Controlled-release Group Research Articles

Clinical Trial: Efficacy of Mosapride Controlled-release and Nortriptyline in Patients With Functional Dyspepsia: A Multicenter, Double-placebo, Double-blinded, Randomized Controlled, Parallel Clinical Study.

Prokinetic agents and neuromodulators are among the treatment options for functional dyspepsia (FD), but their comparative efficacy is unclear. We aimed to compare the efficacy of mosapride controlled-release (CR) and nortriptyline in patients with FD after 4 weeks of treatment. Participants with FD were randomly assigned (1:1) to receive mosapride CR (mosapride CR 15 mg and nortriptyline placebo) or nortriptyline (mosapride CR placebo and nortriptyline 10 mg) in double-placebo, double-blinded, randomized controlled, parallel clinical study. The primary endpoint was defined as the proportion of patients with overall dyspepsia improvement after 4 weeks treatment. The secondary endpoints were changes in individual symptom scores, anxiety, depression, and quality of life. One hundred nine participants were recruited and assessed for eligibility, and 54 in the mosapride CR group and 50 in the nortriptyline group were included in the modified intention-to-treat protocol. The rate of overall dyspepsia improvement was similar between groups (53.7% vs 54.0%, P = 0.976). There was no difference in the efficacy of mosapride CR and nortriptyline in a subgroup analysis by FD subtype (59.3% vs 52.5% in postprandial distress syndrome, P = 0.615; 44.4% vs 40.0% in epigastric pain syndrome, P = > 0.999; 50.0% vs 59.1% in overlap, P = 0.565; respectively). Both treatments significantly improved anxiety, depression, and quality of life from baseline. Mosapride CR and nortriptyline showed similar efficacy in patients with FD regardless of the subtype. Both treatments could be equally helpful for improving quality of life and psychological well-being while also relieving dyspepsia.

Study Explores Effects of Hypnotics on Suicidal Ideation

Study Explores Effects of Hypnotics on Suicidal Ideation

Clinical evaluation of ropinirole controlled-release formulation at 18–24 mg/day in Japanese patients with Parkinson's disease

IntroductionThere has been no clinical data on Japanese patients with Parkinson's disease with which to examine whether motor symptoms improve and to assess the safety profile after the dose of ropinirole was increased in those who had not achieved an optimal response to the ropinirole immediate-release formulation 15 mg/day or the controlled-release (CR) formulation 16 mg/day. MethodsThis was a multicenter, randomized, double-blind study, followed by an open-label, long-term study. Participants were randomized at a ratio of 3:1 to the high-dose ropinirole CR (18–24 mg/day) group or the maintenance ropinirole CR 16 mg/day group. ResultsIn the high-dose ropinirole CR group (N = 61), the Japanese unified Parkinson's disease rating scale Part III total score at week 12 was significantly decreased compared with the baseline total score (−4.8 ± 5.95, [95% CI, −6.3 to −3.2], p < 0.001). However, a comparable decrease was also observed in the maintenance ropinirole CR 16 mg/day group (N = 20) (−5.7 ± 5.18, [95% CI, −8.1 to −3.3]), with no statistically significant difference in the adjusted mean change between the high-dose and maintenance groups (0.5 [95% CI, −2.4 to 3.4]). Plasma drug concentrations increased at doses higher than 16 mg/day, but did not increase significantly in a dose-dependent manner at doses of 18–24 mg/day. No adverse events were found that would affect the known safety profile of ropinirole. ConclusionThis study did not demonstrate the difference in efficacy between the high-dose ropinirole CR group and the maintenance ropinirole CR group. Clinical trial registrationClinicalTrials.gov identifier: NCT01929317.

Tolerability and efficacy of tapentadol extended release in elderly patients ≥ 75 years of age with chronic osteoarthritis knee or low back pain.

Management of chronic pain in elderly adult patients is often complicated by analgesic medication-related side effects. This post hoc analysis of pooled data evaluated the tolerability and analgesic efficacy of tapentadol extended release (ER) compared with oxycodone controlled release (CR) in elderly adult patients (≥ 75 years of age) with moderate to severe, chronic osteoarthritis knee or low back pain. Data were pooled from three similarly designed, randomized, doubleblind, placebo- and active-controlled, phase 3 studies of tapentadol ER for moderate to severe, chronic osteoarthritis knee (NCT00421928, NCT00486811) or low back (NCT00449176) pain, and data for patients ≥ 75 years of age were evaluated. Each study consisted of a 3-week titration and 12-week maintenance period. Patients received placebo, tapentadol ER (100-250 mg bid), or oxycodone HCl CR (20-50 mg bid). Tolerability was evaluated using adverse event reporting. Efficacy was evaluated using pain intensity ratings (11-point numerical rating scale). For patients ≥ 75 years of age (n = 210), incidences of gastrointestinal treatment-emergent adverse events (TEAEs) overall and TEAEs of vomiting and the composite of nausea and/or vomiting were significantly lower in the tapentadol ER group compared with the oxycodone CR group (all p ≤ 0.0206). Tapentadol ER treatment was associated with significant reductions in pain intensity from baseline to week 15 compared with placebo (p = 0.0075); differences between the oxycodone CR and placebo groups failed to reach statistical significance (p = 0.1195), likely related to a higher treatment discontinuation rate in the oxycodone CR group. No significant differences were observed between the tapentadol ER and oxycodone CR groups in the change in pain intensity from baseline to week 15 (p = 0.2135). In elderly adult patients ≥ 75 years of age with moderate to severe, chronic osteoarthritis knee or low back pain, tapentadol ER (100-250 mg bid) provided significant pain relief compared with placebo and had a better overall gastrointestinal tolerability profile than oxycodone CR.

