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Maen Hussein,1 Marina Maglakelidze,2 Donald A Richards,3 Marielle Sabatini,4 Todd A Gersten,5 Keith Lerro,6 Ivan Sinielnikov,7 Alexander Spira,8,9 Yili Pritchett,10 Joyce M Antal,10 Rajesh Malik,10 J Thaddeus Beck11 1Florida Cancer Specialists, Leesburg, FL, USA; 2LLC Arensia Exploratory Medicine, Tbilisi, Georgia; 3Texas Oncology-Tyler, US Oncology Research, Tyler, TX, USA; 4Saint Leon Hospital, Bayonne, France; 5Florida Cancer Specialists, West Palm Beach, FL, USA; 6Regional Medical Oncology Center, Wilson, NC, USA; 7Volyn Regional Oncology Center, Lutsk, Ukraine; 8Virginia Cancer Specialists, Fairfax, VA, USA; 9US Oncology Research, The Woodlands, TX, USA; 10G1 Therapeutics, Inc., Research Triangle Park, NC, USA; 11Highlands Oncology Group, Fayetteville, AR, USACorrespondence: Maen HusseinFlorida Cancer Specialists, Leesburg, FL, USATel +1 352-787-9448Email mhussein@flcancer.comPurpose: Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression (CIM) by protecting hematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myeloprotection). Here, we investigated the myeloprotective effects of trilaciclib among patients at increased risk of CIM.Patients and Methods: Data were pooled from three randomized, double-blind, placebo-controlled, phase 2 clinical studies of trilaciclib administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Myeloprotective outcomes were evaluated in patient subgroups based on age (< 65 or ≥ 65 years), risk of chemotherapy-induced febrile neutropenia (FN), and risk of anemia or red blood cell (RBC) transfusions. For the FN and anemia analyses, risk factors were identified from published literature and used to classify patients into FN and anemia risk categories. Subgroup analysis based on age was also performed on patient reported outcome (PRO) measures.Results: In total, 123 patients received trilaciclib and 119 patients received placebo. Myeloprotective benefits of trilaciclib were observed regardless of age, with greater effects observed among patients aged ≥ 65 years. Across FN risk factors and categories, trilaciclib had beneficial effects on neutrophil-related endpoints vs placebo, with greater effects observed in patients at higher risk of FN. Effects on RBC-related endpoints favored trilaciclib vs placebo, regardless of anemia risk factors and categories. Improvements in PROs with trilaciclib were observed irrespective of age group, but with greater improvements and less deterioration from baseline observed in older patients.Conclusion: By both decreasing the incidence of CIM and improving quality of life, trilaciclib has the potential to allow patients receiving chemotherapy for ES-SCLC, including patients who are older or more vulnerable to CIM, to receive chemotherapy on schedule and at standard-of-care doses, and to improve the experience for patients receiving chemotherapy to treat ES-SCLC.Clinical Trial Numbers: NCT02499770; NCT03041311; NCT02514447.Keywords: trilaciclib, myelosuppression, myeloprotection, myelopreservation, chemotherapy, small cell lung cancer more...

Abstract Background Recent analyses of antiepileptic drugs have indicated an increase in the risk of suicidality. The objective of this report was to provide clinical information and an independent meta-analysis of divalproex sodium and suicidality events by analyzing data from 13 placebo-controlled studies and 1 low-dose controlled study. Methods Adverse events considered to be possibly suicide related were identified using the Columbia Classification Algorithm of Suicide Assessment (C-CASA) methodology. Indications included epilepsy, bipolar disorder, migraine prophylaxis, impulsive aggression, and dementia. Narratives were produced for every event, and suicidality event ratings were performed by a third party blinded to treatment assignment. Statistical analyses were conducted using methodology similar to that reported by the US Food and Drug Administration (FDA). Results Suicidality events were identified in 5 of the 13 placebo-controlled studies. Of the 1,327 (0.83%) subjects taking divalproex sodium, 11 had suicidality events: 2 suicide attempts and 9 suicidal ideation. Of 992 (0.91%) subjects taking placebo, 9 had suicidality events: 1 preparatory act toward suicide, 2 suicide attempts, and 6 suicidal ideation. Across placebo-controlled studies, the overall estimated odds ratio (OR) of suicidal behavior or ideation was 0.72 (95% CI 0.29 to 1.84). The OR for suicidal behavior was 0.37 (95% CI 0.04 to 2.58), and the OR for suicidal ideation was 0.90 (95% CI 0.31 to 2.79). Conclusions In this meta-analysis, divalproex sodium does not appear to increase the risk of suicide-related adverse events relative to placebo in the populations studied. Clinicians should nonetheless remain vigilant in assessing suicidality, not only in patients treated for mental disorders with inherently high suicide risk, but also in patients taking antiepileptic medications. more...

