to interferon alone in genotype 1 HCV relapsers. The use of oral cyclophilin inhibitors as part of a combination regime for treatment of hepatitis C, especially to deter resistance, holds promise.

Efficacy and tolerability of first-line triple therapy with levofloxacin and amoxicillin plus esomeprazole or rabeprazole for the eradication of Helicobacter pylori infection and the effect of CYP2C19 genotype: A 1-week, randomized, open-label study in chinese adults

Background: First-line triple therapy with levofloxa- cin and amoxicillin plus a proton pump inhibitor has been reported to be effective and well tolerated in the eradication of Helicobacter pylori infection. Studies have reported that cytochrome P450 (CYP) 2C19 genotypes may affect the clinical efficacy of clarithromycinbased triple therapies, although there is only one report of such an effect with levofloxacin-based triple therapies. Objectives: This study evaluated the clinical efficacy and tolerability of a 1-week course of triple therapy with levofloxacin and amoxicillin plus esomeprazole or rabeprazole as first-line treatment for H pylori infection in Chinese adults. It also investigated whether CYP2C19 genotype status affected rates of H pylori eradication with these regimens. Methods: Consecutive patients undergoing upper endoscopy at the First Affiliated Hospital of Nanjing Medical University between May 2008 and January 2009 were evaluated for inclusion. Eligible patients were those who tested positive for H pylori infection on biopsy-based testing (ie, histology and an in-house rapid urease test) or a validated 13C-urea breath test. Patients were randomized in an open-label fashion to receive levofloxacin 500 mg/d and amoxicillin 1000 mg BID plus either esomeprazole 20 mg BID (group A), esomeprazole 40 mg BID (group B), or rabeprazole 10 mg BID (group C) for 1 week. Patients were asked to record adverse events in a diary. Trained study assistants contacted patients by telephone within the first week after completion of therapy to collect data on drug compliance and adverse events. H pylori status was determined 4 weeks after the end of therapy using a 13C-urea breath test. Rates of H pylori eradication were calculated in the intent-to-treat (ITT) and per-protocol (PP) populations. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment-length polymorphism method. Results: Of 199 consecutive patients screened for eligibility, 184 H pylori-positive patients were enrolled in the study (61 in group A, 62 in group B, and 61 in group C). The overall sample was balanced in terms of age, sex, endoscopic diagnosis, and history of smoking. Rates of H pylori eradication in the ITT and PP populations were as follows: group A—85.2% (52/61) and 86.7% (52/60), respectively; group B—87.1% (54/62) and 90.0% (54/60); and group C—75.4% (46/61) and 75.4% (46/61). There were no significant differences in eradication rates among groups, nor were there any differences in rates of compliance (98.4%, 96.8%, and 100% in groups A, B, and C, respectively) or adverseevent profiles. Fifteen patients (7.6%) reported adverse events during the study (5 [8.2%] in group A, 6 [9.7%] in group B, and 4 [6.6%] in group C). The adverse events included diarrhea (6 patients), dizziness (5), abdominal pain (2), nausea (1), and skin rash (1). Three patients discontinued treatment because of adverse events ( 1 due to skin rash in group A and 2 due to dizziness in group B). In the 147 patients included in the PP analysis of the effect of CYP2C19 genotype, eradication rates were 88.9% (32/36) in poor metabolizers, 82.0% (50/61) in heterozygous extensive metabolizers, and 82.0% (41/50) in homozygous extensive metabolizers. Eradication rates did not differ significantly among genotype groups. Conclusions: One week of first-line triple therapy with levofloxacin and amoxicillin plus esomeprazole 20 or 40 mg BID or rabeprazole 10 mg BID was associated with H pylori eradication rates of 85.2%, 87.1%, and 75.4%, respectively, with no significant differences between treatment groups. There were no significant differences in eradication of H pylori by CYP2C19 genotype in this small population of Chinese adults.

An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis.