Phase 1 Study Results of a Novel Controlled-Release Formulation of Anagrelide (GALE-401) for the Treatment of Thrombocytosis

Introduction: Despite recent advances in the diagnosis and management of myeloproliferative neoplasms (MPNs), treatment of essential thrombocythemia (ET) has remained largely unchanged since the introduction of anagrelide in the US during 1997. Anagrelide is indicated for the treatment of thrombocythemia, to reduce the elevated platelet count and risk of thrombosis, and to ameliorate symptoms including thrombohemorrhagic events. The primary pharmacological effect of anagrelide is inhibition of megakaryocyte hypermaturation leading to reduced platelet production. Anagrelide also inhibits cyclic AMP phosphodiesterase III (PDE3), and common drug related adverse events (AEs; e.g., headache, palpitations, fluid retention, nausea and diarrhea) are believed to be due to this mechanism. Although initiating treatment at low doses and slowly increasing the dose to reach a target decreased platelet count may mitigate AEs, over 20% of patients still withdraw from treatment due to poor tolerability. As the currently marketed anagrelide product is an immediate release (IR) formulation with peak plasma concentrations (Cmax) that may exceed that needed for platelet reduction and cause unwanted PDE3 inhibition and AEs, an alternate formulation that modifies this pharmacokinetic (PK) profile may improve patient tolerability, adherence and treatment outcomes. This has led to the development and study of a controlled-release (CR) formulation of anagrelide (GALE-401).Methods: 98 healthy adult subjects were enrolled among 5 Phase 1 clinical trials of anagrelide CR, including 12 placebo-control subjects and 86 subjects who received single or multiple doses ranging from 0.2 to 0.6 mg twice daily (b.i.d.) for up to 41 days. The trials included an open-label, single dose developmental study; two placebo-controlled multiple dose ranging studies; a food effect study; and a comparative crossover PK study vs. IR reference product. Safety parameters included routine laboratory, ECG, and clinical evaluations. PK was assessed by measurements of plasma anagrelide and its active metabolite using a validated HPLC-MS/MS method. Pharmacodynamic activity was assessed by daily platelet count determinations in the multiple dosing studies.Results: Single doses of anagrelide CR were well tolerated, and the only drug-related AE reported in 2 or more subjects was headache. In the b.i.d. dose-ranging studies, the frequency and severity of AEs were similar between anagrelide CR and placebo groups, with the exception of decreased platelet counts in subjects receiving anagrelide CR. All AEs were transient, mild or moderate in severity, and no severe or serious AEs were reported.Anagrelide CR demonstrated dose proportional PK characteristics. Following a single 0.5 mg dose in the fasted state, the mean time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2) were 2.0±1.5 hrs and 10.4±9.3 hrs (mean ± SD), respectively; in contrast, Tmax and t1/2 following IR was 1.0±0.9 hrs and 1.4±0.2 hrs, respectively. Cmax and total plasma exposure (AUC0-inf) with anagrelide CR were reduced to 26% and 59% of IR, respectively. However, steady-state PK following 6 daily 0.5 mg b.i.d. doses of anagrelide CR or IR showed similar AUC0-inf values, while Cmax with anagrelide CR remained nearly unchanged (29%). Plasma exposure was higher when anagrelide CR was administered in the fed state, as demonstrated by the ratio of least-squares mean values for Cmax and AUC0-t, which were increased by 100% and 60%, respectively.The platelet lowering effect of anagrelide CR was evident in the 2 multiple dose ranging studies. In a placebo-controlled study of 0.2 to 0.6 mg b.i.d. dosing for up to 21 days, a dose-related decrease in platelet counts was observed, and the 0.6 mg cohort was halted early due to excessive platelet reductions. Anagrelide CR did not have a relevant impact on platelet function as assessed by template bleeding time. [Display omitted] Conclusion: Anagrelide CR is a promising, novel formulation of anagrelide that exhibited the desired PK profile of a significantly reduced Cmax, while maintaining plasma exposure to induce platelet count reductions. The product was well tolerated with an AE profile that was not distinguishable from placebo. These data support the importance of an ongoing Phase 2 study in patients with MPN-related thrombocytosis, including ET. DisclosuresLaliberte:Galena Biopharma, Inc.: Employment, Equity Ownership. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties. Hamilton:Galena Biopharma, Inc.: Employment, Equity Ownership.