Objective: To examine impact of age, gender, origin, duration of diabetic neuropathy, type of diabetes, and pain severity on treatment outcome of duloxetine (DLX) in the management of diabetic peripheral neuropathic pain (DPNP). Methods: Data from 3 12-week, multicenter, double-blind, placebo-controlled studies (1-3) were pooled. In Study 1, 457 patients with DPNP were randomly assigned to DLX 20 mg QD, 60 mg QD, 60 mg BID, or placebo. In Studies 2 and 3, 334 and 348 patients, respectively, were randomly assigned to DLX 60 mg QD, 60 mg BID, or placebo. DLX 20 mg QD was not included in the analyses due to its ineffectiveness found in Study 1. Primary efficacy measure was the weekly mean score of 24-Hour Average Pain Severity collected by patient’s diary on 11-point Likert scale. Subgroup impact was evaluated for combined DLX doses with references to placebo group. Results: DLX 60 mg QD and 60 mg BID significantly improved weekly mean scores of 24-Hour Average Pain Severity in each study (p < 0.001). There were no statistical significant (p < 0.1) interactions of treatment with age (<65 or ≥65), gender (male or female), origin (Caucasian or other), duration of diabetic neuropathy (<2, 2–<6, or ≥6 years), type of diabetes (Type I or Type II) with an exception for pain severity (BPI average pain <6 or ≥6). DLX effect was observed for both severe and less severe groups with more separation on the severe group. The superiority of DLX over placebo was observed within almost each of the stratum with the exception of Type I patient group, which demonstrated the advantage of DLX treatment with p = 0.123. The magnitude of change was slightly higher in Type II patients than in those with Type I; however, Type I group sample size was much smaller which may account for the statistical insignificance. DLX was safe and well tolerated with less than 20% discontinuation due to AEs, while showing no interference with diabetic control. Conclusion: These studies suggested that DLX was effective and safe in the treatment of DPNP, and its effectiveness was invariant with respect to baseline conditions. Funding provided by Eli Lilly and Company. [Copyright &y& Elsevier] more...

Background: Chemotherapy-induced myelosuppression (CIM) and its sequalae cause significant side effects and harm to quality of life. Trilaciclib is an intravenous CDK4/6 inhibitor that is administered prior to chemotherapy to protect hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection)., Patients and Methods: Data from three randomized, double-blind, placebo-controlled studies (NCT02499770, NCT03041311, and NCT02514447) were pooled to evaluate the effects of trilaciclib administered prior to standard-of-care chemotherapy (first-line etoposide plus carboplatin [E/P], first-line E/P plus atezolizumab, and second-/third-line topotecan) in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary endpoints were duration of severe neutropenia (absolute neutrophil count < 0.5 × 10 9 cells/L) in cycle 1 and occurrence of severe neutropenia. Additional prespecified endpoints further assessed the effect of trilaciclib on myeloprotection, health-related quality of life (HRQoL), antitumor efficacy, and safety., Results: Of 242 randomized patients, 123 received trilaciclib and 119 received placebo. Compared with placebo, administration of trilaciclib prior to chemotherapy resulted in significant decreases in most measures of multilineage CIM. The reduction in hematologic toxicity translated into the reduced need for supportive care interventions and hospitalizations due to CIM or sepsis and improvements in HRQoL domains related to the protected cell lineages, including fatigue, physical wellbeing, and functional wellbeing. Antitumor efficacy was similar for patients receiving trilaciclib or placebo., Conclusion: Administering trilaciclib prior to chemotherapy resulted in clinically meaningful reductions in CIM and its consequences and improved patient HRQoL, with no impact on the antitumor efficacy of three individual chemotherapy regimens used in the first- or second-/third-line treatment of ES-SCLC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: Supportive care interventions used to manage chemotherapy-induced myelosuppression (CIM), including granulocyte colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib., Methods: Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1-4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated., Results: The use of G-CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G-CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration., Conclusions: By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES-SCLC., Trial Registration: ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447)., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.) more...

Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double-blind, placebo-controlled Phase II study in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count <0.5 × 10 9 cells per L) in Cycle 1 and occurrence of SN during the treatment period. Other endpoints were prespecified to assess the effects of trilaciclib on additional measures of myelopreservation, patient-reported outcomes, antitumour efficacy and safety. Fifty-two patients received trilaciclib prior to E/P/A and 53 patients received placebo. Compared to placebo, administration of trilaciclib resulted in statistically significant decreases in the mean duration of SN in Cycle 1 (0 vs 4 days; P < .0001) and occurrence of SN (1.9% vs 49.1%; P < .0001), with additional improvements in red blood cell and platelet measures and health-related quality of life (HRQoL). Trilaciclib was well tolerated, with fewer grade ≥3 adverse events compared with placebo, primarily due to less high-grade haematological toxicity. Antitumour efficacy outcomes were comparable. Administration of trilaciclib vs placebo generated more newly expanded peripheral T-cell clones (P = .019), with significantly greater expansion among patients with an antitumour response to E/P/A (P = .002). Compared with placebo, trilaciclib administered prior to E/P/A improved patients' experience of receiving treatment for ES-SCLC, as shown by reduced myelosuppression, and improved HRQoL and safety profiles., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.) more...

Background: Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan., Objective: We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan., Study Design: We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics., Methods: Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8., Results: Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin)., Conclusions: We conclude that thoracic bioimpedance did not reflect changes in weight gain or edema with atrasentan treatment in this study. However, the sample size was small, and it may be of interest to explore the use of thoracic bioimpedance in a larger population to understand its potential clinical use in monitoring fluid retention in patients with chronic kidney disease who receive ET receptor antagonists. more...

Background: Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25-75 mg) and an open-label extension study (75 mg)., Methods: The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10-24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies., Results: A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (-2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, -0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, -0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, -1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters., Conclusions: In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies., Trial Registration: ClinicalTrials.gov NCT01527916 , Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935 . Registered 29 August 2012 (open-label extension study). more...

Introduction: The safety and efficacy of the novel α7 nicotinic acetylcholine receptor agonist ABT-126 were investigated in subjects with mild-to-moderate Alzheimer's dementia (AD)., Methods: Subjects not currently receiving acetylcholinesterase inhibitors were randomized to ABT-126 (5 or 25 mg once daily), donepezil 10 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the change from baseline to final evaluation in the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score., Results: A total of 274 subjects were randomized. Although the study did not meet its primary end point, trends toward improvement were seen with ABT-126 25 mg (least squares mean [standard error] difference from placebo -1.19 [0.90]; one-sided P  = .095) and donepezil (-1.43 [0.90]; one-sided P  = .057) on the 11-item ADAS-Cog total score change from baseline to the final evaluation. ABT-126 5 mg was numerically similar to placebo. An exposure-response analysis indicated a statistically significant relationship between ABT-126 exposure and the change from baseline in ADAS-Cog, with no evidence of a plateau. No clinically meaningful differences in safety were observed among treatment groups., Discussion: Although the ABT-126 25 mg dose did not demonstrate statistically significant improvement, results of the exposure-response analysis suggest that higher doses may produce better efficacy, and the safety profile of ABT-126 in this study supports additional studies with higher doses in subjects with mild-to-moderate AD., Clinical Trial Register Number: NCT00948909. more...

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors., (Copyright © 2014 by the American Society of Nephrology.) more...

