Mean Change From Baseline Research Articles

146 Efficacy and Safety of the Asenapine Transdermal Patch, HP-3070, for Schizophrenia: A Phase 3, Randomized, Placebo-Controlled, Inpatient Study

Asenapine is a 2nd-generation antipsychotic currently marketed as a sublingual (SL) tablet in the US for the treatment of schizophrenia. HP-3070, asenapine transdermal system, is a patch for treatment of schizophrenia in adults. Low- and high- HP-3070 doses deliver asenapine concentrations that are similar to SL asenapine 5 mg BID and 10 mg BID, respectively, but with fewer peak and trough fluctuations. In this Phase 3, randomized, double-blind, placebo (PBO)-controlled, 6-week inpatient study, adults with schizophrenia having baseline Positive and Negative Syndrome Scale (PANSS) total score ≥80 and Clinical Global Impression-Severity of Illness Scale (CGI-S) score ≥4 were randomized 1:1:1 to HP 3070 high-dose, HP-3070 low-dose, or PBO.The primary efficacy objective was Week 6 PANSS score change from baseline (CFB) vs PBO.The key secondary objective was Week 6 CGI-S CFB vs PBO. Safety assessments included treatment-emergent adverse events (TEAEs), laboratory results, vital signs, dermal safety, and extrapyramidal symptoms (EPS) assessments. A total of 616 patients were randomized, with 486 patients completing the study. Discontinuation rates were 23.3%, 18.6%, and 21.4% for HP-3070 high-dose, HP-3070 low-dose, and PBO, respectively; withdrawal of consent and AEs were the most common reasons for discontinuation. Demographics and baseline characteristics were well-balanced among treatment groups.For PANSS total score, least squares mean (LSM) (standard error [SE]) estimates of the treatment comparison (HP-3070 vs PBO) for CFB at Week 6 were -4.8 (1.634; 95% CI: -8.06, -1.64; p=0.003) and -6.6 (1.630; 95% CI: 9.81, 3.40; p<0.001) for HP-3070 high- and low-dose, respectively. For CGI-S CFB at Week 6, LSM (SE) for the treatment comparison were 0.4 (0.100; 95% CI: 0.55, 0.16; p<0.001) for HP 3070 high-dose and 0.4 (0.099; 95% CI: 0.64, 0.25; p<0.001) for low-dose.No deaths or serious TEAEs related to study treatment occurred. The HP-3070 safety profile was consistent with SL asenapine. Incidence of TEAEs at the patch application site was higher for HP-3070 (14.2% high-dose, 15.2% low-dose) than for PBO (4.4%); most of these events were mild or moderate in severity. PBO patients had higher rates of psychiatric disorders (24.3% vs 15.7% and 17.6% for HP-3070 high- and low-dose, respectively), with insomnia and anxiety as most common. Study treatment discontinuations due to application site reactions or skin disorders were low (≤0.5%) across treatment groups. There was no marked mean CFB for vital signs or electrocardiogram parameters, nor treatment differences observed on EPS assessments. In this study, HP-3070 was efficacious, safe, and well-tolerated for treating schizophrenia in adults; both doses met primary and key secondary endpoints. As the first transdermal antipsychotic patch in the US, HP-3070 will provide patients a novel treatment option. Funded by Noven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical Co.

497 MD-7246, a Delayed-Release Formulation of Linaclotide Targeting Visceral Pain Associated With IBS-D, Does Not Impact Bowel Frequency or Stool Consistency in Healthy Volunteers: Results From Phase I Trial