Efficacy and Safety of Oxycodone/Naloxone Controlled Release in Comparison with Oxycodone Controlled Release in Korean Patients with Cancer Pain

ABSTRACT Aim: Oxycodone/naloxone controlled release (CR) was developed for the management of opioid-induced constipation through the local antagonistic effect of naloxone in the gut wall, while maintaining analgesia due to low bioavailability of oral naloxone. We compared the efficacy and safety of oxycodone/naloxone CR with oxycodone CR in Korean cancer pain patients. Methods: We enrolled the patients with cancer pain who had NRS score ≥4 (Numeric Rating Scale 0-10) and needed strong opioid therapy in a randomized, multicenter, open label, non-inferiority, phase IV study. The initial dose of oxycodone/naloxone CR was 20/10 mg per day which could be up-titrated according to investigator's opinion to a maximum of 80/40 mg per day. The primary outcome was the difference in NRS score at 4 weeks from baseline by intention-to-treat analysis, and the margin of non-inferiority was set to be 1.5. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) and bowel habit change were also evaluated as the secondary outcomes. Results: Total 132 patients were enrolled and 128 (64 patients in each group), 117 (58 in oxycodone/naloxone CR group) patients were included in safety set and full analysis set, respectively. The mean daily doses of oxycodone/naloxone CR and oxycodone CR group were 29.7 ± 15.2 and 26.9 ± 13.8 mg, respectively. In full analysis set, the difference in NRS at 4 weeks from baselines between the treatments with oxycodone/naloxone CR and oxycodone CR was -0.027, with the two-sided 95% confidence interval (CI) ranged from -0.830 to 0.776. The upper boundary of the 95% CI was below the margin of 1.5, confirming the non-inferiority of oxycodone/naloxone CR to oxycodone CR (p = 0.0001). The results of EORTC QLQ-C30 and bowel habit change showed that there were no statistically significant differences between the two groups. The incidence of adverse drug reactions (ADRs) was 38/64 (59.4%) in oxycodone/naloxone CR group and 41/64 (64.1%) in oxycodone CR group (p = 0.5850). Conclusions: Oxycodone/naloxone CR was non-inferior to oxycodone CR for controlling cancer pain in Korean patients with similar incidence of ADRs. Disclosure: J. Kang: this study was sponsored by Mundipharma Korea LTD.; B.S. Kim: This study was sponsored by Mundipharma Korea Ltd.; J. Jin: This study was sponsored by Mundipharma Korea Ltd.; J.H. Kwon: This study was sponsored by Mundipharma Korea Ltd.; I. Woo: This study was sponsored by Mundipharma Korea Ltd.; Y. Ko: This study was sponsored by Mundipharma Korea Ltd.; S. Park: This study was sponsored by Mundipharma Korea Ltd.; H.Y. Kim: This study was sponsored by Mundipharma Korea Ltd. HY Kim is Medical Manager of the company.

Vascular endothelial growth factor-loaded poly(lactic-co -glycolic acid) microspheres-induced lateral axonal sprouting into the vein graft bridging two healthy nerves: Nerve graft prefabrication using controlled release system

The most commonly used surgical technique for repairing segmental nerve defects is autogenous nerve grafting; however, this method causes donor site morbidity. In this study, we sought to produce prefabricated nerve grafts that can serve as a conduit instead of autologous nerve using a controlled release system created with vascular endothelial growth factor (VEGF)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres. The study was performed in vitro and in vivo. For the in vitro studies, VEGF-loaded PLGA microspheres were prepared. Thirty rats were used for the in vivo studies. Vein grafts were sutured between the tibial and peroneal nerves in all animals. Three groups were created, and an epineural window, partial incision, and microsphere application were performed, respectively. Walking track analysis, morphologic, and electron microscopic assessment were performed at the end of the eight weeks. Microspheres were produced in spherical shapes as required. Controlled release of VEGF was achieved during a 30-days period. Although signs of nerve injury occurred initially in the partial incision groups according to the indexes of peroneal and tibial function, it improved gradually. The index values were not affected in the other groups. There were many myelinated fibers with large diameters in the partial incision and controlled release groups, while a few myelinated fibers that passed through vein graft in the epineural window group. Thereby, prefabrication was carried out for the second and third groups. It was demonstrated that nerve graft can be prefabricated by the controlled delivery of VEGF.