Chronic airway infection with Pseudomonas aeruginosa (PA) causes morbidity and mortality in patients with cystic fibrosis (CF). Additional anti-PA therapies are needed to improve health status and health-related quality of life. AIR-CF3 was an international 18-month, open-label study to evaluate the safety and efficacy of repeated courses of aztreonam for inhalation solution (AZLI, now marketed as Cayston®) in patients aged ≥ 6 years with CF and PA infection who previously participated in one of two Phase 3 studies: AIR-CF1 or AIR-CF2. Patients received up to nine courses (28 days on/28 days off) of 75 mg AZLI two (BID) or three times daily (TID) based on randomization in the previous trials. 274 patients, mean age 28.5 years (range: 8-74 years), participated. Mean treatment adherence was high (92.0% BID group, 88.0% TID group). Hospitalization rates were low and adverse events were consistent with CF. With each course of AZLI, FEV(1) and scores on the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom scale improved and bacterial density in sputum was reduced. Benefits waned in the 28 days off therapy, but weight gain was sustained over the 18 months. There were no sustained decreases in PA susceptibility. A dose response was observed; AZLI TID-treated patients demonstrated greater improvements in lung function and respiratory symptoms over 18 months. Repeated intermittent 28-day courses of AZLI treatment were well tolerated. Clinical benefits in pulmonary function, health-related quality of life, and weight were observed with each course of therapy. AZLI is a safe and effective new therapy in patients with CF and PA airway infection.

Differences in Healthcare Resource Utilization and Costs Based on PPI Dosing Regimen Among Gastroesophageal Reflux Disease (GERD) Patients

Purpose: The aim of this study was to determine potential differences in overall and GERD-related healthcare utilization and costs for GERD patients using either once-daily (QD) or twice-daily (BID) proton pump inhibitor (PPI) therapy. Methods: Using the HealthCore Integrated Research Database (HIRD) GERD patients (ICD-9 codes 530.10, 530.11, 530.12, 530.19, 530.81, 530.13 or 787.1x) were identified from 01/01/2004 to 06/30/2009, having at least two PPI pharmacy claims (index date) from 01/01/2005 to 06/30/2008. Continuous eligibility for 12 months before and after the index date and ≥ 18 years of age were required. Based on the PPI dosing regimen throughout the post-index period, calculated as the ratio of quantity of medication dispensed/number of days supply, GERD patients were classified as QD (ratio of <1.5) or BID (ratio of ≥1.5) PPI users. We determined 12-month post index healthcare utilization and costs stratified by QD or BID dosing. Descriptive and multivariate statistics were conducted. Results: This study included 248,386 GERD patients with a mean age of 52.8 (+13.93) years and 56% females. Based on the dosing regimen, 90% (n=222,759) were classified as QD and 10% (n=25,627) as BID PPI users. Patients with BID PPI dosing were more likely to have comorbid conditions including Barrett's esophagus [5% (n=1,272) in the BID group vs. 2% (n=4,568) in the QD group, p<0.05] and cardiovascular disease [25% (n=6,408) in the BID vs. 20% (n=44,521) in the QD group, p<0.05]. The mean (+SD) Deyo-Charlson Comorbidity Index scores for the QD and BID groups were 0.70 (+1.37) and 0.89 (+1.54; p<0.05). In the 12-month post-index period, a significantly (p<0.05) lower proportion of QD PPI users had at least one GERD-related inpatient visit (5% vs. 7%), outpatient visit (49% vs. 60%) and/or office visit (38% vs. 48%) compared to BID PPI users. The mean (+SD) annual total GERD-related healthcare costs were $2,065 (+$6,636) versus $3,749 (+$11,081) for QD and BID patients, respectively, p<0.05. Multivariate results showed that dosing regimen was a significant predictor of total GERD-related healthcare costs (excluding GERD-related pharmacy costs), with BID PPI users having 67% more costs compared to QD PPI users. Conclusion: Patients receiving BID PPI's had significantly higher comorbidities, greater healthcare resource utilization and overall costs compared to GERD patients using QD PPI regimens. Further research is warranted to determine the impact of co-morbid conditions on PPI dosing regimens and healthcare resource utilization and costs.

Safety and tolerability of lersivirine, a nonnucleoside reverse transcriptase inhibitor, during a 28-day, randomized, placebo-controlled, Phase I clinical study in healthy male volunteers