INTRODUCTION: MD-7246 is a delayed-release formulation of linaclotide (LIN), releasing drug in the distal ileum, under development for treating visceral pain with limited pro-secretory effects. LIN, a GC-C agonist, is approved as an immediate-release (IR) formulation, releasing in the stomach, for treating irritable bowel syndrome with constipation and chronic idiopathic constipation. This study assessed the safety, tolerability, and pharmacokinetics of MD-7246 and explored select pharmacodynamic (PD) parameters. METHODS: This double-blind, placebo-controlled study randomized healthy adult volunteers to placebo or 1 of 3 daily doses of MD-7246 for 7 days. Safety and tolerability were assessed at each dose prior to dose escalation. PD assessments for spontaneous bowel movement [SBM]/week and stool consistency (Bristol stool form scale [BSFS]) were recorded in a diary. RESULTS: Placebo, low, mid, or high doses of MD-7246 were received by 6 subjects each. Neither LIN nor its active metabolite were detected in plasma after 7 days of oral administration and no intact tablets were discovered in any subject's stool. The median and interquartile range (IQR) for change from baseline (CFB) in SBM and BSFS were similar and overlapping for placebo and all 3 MD-7246 dose groups (median (IQR) CFB: SBM: -2.6 (-4.6, 2.9), -1.9 (-4.4, -1.4), -1.3 (-2.0, 0.0), and 0.0 (-7.7, 0.9); BSFS: 0.4 (-0.2, 1.0), 0.2 (-1.0, 0.9), 0.2 (-0.4, 1.0) and 0.4 (-0.3, 1.8) in placebo and low, mid, and high MD-7246 doses, respectively). MD-7246 was well tolerated and there were no adverse events of diarrhea reported in any subject (placebo or MD-7246). For comparison, the PD effects of LIN (290 µg) IR formulation was evaluated in a previous food effect study in healthy volunteers (n = 18). SBM frequency and BSFS showed an increase from baseline (median (IQR) CFB: SBM: 3.5 (3.0, 8.0) and 1.0 (0.0, 4.0); BSFS: 2.3 (2.1, 2.8) and 1.6 (1.3, 2.4) in fed and fasted state, respectively) with a greater mean CFB in the fed state vs. the fasted (P &lt; 0.01). Diarrhea was reported in those who received IR LIN 290 µg. CONCLUSION: MD-7246, a delayed-release formulation of LIN, was safe and well tolerated for 7 days at all 3 doses. MD-7246 appears to have distinct clinical properties from the approved LIN 290 µg IR formulation and showed no effect on SBM frequency or stool consistency. In comparison, SBM frequency increased and stool consistency shifted to looser stools in healthy volunteers following LIN 290 µg IR QD for 7 days.

Effects of Ingesting a Food Bar Containing Whey Protein and Isomalto‐Oligosaccharides on Performance and Recovery from an Acute Bout of Resistance‐Exercise and Sprint‐Conditioning

We previously reported that consuming a food bar (FB)containing whey protein and the plant fiber isomalto‐oligosaccharides [IMO] hada lower glycemic but similar insulinemic response as a high glycemic indexcarbohydrate. Therefore, we hypothesized that ingestion of this FB prior to, during, and following intense exercise would better maintain glucosehomeostasis and exercise capacity during exercise as well as hasten recovery incomparison to a carbohydrate matched placebo (PLA). Twelve resistance‐trainedmales participated in an open label, randomized, counterbalanced, cross‐overtrial with a 7‐d washout period. Participants consumed a carbohydrate matcheddextrose PLA or a FB containing 20 g of whey, 25 g of IMO, and 7 g of fat 30‐min prior to, mid‐way, and following intense exercise. Participantsperformed 11 resistance‐exercises (3 sets of 10 repetitions at 70% of onerepetition maximum) followed by performing agility and sprint conditioningdrills for time. Participants donated blood samples, performed isokineticstrength tests, and rated perceptions of muscle soreness and hypoglycemia priorto and following exercise and after 48 hours of recovery. Data were analyzed bygeneral linear model repeated measures and are reported as mean change frombaseline with 95% confidence intervals. Results revealed that blood glucose wassignificantly higher 30‐min post‐ingestion with PLA (PLA 3.1 [2.0, 4.3], FB 0.8[0.2, 1.5] mmol/L, p=0.001) while post‐exercise ratio of insulin to glucose wasgreater with FB (PLA 0.04 [0.00, 0.08], FB 0.11 [0.07, 0.15], p=0.013, η2=0.25). Total lifting volume was maintained toa greater degree from Set 1 to Set 3 with FB than PLA (PLA −198.26 [−320.1, −76.4], FB −81.7 [−203.6, 40.1] kg, p=0.175, η2=0.08). Ratings of muscle soreness of thedistal vastus medialis to a standard amount of pressure were lower with FB (PLA1.88 [0.60, 3.17]; FB 0.29 [−0.99, 1.57] cm, p=0.083, η2=0.13). However, no significant differences were observed between treatments in sprintperformance, isokinetic strength, markers of catabolism, stress and sexhormones, or inflammatory markers. Results indicate that ingestion ofthis FB can positively affect glucose homeostasis, sustain exerciseperformance, and lessen perceptions of muscle soreness after intense training.Support or Funding InformationThis study was supported internally by Dr. Richard B. Kreider and the Exercise and Sport Nutrition Laboratory at Texas A&amp;M University as part of a student dissertation. Dr. Conrad Earnest served as a Director of Clinical Sciences for Nutrabolt. Dr. Kreider served as a university approved scientific advisor for Nutrabolt. Dr. Peter Murano serves as Texas A&amp;M University approved quality assurance supervisor.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The efficacy of pregabalin for treating pain associated with diabetic peripheral neuropathy in subjects with type 1 or type 2 diabetes mellitus