Co-delivery of Adipose-Derived Stem Cells and Growth Factor-Loaded Microspheres in RGD-GraftedN-Methacrylate Glycol Chitosan Gels for Focal Chondral Repair

The coencapsulation of growth factor-loaded microspheres with adipose-derived stem cells (ASCs) within a hydrogel matrix was studied as a potential means to enhance ASC chondrogenesis in the development of a cell-based therapeutic strategy for the regeneration of partial thickness chondral defects. A photopolymerizable N-methacrylate glycol chitosan (MGC) was employed to form an in situ gel used to encapsulate microspheres loaded with bone morphogenetic protein 6 (BMP-6) and transforming growth factor-β3 (TGF-β3) with human ASCs. ASC viability and retention were enhanced when the Young's modulus of the MGC ranged between 225 and 380 kPa. Grafting an RGD-containing peptide onto the MGC backbone (RGD-MGC) improved ASC viability within the gels, remaining at greater than 90% over 14 days in culture. The effects of BMP-6 and TGF-β3 released from the polymer microspheres on ASC chondrogenesis were assessed, and the level of differentiation was compared to ASCs in control gels containing nongrowth factor-loaded microspheres cultured with and without the growth factors supplied in the medium. There was enhanced expression of chondrogenic markers at earlier time points when the ASCs were induced with the sustained and local release of BMP-6 and TGF-β3 from the microspheres. More specifically, the normalized glycosaminoglycan and collagen type II protein expression levels were significantly higher than in the controls. In addition, the ratio of collagen type II to type I was significantly higher in the microsphere delivery group and increased over time. End-point RT-PCR analysis supported that there was a more rapid induction and enhancement of ASC chondrogenesis in the controlled release group. Interestingly, in all of the assays, there was evidence of chondrogenic differentiation when the ASCs were cultured in the gels in the absence of growth factor stimulation. Overall, the co-delivery of growth-factor-loaded microspheres and ASCs in RGD-modified MGC gels successfully induced ASC chondrogenesis and is a promising strategy for cartilage repair.

Comparison between Two Calcium Antagonists: Blood Pressure Reduction and Renal Effects in Hypertensive Patients with Type 2 Diabetes

Several types of Ca channel blockers (CCBs) which have unique organ protective effects are commercially available all over the world. However, the hypotensive and pleotropic effect in CCBs are not sufficiently assessed in the diabetic patient with refractory hypertension for angiotensin receptor blocker (ARB). We conducted a pilot study to compare the efficacy of two different CCBs (azelnidipine and nifedipine controlled release (CR)) in 55 hypertensive patients with type 2 diabetes who had not achieved their target blood pressure (BP) with ARB monotherapy. Patients were randomly assigned to receive azelnidipine (8–16 mg/day) or nifedipine CR (10–40 mg/day) concomitantly with valsartan (80 mg/day). There were no significant differences in baseline characteristics between the two groups. The final dose of azelnidipine and nifedipine CR was 13.3±3.9 and 17.1±9.4 mg/day, respectively. However the target BP (<130/80mmHg) achievement rate was higher in the earlier phase of the combination therapy with nifedipine CR than that of the azelnidipine group, the rates after 6 months were comparable between the groups (83 vs. 66%). The systolic blood pressure was significantly lower in the nifedipine CR group from 2 to 6 months after the combination therapy (P<0.05, respectively). Both groups showed no significant changes in blood glucose and hemoglobin A1c. There were no significant differences in the urinary albumin/creatinine ratio and estimated Glomerular Filtration Rate (eGFR). In conclusion, the adjunctive therapy of nifedipine CR was superior to that of azelnidipine for decreasing blood pressure and achieving the target blood pressure, especially in the earlier phase of the diabetic patient with refractory hypertension for ARB. However the nephroprotective effect of nifedipine CR combination therapy was comparable to that of azelnidipine. Keywords: Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, albumin creatinine ratio, calcium channel blocker, estimated Glomerular Filtration Rate, diabetes, Glucose metabolism, hypertension, Renal function

Safety and Tolerability of Once-Daily Controlled-Release Carvedilol 10-80mg in Japanese Patients With Chronic Heart Failure

The aim of the present study was to assess the safety and tolerability of the controlled-release (CR) formulation of the β-blocker carvedilol in Japanese patients with chronic heart failure (HF). In this multicenter, randomized, open-label, phase I/II dose-escalation study, 41 patients receiving standard therapy for chronic HF were randomized in a ratio of 1:1 to carvedilol CR or immediate-release (IR) carvedilol. The primary objective was to evaluate the tolerability and safety of escalating doses of carvedilol CR (10-40 mg/day), with a reference arm of 5-20 mg/day of carvedilol IR. In addition, the tolerability and safety of titration to a carvedilol CR dose up to 80 mg/day were examined, as were plasma concentrations of carvedilol and changes in vital signs. The proportions of patients who completed 40-mg/day carvedilol CR and 20-mg/day carvedilol IR were 42% (8/19) and 50% (11/22), respectively. In the CR group, 7/19 (37%) attained a dose of 80 mg. During the primary evaluation period, 7/19 (37%) and 4/22 (18%) patients experienced drug-related adverse events in the CR and IR groups, respectively, the characteristics of which were similar between groups. No new safety issues emerged in Japanese chronic HF patients treated with carvedilol CR in contrast to those known in carvedilol IR.