Background: Lersivirine is a nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1. Objective: The goal of this study was to investigate the safety and tolerability of multiple oral doses of lersivirine administered to healthy male subjects to assist in the planning of longer term studies. Methods: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter, Phase I clinical study in fasting, healthy male volunteers. Subjects were randomly assigned in a ratio of 7:7:4:4 to receive lersivirine 500 mg BID, lersivirine 750 mg once daily, efavirenz 600 mg once daily, or placebo once daily for 28 days. Safety and tolerability were assessed throughout the study by continuous collection of adverse events (AEs), including adverse drug reactions, illnesses with onset during the study, exacerbation of previous illnesses, and clinically significant changes in physical examination findings. Vital sign measurements and ECGs were performed at screening; on day 1 (predose and 2, 3, and 4 hours postdose); on days 7, 14, 21, and 28 (predose); at discharge; and at follow-up. Safety laboratory tests (including hematology, chemistry, and urinalysis) were performed at screening; days 0, 7, 14, 21, and 27; and at follow-up. Results: Of the 66 healthy male subjects enrolled (age range, 21–51 years; body mass index, 18.1–29.9 kg/m 2), 40 were white, 22 were Asian, 3 were black, and 1 was of mixed race. There were no clinically significant laboratory abnormalities, including changes in lipid profile, liver or renal function test results, or ECG findings. Overall, 86% (18/21) of subjects in the lersivirine 500-mg BID group, 81% (17/21) in the lersivirine 750-mg once-daily group, 92% (11/12) in the efavirenz 600-mg once-daily group, and 92% (11/12) in the placebo group experienced at least one treatment-related AE. Eight subjects were permanently discontinued from the study; 4 subjects in the efavirenz group (3 of whom participated in the trial at the Brussels study center) were permanently discontinued due to AEs considered to be treatment related. No subjects receiving lersivirine permanently discontinued the study due to treatment-related AEs, although one subject temporarily discontinued treatment. In addition, 4 subjects withdrew consent (2 subjects [1 of whom was at the Brussels study center] receiving lersivirine 750 mg once daily and 2 subjects [1 of whom was at the Brussels study center] receiving efavirenz). There were no deaths or serious AEs in any of the study groups. Conclusion: Lersivirine appeared to be well tolerated after 28 days of continuous dosing in this small, selected group of young, healthy male volunteers.

Comparison of once-daily versus twice-daily dosing of valsartan in patients with chronic stable heart failure

The safety of once-daily (qd) dosing of valsartan in heart failure (HF) patients is not known. This 10-week, double-blind trial examined the relative safety and efficacy of valsartan administered qd versus twice-daily (bid). HF patients (NYHA class II-III) receiving diuretics (87%), angiotensin-converting enzyme inhibitors (98%), beta-blockers (92%), aldosterone antagonists (25%), or digoxin (32%) were randomized to valsartan 40 mg bid (n = 60) or 80 mg qd (n = 55) and titrated to a maximum dose of 320 mg/day; doubling the dose every 2 weeks. Clinical and biochemical parameters were measured at Weeks 2, 4, 6, and 10. The average dose of valsartan at the end of study was 245 mg in the bid group vs 256 mg in the qd group (P = NS). Similar proportions of patients tolerated qd vs bid dosing (bid 67% vs qd 68%). Outcome measures including reduction in blood pressure, incidence of hypotension, renal impairment, orthostatic dizziness or fatigue, changes in serum K(+), creatinine, cystatin-C, and estimated glomerular filtration rate were similar between the 2 groups at all time-points. Brain natriuretic peptide levels decreased and plasma renin activity increased from baseline by the same amount in both groups at all time-points. Valsartan administered qd has a similar safety and tolerability profile with comparable 24-hour RAAS blockade, as assessed by increases in PRA, as bid dosing in patients with moderate to severe (NYHA class II-III) heart failure.

Once Daily Everolimus Is Safe and Effective in De Novo Renal Transplant Recipients: Six-Month Results of a Pilot Study

Introduction The half-life of everolimus is approximately 28 hours, but everolimus is normally administered twice a day. The aim of this prospective, single-center, exploratory study was to compare the efficacy and safety of a once a day (OD) everolimus regimen versus the standard twice a day regimen (BID) for immunosuppressive therapy in renal transplantation. Methods Forty de novo renal transplant recipients prospectively assigned to OD ( n = 21) or BID ( n = 19) were followed for 6 months. In the OD group, everolimus was given orally once a day to target a trough blood level of 2–6 ng/mL. In the BID, group everolimus was given twice a day to target a trough blood level of 3–12 ng/mL. All patients also received induction treatment with basiliximab and low-dose calcineurin inhibitors. Results At 6 months follow-up, patient and graft survivals were 100%; renal function and acute rejection rates were similar between the 2 regimens. Patients in the OD group showed significantly lower cholesterol and triglyceride levels compared with those in the BID group, namely, total cholesterol level, OD 212 ± 54 versus BID 249 ± 59 mg/dL ( P < .05), and serum triglycerides, OD 162 ± 72 versus BID 245 ± 133 mg/dL ( P < .02). Discussion This study showed that OD administration of everolimus provided excellent patient and graft survivals and good renal function without an increased incidence of acute rejection episodes. The lipid profile was significantly better among patients receiving everolimus OD. These findings suggested that everolimus can be safely administered once a day.