Objective: The objective of this study was to compare the efficacy and safety of pregabalin for painful diabetic peripheral neuropathy (pDPN) in subjects with type 1 (T1DM) or 2 diabetes mellitus (T2DM).Methods: Pooled data from 10 randomized clinical trials (pregabalin-treated T1DM and T2DM subjects with pDPN) were analyzed for change from baseline (CFB) scores (pain and sleep disturbance) using mixed model repeated measures (MMRM) through Week 12 and last observation carried forward (LOCF). Adverse events (AEs) were recorded.Results: Pregabalin-treated (T1DM 156 [8.7%]; T2DM 1632 [91.3%]) and placebo subjects (T1DM 92 [9.6%]; T2DM 868 [90.4%]) had comparable baseline demographic characteristics between treatment groups within the same diabetes type. T2DM (vs. T1DM) subjects were ∼10 years older. With pregabalin and placebo, respectively, mean ± SD baseline pain (T1DM: 6.2 ± 1.4 and 6.5 ± 1.6; T2DM: 6.5 ± 1.5 and 6.4 ± 1.5) and sleep scores (T1DM: 5.2 ± 2.4 and 5.2 ± 2.7; T2DM: 5.3 ± 2.5 and 5.1 ± 2.5) were comparable. Using MMRM, mean CFB treatment differences (pregabalin minus placebo) were significantly different for pain and sleep with either diabetes types (all weeks p < .05). With LOCF, pregabalin’s odds ratios (ORs) of achieving 30% pain reduction were similar with T2DM (OR, 1.91, 95% CI [1.61, 2.27]) and T1DM (2.01 [1.18, 3.44]) (both p ≤ .01). Pregabalin’s ORs of 30% improvement in sleep quality were 1.81 (95% CI, 1.06, 3.09) with T1DM and 2.01 (1.69, 2.39) with T2DM (both p < .05). AEs were consistent with the known safety profile of pregabalin.Conclusions: Pregabalin significantly improved pain and sleep quality, without a clinically meaningful difference between diabetes types.ClinicalTrial.gov registration: NCT00156078, NCT00159679, NCT00143156, NCT00553475.

Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study

ObjectivesTo assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid...

Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: Results from a randomized phase II trial

Objectives: This phase II, dose-ranging, double-blind, placebo-controlled, randomized study (NCT01463059) evaluated efficacy and safety of olokizumab (OKZ), a humanized anti-interleukin 6 monoclonal antibody, in Asian patients with moderately-to-severely active rheumatoid arthritis (RA) who had previously failed anti-TNF therapy.Methods: Patients were randomized to one of six treatment arms: placebo or OKZ (60 mg/120 mg/240 mg every four weeks [Q4W]; or 60 mg/120 mg every two weeks [Q2W]); stratified by country and number of prior anti-TNFs. Primary efficacy variable was Week 12 change from baseline (CFB) in DAS28 CRP for 4-week cumulative dose groups of OKZ and placebo; secondary efficacy variables were Week 12 ACR20/ACR50/ACR70 response rates. Patients continued MTX treatment from baseline, without additional csDMARDs.Results: Of 119 randomized patients, 88.2% completed the study. Greater improvements in DAS28(CRP) mean CFB at Week 12 were observed in all OKZ 4-week cumulative dose groups (60 mg/120 mg/240 mg) versus placebo (p < 0.0001). Week 12 ACR20/ACR50 response rates were higher in all OKZ cumulative dose groups versus PBO (p < 0.05). Incidences of adverse events were similar across OKZ 4-week cumulative dose groups (76.9–84.4%) and placebo (82.8%) with no deaths.Conclusions: OKZ demonstrated improvements in efficacy variables versus placebo in Asian patients with moderately-to-severely active RA who had previously failed anti-TNF therapy. The safety profile was as expected for this class of drug.