Paroxetine controlled‐release formulation in the treatment of major depressive disorder: A randomized, double‐blind, placebo‐controlled study in Japan and Korea

The main purpose of this study was to evaluate the efficacy of paroxetine controlled-release (CR) formulation compared to placebo. A secondary objective was to test the hypothesis that the CR decreases selective-serotonin-reuptake-inhibitors-induced nausea as its formulation allows more distal gastrointestinal absorption than the paroxetine immediate-release (IR) formulation. We conducted this study in Japanese and Korean patients with major depressive disorder (MDD) in order to demonstrate the efficacy and safety of paroxetine CR compared with placebo. The primary efficacy end-point was the adjusted mean change from baseline in the 17-item Hamilton Rating Scale for Depression total score at Week 8. A total of 416 patients with MDD were randomly assigned to the CR, IR and placebo groups. The mean change from baseline in the 17-item Hamilton Rating Scale for Depression was -12.8 in the CR group, -12.5 in the IR group, and -10.4 in the placebo group, which showed a statistically significant difference compared to placebo in CR (P < 0.001) and IR (P = 0.015). The incidence of adverse events was 65% in CR, 69% in IR and 55% in placebo. The adverse events were mostly mild or moderate in severity. In the early treatment period, when initiated from 12.5 mg, the incidence of nausea in the CR group was 6%, which was comparable with that of placebo (5%). Paroxetine CR is efficacious in the acute treatment of MDD and may have the potential benefit of decreasing the incidence of nausea in the early treatment period.

Efficacy and Safety of Tapentadol Extended Release Compared with Oxycodone Controlled Release for the Management of Moderate to Severe Chronic Pain Related to Osteoarthritis of the Knee

Tapentadol is a novel, centrally acting analgesic with mu-opioid receptor agonist and norepinephrine reuptake inhibitor activity. to evaluate the efficacy and safety of Tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain. this was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received Tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive Tapentadol ER 100-250 mg twice daily, oxycodone HCl CR 20-50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation. efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], -0.7 [-1.04, -0.33]), and throughout the maintenance period (-0.7 [-1.00, -0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], -0.3 [-0.67, -0.00]) but not at week 12 (-0.3 [-0.68, 0.02]). A significantly higher percentage of patients achieved > or =50% improvement in pain intensity in the Tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved > or =50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, Tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342). treatment with Tapentadol ER 100-250 mg twice daily or oxycodone HCl CR 20-50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with Tapentadol ER than with oxycodone CR.

Safety and tolerability of tapentadol extended release (ER) versus oxycodone controlled release (CR) in elderly patients with chronic low back or osteoarthritis pain

In a phase 3, randomized, open-label, 1-year safety study in adults with moderate-to-severe chronic low back or osteoarthritis pain, tapentadol ER (100-250mg bid) provided similar pain relief to oxycodone HCl CR (20-50mg bid), with improved gastrointestinal tolerability (ClinicalTrials.gov Identifier:NCT00361504). This post-hoc analysis evaluated incidences of and study discontinuations due to overall and gastrointestinal treatment-emergent adverse events (TEAEs) among patients ≥65 years of age. Times to onset of and discontinuations due to constipation, nausea, or vomiting were estimated using Kaplan-Meier plots (treatment differences compared using the log-rank test); the percentage of treatment days with these TEAEs was calculated (treatment differences compared using the Wilcoxon test). Of 1,117 patients analyzed for safety, 312 were ≥65 years (tapentadol ER, n=245; oxycodone CR, n=67). Among patients ≥65 years in the tapentadol ER and oxycodone CR groups, respectively, 87.8% and 94.0% of patients reported ≥1 TEAE and 57.6% and 76.1% of patients reported gastrointestinal TEAEs (most were mild or moderate). Patients ≥65 years who received tapentadol ER versus oxycodone CR experienced significantly lower percentages of treatment days with nausea (5.39% vs 14.0%), vomiting (2.4% vs 7.2%), or constipation (14.9% vs 31.6%); all nominal P≤0.0021. Times to first onset of these TEAEs were significantly longer with tapentadol ER versus oxycodone CR (all nominal P≤0.0002 [log-rank test]). In the tapentadol ER and oxycodone CR groups, respectively, any TEAE led to study discontinuation in 33.1% and 49.3% and gastrointestinal TEAEs led to study discontinuation in 14.3% and 31.3% of patients ≥65 years. Times to withdrawal due to nausea, vomiting, or constipation were significantly longer with tapentadol ER versus oxycodone CR (all nominal P≤0.0099). Tapentadol ER was associated with better gastrointestinal tolerability and a lower rate of study discontinuations due to TEAEs than oxycodone CR in patients ≥65 with moderate-to-severe chronic pain. (OMJSA and Grünenthal GmbH supported this study.)