Background: Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube., Methods: In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥ 30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994., Findings: From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4.04 h (SE 0.65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2.14 h (0.66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to -0.76]; p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel group and 2.24 h (0.76) in the immediate-release oral group (difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube., Interpretation: Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study., Funding: AbbVie., (Copyright © 2014 Elsevier Ltd. All rights reserved.) more...

Background: ABT-288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers., Objective: Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimer's dementia., Methods: The study used a randomized, double-blind, placebo- and active-controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT-288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score., Results: The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT-288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting., Conclusion: ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimer's dementia. more...

Levodopa-carbidopa intestinal gel (LCIG) delivered continuously via percutaneous endoscopic gastrojejunostomy (PEG-J) tube has been reported, mainly in small open-label studies, to significantly alleviate motor complications in Parkinson's disease (PD). A prospective open-label, 54-week, international study of LCIG is ongoing in advanced PD patients experiencing motor fluctuations despite optimized pharmacologic therapy. Pre-planned interim analyses were conducted on all enrolled patients (n = 192) who had their PEG-J tube inserted at least 12 weeks before data cutoff (July 30, 2010). Outcomes include the 24-h patient diary of motor fluctuations, Unified Parkinson's Disease Rating Scale (UPDRS), Clinical Global Impression-Improvement (CGI-I), Parkinson's Disease Questionnaire (PDQ-39), and safety evaluations. Patients (average PD duration 12.4 yrs) were taking at least one PD medication at baseline. The mean (±SD) exposure to LCIG was 256.7 (±126.0) days. Baseline mean "Off" time was 6.7 h/day. "Off" time was reduced by a mean of 3.9 (±3.2) h/day and "On" time without troublesome dyskinesia was increased by 4.6 (±3.5) h/day at Week 12 compared to baseline. For the 168 patients (87.5%) reporting any adverse event (AE), the most common were abdominal pain (30.7%), complication of device insertion (21.4%), and procedural pain (17.7%). Serious AEs occurred in 60 (31.3%) patients. Twenty-four (12.5%) patients discontinued, including 14 (7.3%) due to AEs. Four (2.1%) patients died (none deemed related to LCIG). Interim results from this advanced PD cohort demonstrate that LCIG produced meaningful clinical improvements. LCIG was generally well-tolerated; however, device and procedural complications, while generally of mild severity, were common., (Copyright © 2013 Elsevier Ltd. All rights reserved.) more...

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4β2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted. more...

Background: Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146)., Methods and Results: One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03)., Conclusions: Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation., (Copyright © 2012 Mosby, Inc. All rights reserved.) more...

Aims: Progression of chronic kidney disease (CKD) in patients with diabetes is a growing problem. Diabetes is associated with elevated endothelin-1 (ET-1) and enhanced renal expression of the endothelin A receptor (ETAR). Atrasentan, a highly selective ETAR antagonist, reduces albuminuria in patients with DN. KEY METHODS: This was a randomized, double-blind trial of subjects with type 2 diabetes on renin-angiotensin system (RAS) inhibitors having eGFR >20 ml/min, and urine albumin-to-creatinine ratio (UACR) of 100-3000 mg/g, who were allocated to placebo, 0.25, 0.75 or 1.75 mg atrasentan., Key Findings: UACR was reduced in the 0.75 mg and 1.75 mg groups (42% and 35% vs placebo, P<0.011) over the 8 week treatment period. Edema was reported in 21 subjects: 62% of edema events emerged during the first 4 weeks. There were no significant changes in serum hsCRP, IL-6, NT-pro-BNP, ET-1, urine TGFb or MCP-1. Urine NGAL was reduced 24% in the 1.75 mg group (P=0.044). Hispanic subjects (58% of total) tended to have greater UACR reductions than non-Hispanics (0.75 mg dose: Hispanic: 41-60%; non-Hispanic: 18-37%; P=0.012 and 0.048 vs placebo, respectively) without different rates of edema. Mean UACR reduction in subjects receiving maximum doses of RAS inhibitors (38%) was 32% and 35% in the 0.75 and 1.75 mg groups, respectively, and similar to overall UACR changes., Significance: Edema formation was dose-dependent and occurred early. The decrease in urine NGAL warrants further study in renal tubular disease attenuation. UACR responses based on ethnicity need further characterization. Results suggest atrasentan may have additive effects to RAS inhibition in treatment of DN., (Copyright © 2012 Elsevier Inc. All rights reserved.) more...