Impact of Methadone Dose and Baseline Bowel Movement Frequency on Efficacy of Lubiprostone for Opioid-Induced Constipation

Introduction: Opioid-induced constipation (OIC) is a frequent side-effect of opioids due to disruption of GI electrolyte and fluid secretion by opioid receptor binding. Lubiprostone (LUB) induces fluid secretion via activation of ClC-2 chloride channels in intestinal epithelium, bypassing these antisecretory effects. LUB efficacy was evaluated in 2 identically designed, randomized, placebo (PBO)-controlled 12-week, phase 3 studies in subjects with chronic, non-cancer pain and documented OIC. Study 0631 met the primary efficacy endpoint, Study 0632 did not. Demographic and baseline characteristics were comparable, but 0632 had more subjects with ≥3 spontaneous bowel movements (SBMs) per week at baseline and a 32% higher mean morphine-equivalent daily dose (MEDD) for subjects taking methadone. Methadone dose-dependently attenuates the ClC-2-mediated secretory effect of LUB (Cuppoletti et al., Cell Biochem Biophys 2013;66:53-63). We assessed the impact of baseline SBM frequency and methadone use on LUB efficacy. Methods: Post-hoc sensitivity analyses examined overall change from baseline (CFB) in SBM frequency in subjects with <3 SBMs per week at baseline taking only non-methadone-type opioids. Regression analysis evaluated the relationship between methadone MEDD and overall SBM frequency. Results: For the protocol-specified intent-to-treat population, overall mean CFB in SBM frequency for LUB vs. PBO was significantly greater for 0631 (2.7 vs 2.1; P=0.0047), but not for 0632 (2.6 vs 2.3; P=0.2242). When the 0632 population is adjusted to include only subjects with <3 SBMs per week at baseline, the p-value decreases to p=0.1401 (2.7 vs. 2.4 SBMs per week for LUB vs. PBO). Removal of subjects taking methadone from the 0632 analysis results in near statistical significance (2.8 vs. 2.3 SBMs per week for LUB vs. PBO; p=0.0548), showing the substantial impact of methadone use. Despite the smaller population, overall CFB in SBM frequency for only subjects with <3 SBMs per week at baseline and taking non-methadone opioids was statistically significant for LUB vs. PBO in both studies 0631 (2.9 vs. 2.3 SBMs per week, p=0.0086) and 0632 (2.9 vs. 2.4 SBMs per week, p=0.0479). Regression analysis also showed a MEDD-dependent trend in the methadone effect on LUB efficacy. In both studies, adverse events for LUB were mild to moderate and mainly GI-related. Conclusion: Overall, LUB significantly increases overall SBM frequency in subjects with <3 SBMs at baseline; efficacy is decreased by high-dose methadone. LUB is well tolerated in OIC subjects. These results are consistent with those of a separate randomized, PBO-controlled study of LUB efficacy that excluded methadone subjects. Disclosure - Dr.Cryer - Consultant: Sucampo Pharma Americas LLC; Dr. Lichtlen - Consultant: Sucampo AG; Mr. Wang - Employee: Sucampo Pharma Americas, LLC; Ms. Losch-Beridon: Employee and Stockholder: Sucampo Pharma Americas, LLC. This research was supported by an industry grant from Sucampo Pharma Americas, LLC; Takeda Pharmaceuticals International, Inc.

SAT0084 Effects of different steroid doses on adverse events and radiographic progression of certolizumab pegol-treated rheumatoid arthritis patients

BackgroundUse of oral corticosteroids (CS) in rheumatoid arthritis (RA) remains controversial. While short-term use in early disease or during flares is suggested to reduce inflammation and erosion, side effects and...