Controlled-release oxycodone alone or combined with gabapentin for management of malignant neuropathic pain

Objective: To evaluate the analgesic efficacy of controlled-release (CR) oxycodone and gabapentin in malignant neuropathic pain (NP). Methods: Patients with malignant NP were enrolled and baseline pain intensity (PI) was recorded. They initially took one week CR oxycodone and were allocated to two different groups at day 8 by reevaluated PI. Patients with mild pain went to CR oxycodone mono-therapy group (OO group) and took another two weeks CR oxycodone. Others went to (CR oxycodone combined gabapentin group (OG group) and received additional gabapentin. Daily doses and side effects were recorded. Results: Fifty-eight (92.06%) of the 63 enrolled patients completed the initial week’s therapy. Twenty-two (37.93%) went to OO group and PI significantly reduced at day 15 (2.00 vs. 2.62, P=0.004), but not improved at day 22 (1.90 vs. 2.00, P=0.54). Thirty-six (62.07%) patients went to OG group and PI was significantly reduced at day 15 (4.47 vs. 2.94, P Conclusion: Malignant NP may be well controlled by oxycodone mono-therapy. Early combination with gabapentin is sensible when pain is not satisfactory relieved by oxycodone alone. The side effects of them are manageable.

Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study

A controlled-release (CR) formulation of zileuton was developed to simplify administration from 600 mg 4 times daily (Zyflo) to 1,200 mg twice daily. To evaluate the efficacy of zileuton CR, two 600-mg tablets twice daily, compared with placebo. Patients with moderate asthma treated with short-acting beta-agonists only were randomized to receive zileuton CR, 1,200 mg twice daily (n = 206); placebo CR, twice daily (n = 203); zileuton immediate-release (IR), 600 mg 4 times daily (n = 101); or placebo IR, 4 times daily (n = 103), for 12 weeks. The primary efficacy variable was change from baseline in morning trough forced expiratory volume in 1 second (FEV1). Improvement in trough FEV1 was observed after 2 weeks of treatment (P = .001) and was maintained throughout the study. After 12 weeks of dosing, FEV1 improved by a mean of 0.39 L (20.8%) in the zileuton CR group vs 0.27 L (12.7%) in the placebo CR group (P = .02). A significant decline in beta-agonist use and a smaller proportion of patients reporting asthma exacerbations were observed in the zileuton CR group vs the placebo CR group. Adverse event profiles were similar across treatment groups. Elevations in alanine aminotransferase levels at least 3 times the upper limit of normal that reversed after drug withdrawal were seen in 5 zileuton CR-treated patients (2.5%) vs 1 placebo CR-treated patient (0.5%). Treatment with zileuton CR, 1,200 mg twice daily, resulted in a significant improvement in asthma control, and the safety and efficacy profile was similar to that observed with zileuton IR, 600 mg 4 times daily (Zyflo).

Evaluation of the effectiveness and tolerability of controlled-release diclofenac-potassium versus immediate-release diclofenac-potassium in the treatment of knee osteoarthritis