906 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Lubiprostone for the Treatment of Opioid-Induced Bowel Dysfunction in Patients With Chronic, Non-Cancer Pain

blind, placebo-controlled dose-definition study in patients with CIC. Patients were screened, completed a 2 week run-in phase assessing constipation and compliance with protocol procedures, then were randomized to either placebo BID, ATI-7505 20 mg, 40 mg, 80 mg or 120 mg BID orally. A total of 214 patients were randomized, 210 patients treated, and 173 patients completed 1 month. The primary outcome was total number of SBMs during Week 1 compared with placebo; secondary outcomes were time to first SBM, complete SBMs (CSBMs) and responders (<3 SBMs/wk X 4 wks, no rescue meds). All doses of ATI7505 resulted in a greater mean number of SBMs during Week 1 compared to placebo. Placebo-treated patients had a mean±SD of 3.9±2.3 SBMs compared to 5.7±3.5, 5.0±3.7, 6.7±5.3 and 5.2±3.2 SBM in the 20 mg, 40 mg, 80 mg and 120 mg BID groups, respectively. The 80 mg BID group was statistically significant vs placebo (p=0.0054) at Week 1. Median time to first SBM was reduced in all ATI-7505 treatment groups compared to placebo (15.820.4 hrs vs 40.0 hrs, respectively), and reached statistical significance for the 40 mg and 80 mg ATI-7505 groups. A maximal responder difference was seen with 80 mg ATI-7505 vs placebo for SBMs 51.2% vs 24.4% (p=0.0132) and CSBMs 26.8% vs 4.9% (p=0.0078), respectively. ATI-7505 was well tolerated. AE frequency, including headache, diarrhea, nausea and vomiting, was similar to placebo in all ATI-7505 dose groups except the 120 mg BID group, where abdominal pain and headache were more frequently reported. These phase II results suggest ATI-7505 is a promising new treatment for CIC and further studies are warranted.

Efficacy and Safety of Asenapine in a Placebo- and Haloperidol-Controlled Trial in Patients With Acute Exacerbation of Schizophrenia

Asenapine is approved by the Food and Drugs Administration in adults for acute treatment of schizophrenia or of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. In a double-blind 6-week trial, 458 patients with acute schizophrenia were randomly assigned to fixed-dose treatment with asenapine at 5 mg twice daily (BID), asenapine at 10 mg BID, placebo, or haloperidol at 4 mg BID (to verify assay sensitivity). With last observations carried forward (LOCF), mean Positive and Negative Syndrome Scale total score reductions from baseline to endpoint were significantly greater with asenapine at 5 mg BID (-16.2) and haloperidol (-15.4) than placebo (-10.7; both P < 0.05); using mixed model for repeated measures (MMRM), changes at day 42 were significantly greater with asenapine at 5 and 10 mg BID (-21.3 and -19.4, respectively) and haloperidol (-20.0) than placebo (-14.6; all P < 0.05). On the Positive and Negative Syndrome Scale positive subscale, all treatments were superior to placebo with LOCF and MMRM; asenapine at 5 mg BID was superior to placebo on the negative subscale with MMRM and on the general psychopathology subscale with LOCF and MMRM. Treatment-related adverse events (AEs) occurred in 44% and 52%, 57%, and 41% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Extrapyramidal symptoms reported as AEs occurred in 15% and 18%, 34%, and 10% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Across all groups, no more than 5% of patients had clinically significant weight change. Post hoc analyses indicated that efficacy was similar with asenapine and haloperidol; greater contrasts were seen in AEs, especially extrapyramidal symptoms.

Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation

The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation (AF). In this 12-week, parallel-group, multicentre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0-3.0. The study was double-blind to edoxaban dose, but open-label to warfarin. Primary outcomes were occurrence of major and/or clinically relevant non-major bleeding and elevated hepatic enzymes and/or bilirubin. Mean age was 65 +/- 8.7 years and 64.4% were warfarin-naïve. Whereas major plus clinically relevant non-major bleeding occurred in 3.2% of patients randomised to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg bid (10.6%; p=0.002) and 30 mg bid regimens (7.8%; p=0.029), but not with the edoxaban 60 mg qd (3.8%) or 30 mg qd regimens (3.0%). For the same total daily dose of 60 mg, both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group. There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups. The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin. In contrast, the edoxaban bid regimens were associated with more bleeding than warfarin. These results suggest that in this three-month study, edoxaban 30 or 60 mg qd are safe and well-tolerated.