AB0501 Efficacy and safety of certolizumab pegol (CZP) with concomitant methotrexate (MTX) in korean rheumatoid arthritis (RA) patients (PTS) with an inadequate response to MTX

BackgroundCZP as a concomitant therapy to MTX has shown rapid and sustained efficacy in RA pts in previous international clinical trials.ObjectivesTo confirm the efficacy and safety of CZP+MTX in Korean...

SAT0281 Impact of Imputation Methodology on Radiographic Progression Outcomes in the Rapid-Psa Study Of Certolizumab Pegol In Patients With Psoriatic Arthritis

BackgroundRAPID-PsA (NCT01087788) investigates the efficacy and safety of certolizumab pegol (CZP) in psoriatic arthritis (PsA).1ObjectivesTo analyse radiographic progression in PsA patients (pts) in the RAPID-PsA study using different imputation methods...

The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study

BackgroundEmpagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters.MethodsA randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. Treatments: single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1–4 hours after dosing.ResultsThirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18–52] years) were randomised. The placebo-corrected MCfB in QTcN 1–4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2–4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis.Conclusions/interpretationSingle doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers.Trial registrationClinicalTrials.gov: NCT01195675

Loteprednol Etabonate Suspension 0.2% Administered QID Compared With Olopatadine Solution 0.1% Administered BID in the Treatment of Seasonal Allergic Conjunctivitis: A Multicenter, Randomized, Investigator-Masked, Parallel Group Study in Chinese Patients

BackgroundSeasonal allergic conjunctivitis (SAC) is caused by seasonal allergens and usually manifests as ocular itching and bulbar conjunctival injection (redness). Treatment options for SAC include corticosteroids and dual-acting antihistamine and mast-cell stabilizers. ObjectiveOur objective was to compare the efficacy and tolerability of loteprednol etabonate (LE), a C-20 ester-based corticosteroid, with those of olopatadine, a dual-acting antihistamine mast-cell stabilizer, in Chinese patients. MethodsThis was a multicenter, randomized, investigator-masked, parallel group study. Patients with acute SAC experiencing grade 4 ocular itching and grade 2 or higher bulbar conjunctival injection received either LE suspension 0.2% QID at 4-hour intervals or olopatadine solution 0.1% BID at 6- to 8-hour intervals bilaterally for 15 days. Primary efficacy end points included the change from baseline (CFB) in ocular itching and bulbar conjunctival injection at day 15. The primary analysis tested the noninferiority of LE suspension 0.2% to olopatadine solution 0.1%. Tolerability outcomes included the incidence of adverse events (AEs), biomicroscopy findings, visual acuity, and intraocular pressure. ResultsA total of 300 patients were randomly assigned, and 293 were included in the per-protocol population (LE, n = 147; olopatadine, n = 146). Mean (SD) CFB at day 15 in the LE and olopatadine treatment groups, respectively, was −3.74 (0.47) and −3.28 (0.91) for ocular itching and −1.91 (0.52) and −1.71 (0.59) for bulbar conjunctival injection. The 95% CI for the differences in CFB in ocular itching (−0.59 to −0.27) and bulbar conjunctival injection (−0.27 to −0.08) was less than the prespecified noninferiority limit of 0.3. Treatment differences in CFB were significantly better with LE compared with olopatadine for both end points (P ≤ 0.0006). Ocular AEs were few and similar between treatment groups. There were no clinically significant biomicroscopy or visual acuity findings, and no patient experienced a clinically significant increase in intraocular pressure (≥10 mm Hg). ConclusionResults of this investigator-masked study with Chinese patients suggest LE suspension 0.2% was noninferior to olopatadine solution 0.1% for the treatment of SAC. Both LE suspension 0.2% and olopatadine solution 0.1% were well tolerated. ClinicalTrials.gov identifier: NCT01435460.