Abstract. A controlled-release (CR) form of diclofenac-potassium has been developed, which delivers 100 mg over the course of 24 hours. This formulation is administered QD and provides steady plasmatic levels of the drug. The aim of this study was to compare the effectiveness and tolerability of CR diclofenac-potassium versus the immediate-release (IR) formulation, when used for treatment of pain in patients with knee osteoarthritis. This prospective, randomized, double-blind, comparative, multi-center, parallel-group study was conducted in male and female patients who had been previously diagnosed with knee osteoarthritis. Inclusion criteria included knee joint pain and ≥3 of the following: age >50 years, morning rigidity lasting <30 minutes, crackling in the joint, pain with applied pressure to the bones, bone hypertrophy, absence of articular heat, and a radiology status of I to III on the Kellgren-Lawrence scale. Patients were randomly divided into 1 of 2 equal-sized groups: 1 group received diclofenac-potassium IR 50 mg BID for 30 days and 1 group received diclofenac-potassium CR 100 mg QD for 30 days. Patients were assessed at baseline and again at 15 and 30 days after initiation of treatment with a physical examination, pain measurement via 100-mm visual analog scale (VAS), and Western Ontario McMaster (WOMAC) osteoarthritis index questionnaire. Adverse events (AEs) were assessed by direct interrogation, hematology controls, blood chemistry, hepatic tests, coagulation tests, and urine tests performed on patients before treatment initiation and on day 30. Sixty-five patients were screened and 62 patients (mean [SD]age, 61.8 [8.9] years; mean [SD] weight, 71.3 [12.4] kg; female sex, 55 [88.9%]) were included in the study; each study group had 31 patients. After 30 days, both products were equally effective in relieving pain, as measured by VAS (IR, 17.3 vs CR, 21.6; P = NS), and changes in the WOMAC score (IR, 14.5 vs CR, 19.2; P = NS). Significantly more patients in the IR group reported feeling better after 30 days than in the CR group (94% vs 76%; P = 0.002) and, according to the physician's opinion, significantly more patients treated with diclofenac-potassium IR felt better (97% vs 83%; P = 0.03). Significantly more patients in the IR group required rescue medication than those in the CR group (36% vs 26%; P = 0.03). In the CR group, 7 patients experienced AEs: 6 were gastrointestinal (ie, pyrosis, epigastralgia, dyspepsia) and 1 patient experienced increased arterial pressure. One patient from this group discontinued treatment due to a lack of efficacy. In the IR group, 6 patients experienced AEs (ie, tachycardia, epigastralgia, and pyrosis). One patient discontinued because of AEs, and 3 withdrew due to a lack of efficacy. Based on the results from this small study in a Venezuelan population, both IR and CR formulations of diclofenac-potassium have similar effectiveness and tolerability profiles.

Evaluation of the effectiveness and tolerability of controlled-release diclofenac-potassium versus immediate-release diclofenac-potassium in the treatment of knee osteoarthritis

Abstract A controlled-release (CR) form of diclofenac-potassium has been developed, which delivers 100 mg over the course of 24 hours. This formulation is administered QD and provides steady plasmatic levels of the drug. The aim of this study was to compare the effectiveness and tolerability of CR diclofenac-potassium versus the immediate-release (IR) formulation, when used for treatment of pain in patients with knee osteoarthritis. This prospective, randomized, double-blind, comparative, multi-center, parallel-group study was conducted in male and female patients who had been previously diagnosed with knee osteoarthritis. Inclusion criteria included knee joint pain and ≥3 of the following: age >50 years, morning rigidity lasting <30 minutes, crackling in the joint, pain with applied pressure to the bones, bone hypertrophy, absence of articular heat, and a radiology status of I to III on the Kellgren-Lawrence scale. Patients were randomly divided into 1 of 2 equal-sized groups: 1 group received diclofenac-potassium IR 50 mg BID for 30 days and 1 group received diclofenac-potassium CR 100 mg QD for 30 days. Patients were assessed at baseline and again at 15 and 30 days after initiation of treatment with a physical examination, pain measurement via 100-mm visual analog scale (VAS), and Western Ontario McMaster (WOMAC) osteoarthritis index questionnaire. Adverse events (AEs) were assessed by direct interrogation, hematology controls, blood chemistry, hepatic tests, coagulation tests, and urine tests performed on patients before treatment initiation and on day 30. Sixty-five patients were screened and 62 patients (mean [SD]age, 61.8 [8.9] years; mean [SD] weight, 71.3 [12.4] kg; female sex, 55 [88.9%]) were included in the study; each study group had 31 patients. After 30 days, both products were equally effective in relieving pain, as measured by VAS (IR, 17.3 vs CR, 21.6; P = NS), and changes in the WOMAC score (IR, 14.5 vs CR, 19.2; P = NS). Significantly more patients in the IR group reported feeling better after 30 days than in the CR group (94% vs 76%; P = 0.002) and, according to the physician's opinion, significantly more patients treated with diclofenac-potassium IR felt better (97% vs 83%; P = 0.03). Significantly more patients in the IR group required rescue medication than those in the CR group (36% vs 26%; P = 0.03). In the CR group, 7 patients experienced AEs: 6 were gastrointestinal (ie, pyrosis, epigastralgia, dyspepsia) and 1 patient experienced increased arterial pressure. One patient from this group discontinued treatment due to a lack of efficacy. In the IR group, 6 patients experienced AEs (ie, tachycardia, epigastralgia, and pyrosis). One patient discontinued because of AEs, and 3 withdrew due to a lack of efficacy. Based on the results from this small study in a Venezuelan population, both IR and CR formulations of diclofenac-potassium have similar effectiveness and tolerability profiles.