1152 Distinguishing the Impact of Dexlansoprazole on Heartburn Versus Regurgitation in Patients With NERD or EE

Purpose: To determine the impact of dexlansoprazole MR (DEX) on heartburn (HB) and regurgitation severity in nonerosive gastroesphophageal reflux disease (NERD) and erosive esophagitis (EE) patients. Methods: This was a post hoc analysis of patients enrolled in phase 3 studies either assessing the efficacy and safety of DEX vs placebo (PLB) for 24-hour HB relief in NERD or DEX vs lansoprazole (LAN) in EE healing. DEX 30 mg, DEX 60 mg, and PLB were administered to 315, 315, and 317 endoscopically confirmed NERD patients, respectively, in a randomized, double-blind, 4-week study. NERD patients were to have a ≥6 month history of HB. In two 8-week, double-blind, randomized healing studies, 2737 endoscopically confirmed EE patients received DEX 60 mg or LAN 30 mg. In all studies, the Patient Assessment of Upper Gastrointestinal-Symptom Severity questionnaire (PAGISYM) was administered at baseline to assess symptom severity. The PAGI-SYM was also completed at Weeks 2 and 4 of the NERD study, and at Weeks 4 and 8 during the EE healing trials. The PAGI-SYM, a validated questionnaire, includes items assessing severity of HB and regurgitation on a scale of 0 to 5 (no symptoms, mild, moderate, severe and very severe symptoms) yielding a HB/regurgitation subscale. Using the PAGI-SYM questions included in this subscale, we defined separate subscales for HB and regurgitation. Among patients who had both symptoms at baseline (defined as at least mild HB and at least mild regurgitation in the individual subscales), we looked at the change from baseline (CFB) in individual HB and regurgitation subscales along with the original combined HB/regurgitation subscale. Negative CFBs indicate symptom improvement. A CFB of ≥0.55 was considered the minimally important difference for the HB/regurgitation subscale score. Results: In the NERD study, 661 patients had both HB and regurgitation at baseline, as did 1909 patients in the EE study. Table 1 and Table 2 provide the mean CFB in the subscale scores for the NERD and EE patients, respectively. NERD patients receiving DEX 30 and 60 mg experienced significantly greater improvements in symptom severity for both HB and regurgitation compared to PLB. EE patients receiving DEX 60 mg had significantly greater improvements in HB/regurgitation and HB-only subscales at Week 4 compared to those receiving LAN. Conclusions: DEX appears to be effective in improving both the mechanical (regurgitation) and chemical (HB) aspects of GERD symptoms and this improvement is maintained for the duration of treatment. Table 1. NERD

A multicenter, randomized, parallel-group, clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with blepharokeratoconjunctivitis

Objective:To compare the efficacy and safety of loteprednol etabonate 0.5%/tobramycin 0.3% (LE/T) and dexamethasone 0.1%/tobramycin 0.3% (DM/T) ophthalmic suspensions in a Chinese population with ocular inflammation associated with blepharokeratoconjunctivitis (BKC).Research design and methods:This study was a multicenter, randomized, investigator-masked, parallel-group clinical trial. Patients aged ≥18 years with a clinical diagnosis of BKC in at least one eye received LE/T or DM/T administered 4 times daily for 2 weeks. At baseline and on days 3, 8, and 15 (visits 2, 3, and 4), clinical assessments of ocular signs and symptoms, visual acuity (VA), biomicroscopy, and intraocular pressure (IOP) were performed in both eyes.Main outcome measures:The primary efficacy endpoint was the change from baseline (CFB) to visit 4 in the signs and symptoms composite score in designated study eyes using a non-inferiority metric to compare LE/T to DM/T. Safety evaluation included adverse events, biomicroscopy findings, and changes in VA and IOP.Clinical trial registration:NCT number, NCT01028027.Results:A total of 308 patients were included in the per protocol population (n = 156 LE/T, n = 152 DM/T). A significant CFB in composite signs and symptoms was seen with both treatments at each follow-up visit (p < 0.0001). The mean (SD) CFB at visit 4 was −11.63 (4.56) and −12.41 (4.71) in the LE/T and DM/T groups, respectively, and the upper bound of the 90% confidence interval for the difference was less than the prespecified non-inferiority margin. Comparable results were found for secondary efficacy outcomes. Patients treated with DM/T experienced a significantly greater increase in mean CFB in IOP compared to those treated with LE/T at all follow-up visits (p ≤ 0.0186) and nearly twice as many IOP elevations ≥5 mmHg (p = 0.0020).Conclusion:Treatment with LE/T was at least as effective as DM/T in Chinese patients with BKC and had a better safety profile with respect to change in IOP.

Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study

To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone. In this randomized, double-blind, active-controlled, parallel-group study, patients with type 2 diabetes and A1c ≥7.0 and ≤10.0% on metformin (≥1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non-inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52. Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, -0.70 vs. -0.29%; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c ≤7.0 (33.2 vs. 21.3%) and ≤6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, -0.8 vs. -0.2 mmol/L; p < 0.001); and greater improvements in measures of β-cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments. Adding alogliptin to an existing metformin-pioglitazone regimen provided superior glycaemic control and potentially improved β-cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety.

The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses.

To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QT(c) interval in healthy subjects. The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QT(c) I) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained. Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QT(c) I, at any time point. The placebo-corrected MCfB of QT(c) I was -1.1 (90% CI -2.7, 0.5) ms and -2.5 (-4.1, -0.9) ms for linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were ∼24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QT(c) I with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. Therapeutic and significantly supratherapeutic exposure to linagliptin is not associated with QT interval prolongation.

Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules in Patients with Chronic Osteoarthritis Pain

Objective: To assess the efficacy and safety of morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®; MS-sNT), which contain morphine sulfate pellets with a sequestered naltrexone core, in treating patients with chronic, moderate-to-severe osteoarthritis (hip or knee) pain. Patients and Methods: This phase 3 study had an enriched-enrollment, randomized-withdrawal, double-blind, multicenter design. Patients (N = 547) were titrated to an effective dose of MS-sNT (20–160 mg/day). Responders (n = 344) were randomized to 12 weeks maintenance with an effective MS-sNT dose or were tapered to placebo over 2 weeks. The primary efficacy measure was the change from baseline (CFB) in diary average-pain scores (0–10 scale, Brief Pain Inventory [BPI]) from randomization to the last 7 days of the maintenance period. Secondary efficacy measures included the remaining BPI scores and Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. Opioid withdrawal symptoms were assessed by the Clinical Opiate Withdrawal Scale (COWS) and Subjective Opiate Withdrawal Scale (SOWS). The study ran from January 10, 2007 through November 8, 2007. Results: MS-sNT maintained pain control better than placebo (mean CFB, diary average-pain score, −0.2 ± 1.9 vs +0.3 ± 2.1; P = 0.045). Change from baseline for MS-sNT pain-diary score (worst, least, average, current) was superior during the maintenance period visits, weeks 2 to 12 (P < 0.05). WOMAC composite score CFB was superior at most visits. MS-sNT was generally well tolerated, with a typical morphine safety profile. No patient taking MS-sNT as directed experienced withdrawal symptoms. Conclusion: MS-sNT provided effective analgesia in patients with chronic, moderate-to-severe osteoarthritis pain, with a safety profile typical of morphine-containing products. Naltrexone sequestered in MS-sNT had no clinically relevant effect when MS-sNT was taken as directed.

Once-daily Fluticasone Furoate∗ Nasal Spray (FF) Provides 24-hour Symptom Relief In Subjects With Seasonal Allergic Rhinitis (SAR) Caused By Mountain Cedar Pollen ∗USAN approved name