Zolpidem Extended-Release

Zolpidem extended-release, or controlled-release (CR), is a new formulation of zolpidem, a nonbenzodiazepine hypnotic. It is indicated in the US for the treatment of insomnia, characterised by difficulties with sleep onset and/or sleep maintenance. Zolpidem CR is a dual-layered tablet; one layer releases zolpidem immediately and a second layer provides a slower release of additional zolpidem for maintenance of plasma zolpidem concentrations. Efficacy of zolpidem CR was assessed in two 3-week, randomised, double-blind, placebo-controlled, phase III polysomnography trials in younger adult (aged 18-64 years) or elderly (aged > or =65 years) patients with primary insomnia. Patients received nightly zolpidem CR (12.5mg in younger adult and 6.25mg in elderly patients). Efficacy was assessed objectively on nights 1, 2, 15 and 16. Patients who received zolpidem CR had significantly improved objective latency to persistent sleep, wake time after sleep onset and sleep efficiency on assessment nights compared with placebo recipients. In subjective assessments of sleep quality on day 2 and nights 15 and 22, significantly more zolpidem CR than placebo recipients gave favourable responses on a Patient Global Impression scale in the study in younger adult patients. In the other study, significantly more elderly patients in the zolpidem CR group rated their sleep as improved compared with the placebo group. Zolpidem CR was generally well tolerated and appears to have a tolerability profile similar to that of the original formulation of zolpidem.

A randomized, double-blind, parallel-group comparison of controlled- and immediate-release oxybutynin chloride in urge urinary incontinence

Objective: The aim of this study was to evaluate the efficacy and safety of a new PO controlled-release (CR) QD oxybutynin tablet relative to PO immediate-release (IR) TID oxybutynin in patients with urge urinary incontinence (UI).Methods: In this multicenter, double-blind trial, patients with UI (⩾7 episode/wk) and frequency (⩾8 micturitions/d) were randomized to CR or IR oxybutynin for 6 weeks. Patients initiated treatment at 15 mg/d and the dose was adjusted (in 5-mg/d increments) over 2 weeks according to tolerability. Efficacy (UI episodes, voids, absorbent pads used, urgency, and volume voided per micturition) was assessed during the final 2 weeks of treatment. Tolerability was assessed by evaluating adverse events and treatment withdrawals.Results: Of the 125 patients randomized, 94 (75%) were evaluable for efficacy; tolerability was assessed in all patients. In the CR group, 48 patients (91%) were women and 5 (9%) were men; the mean (SD) age was 58.0 (12.4) years (range, 26–78 years). In the IR group, 37 patients (90%) were women and 4 (10%) were men; the mean (SD) age was 60.6 (14.8) years (range, 26–83 years). Both CR and IR oxybutynin significantly reduced the mean number of total UI episodes per week (both P < 0.001 vs baseline). Both treatments produced equivalent reductions in mean voiding frequency and urinary urgency (all P < 0.001 vs. baseline). Significantly more patients rated CR oxybutynin tolerable on the initial dose of 15 mg/d (P = 0.020) and completed the study at a dose of ⩾15 mg/d (P = 0.018). Dry mouth was the most common adverse event, reported by 68% and 72% of patients in the CR and IR oxybutynin groups, respectively.Conclusions: Among the patients with urge UI included in this study, CR oxybutynin was as effective as IR oxybutynin for improving primary symptoms, with the additional benefit of QD administration.

P.3.023 A double-blind, placebo-controlled study of controlled release fluvoxamine for the treatment of generalized social anxiety disorder

This was a randomized double-blind placebo-controlled multicenter study to assess the efficacy, safety, and tolerability of fluvoxamine in a controlled release (CR) formulation for treatment of generalized social anxiety disorder (GSAD). A total of 300 subjects with GSAD were randomly assigned to receive either fluvoxamine CR (N = 149) or placebo (N = 151) for 12 weeks. Mean changes from baseline to end point in Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression Severity of Illness Scale (CGI-S), Sheehan Disability Scale (SDS), as well as the mean end point scores in Clinical Global Impression Improvement Scale (CGI-I) and Patient Global Impression of Improvement Scale (PGI) were compared between the fluvoxamine CR and placebo treatment groups. Arizona Sexual Experience Scale (ASEX), adverse event, and other safety parameters were also assessed. The results demonstrated that fluvoxamine CR was significantly superior to placebo in decreasing LSAS total score (primary measure) starting at week 4. At end point, there was a mean change from baseline of -36.1 +/- 2.7 (37% reduction) in the LSAS total score in the fluvoxamine CR group compared with -27.3 +/- 2.4 (28% reduction) in the placebo group (P = 0.020 for mean change). Fluvoxamine CR was also significantly superior to placebo in SDS, CGI-S, CGI-I at end point (secondary measures). When compared with placebo, fluvoxamine CR did not cause any significant weight gain or clinically significant sexual dysfunction as measured by ASEX. In summary, fluvoxamine CR is an efficacious, safe, and well-tolerated treatment of generalized social anxiety disorder.