RATIONALE: FF is a novel enhanced-affinity steroid being developed for the treatment of rhinitis.METHODS: Three hundred two subjects (≥12 years) with active SAR to mountain cedar pollen were randomized to once-daily FF 110mcg or placebo spray administered in a unique, side-actuated device. Primary endpoint: Mean change from baseline (MCFB) over the entire 2-week treatment period in daily reflective total nasal symptoms scores (rTNSS), which was the sum of 4 symptoms: nasal congestion, itching, rhinorrhea, and sneezing. Key secondary endpoints were MCFB in AM pre-dose instantaneous total nasal symptoms scores (iTNSS), overall response to therapy (ORT), and MCFB in daily reflective total ocular symptoms scores (rTOSS). Total ocular scores were the sum of 3 symptoms: eye itching/burning; tearing/watering; and redness. Nasal and ocular symptom data were analyzed using ANCOVA. ORT was analyzed using logistic regression.RESULTS: For the primary endpoint, MCFB in rTNSS, FF 110mcg was significantly more effective at improving the nasal symptoms of SAR compared with placebo (p = 0.003). FF 110mcg also was significantly more effective for the key secondary endpoints: MCFB in AM pre-dose iTNSS (p <0.001), ORT (p <0.001), and MCFB in rTOSS (p =0.008). The incidence of epistaxis was 7% and 5% in the placebo and FF groups, respectively, but in each group, only 3% were considered drug-related. There were no serious AEs.CONCLUSIONS: The results of this study support the use of once-daily FF 110 mcg for the symptoms of seasonal allergic rhinitis caused by mountain cedar pollen in subjects 12 years of age and older. RATIONALE: FF is a novel enhanced-affinity steroid being developed for the treatment of rhinitis. METHODS: Three hundred two subjects (≥12 years) with active SAR to mountain cedar pollen were randomized to once-daily FF 110mcg or placebo spray administered in a unique, side-actuated device. Primary endpoint: Mean change from baseline (MCFB) over the entire 2-week treatment period in daily reflective total nasal symptoms scores (rTNSS), which was the sum of 4 symptoms: nasal congestion, itching, rhinorrhea, and sneezing. Key secondary endpoints were MCFB in AM pre-dose instantaneous total nasal symptoms scores (iTNSS), overall response to therapy (ORT), and MCFB in daily reflective total ocular symptoms scores (rTOSS). Total ocular scores were the sum of 3 symptoms: eye itching/burning; tearing/watering; and redness. Nasal and ocular symptom data were analyzed using ANCOVA. ORT was analyzed using logistic regression. RESULTS: For the primary endpoint, MCFB in rTNSS, FF 110mcg was significantly more effective at improving the nasal symptoms of SAR compared with placebo (p = 0.003). FF 110mcg also was significantly more effective for the key secondary endpoints: MCFB in AM pre-dose iTNSS (p <0.001), ORT (p <0.001), and MCFB in rTOSS (p =0.008). The incidence of epistaxis was 7% and 5% in the placebo and FF groups, respectively, but in each group, only 3% were considered drug-related. There were no serious AEs. CONCLUSIONS: The results of this study support the use of once-daily FF 110 mcg for the symptoms of seasonal allergic rhinitis caused by mountain cedar pollen in subjects 12 years of age and older.

Improved pH-Metry and Symptom Scores 3 mo Post-ENTERYX®

Purpose: To compare pH-metry and GERD-HRQL scores in ENTERYX treated (EG) vs control (CG) groups. Methods: PPI-dependent and responsive pts were randomized to either EG or CG. CG pts underwent endoscopy; DMSO was sprayed on distal esophagus. 3 mo post initial procedure, EG pts w/ GERD-HRQL score >11 (off PPIs) were eligible for retreatment; CG pts who were off PPIs with GERD-HRQL ≥20 and pH<4.0 for >5% of total time were eligible for crossover to ENTERYX. pH-metry success was defined as either total time pH ≤4.0 for ≤5% or total time pH ≤4.0 reduced ≥50% from baseline. GERD-HRQL score success was defined as either a score of ≤11 or an improvement from baseline ≥9 points. Results: Interim 3-mo data were available for 62 pts (31/group). To date, 61% (19/31) of CG pts crossed over and 13% (4/31) of EG pts were retreated. These initial results reflect outcomes from one ENTERYX treatment. Mean change from baseline (CFB) in pH-metry (% total time pH ≤ 4.0) was −4.3% in EG, vs −0.5% in CG (p < 0.05). pH-metry success was achieved by 50% of EG vs 23% of CG (p < 0.05). EG had more patients achieve GERD-HRQL heartburn score success (83% vs 54%, p < 0.05) and had larger mean CFB for GERD-HRQL heartburn (−14.9 vs −9.2, p < 0.05) than the CG. Conclusions: At 3 mo, ENTERYX Procedure significantly improves pH-metry and GERD-HRQL measures vs control. Furthermore, the proportion of pts eligible for retreatment/crossover was lower in the ENTERYX group than in controls, despite similar eligibility criteria. These results confirm the true effect of ENTERYX in the treatment of GERD.