Context: Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking., Objective: To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2)., Design, Setting, and Participants: Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010., Intervention: Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112)., Main Outcome Measures: Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function., Results: Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group., Conclusion: Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease., Trial Registration: clinicaltrials.gov Identifier: NCT00497146. more...

Background: Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies., Purpose: PRIMO (Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease., Methods: Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis., Limitations: If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making., Conclusions: The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study. more...

Although endothelin-receptor antagonists reduce albuminuria in diabetic nephropathy, fluid retention limits their use. Here, we examined the effect of atrasentan, a selective endothelin A receptor (ET(A)R) antagonist, on albuminuria in a randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy already receiving stable doses of renin-angiotensin system (RAS) inhibitors. We randomly assigned 89 subjects with eGFR >20 ml/min per 1.73 m(2) and a urinary albumin-to-creatinine ratio (UACR) of 100 to 3000 mg/g to placebo or atrasentan (0.25, 0.75, or 1.75 mg daily) for 8 weeks. Compared with placebo, atrasentan significantly reduced UACR only in the 0.75- and 1.75-mg groups (P=0.001 and P=0.011, respectively). Compared with the 11% reduction in the geometric mean of the UACR from baseline to final observation in the placebo group during the study, the geometric mean of UACR decreased by 21, 42, and 35% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups (P=0.291, P=0.023, and P=0.073, respectively). In the placebo group, 17% of subjects achieved ≥40% reduction in UACR from baseline compared with 30, 50, and 38% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups, respectively (P=0.029 for 0.75 mg versus placebo). Peripheral edema occurred in 9% of subjects receiving placebo and in 14, 18, and 46% of those receiving 0.25, 0.5, and 1.75 mg atrasentan, respectively (P=0.007 for 1.75 mg versus placebo). In summary, atrasentan, at the doses tested, is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy., (Copyright © 2011 by the American Society of Nephrology) more...

Background: In chronic kidney disease (CKD), left ventricular hypertrophy (LVH) is prevalent and is associated with increased cardiovascular morbidity and mortality. Vitamin D receptor (VDR) activation attenuates LVH progression in animal models., Methods: PRIMO is a multinational, randomized, double-blinded trial with oral paricalcitol in subjects with stages 3-4 CKD, mild-to-moderate LVH and an LV ejection fraction >50%. The primary endpoint is change in the left ventricular mass index (LVMI) compared with placebo after 48 weeks of treatment. The main secondary endpoints are changes in diastolic function parameters. In this paper, we report baseline characteristics from this study., Results: LVMI was 33.0 ± 7.5 g/m(2.7) for males and 30.8 ± 7.2 g/m(2.7) for females (p = 0.04). LVMI correlated with systolic blood pressure (r = 0.24), urine albumin creatinine ratio (r = 0.39), troponin T (r = 0.29), high-sensitivity C-reactive protein (r = 0.25) and plasma levels of B-type brain natriuretic peptide (r = 0.22); all p < 0.01. In multiple linear regression, each remained independently associated with LVMI. The early diastolic velocity of the lateral mitral annulus (E') was 8.1 ± 2.4 cm/s. E' was inversely correlated with age in univariate (r = -0.14, p = 0.04) and multivariable (p = 0.02) analysis., Conclusion: Among 227 multinational subjects with stages 3-4 CKD, baseline LVMI correlates with baseline blood pressure, urine albumin creatinine ratio and cardiac biomarkers, and baseline diastolic function correlates with age. This research was funded by Abbott Laboratories; ClinicalTrials.gov No. NCT00497146., (Copyright © 2011 S. Karger AG, Basel.) more...

Background: Despite treatment with renin–angiotensin–aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy., Methods: In this multinational, placebo-controlled, double-blind trial, we enrolled patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks’ treatment with placebo,1 μg/day paricalcitol, or 2 μg/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00421733., Findings: Between February, 2007, and October, 2008, 281 patients were enrolled and assigned to receive placebo(n=93), 1 μg paricalcitol (n=93), or 2 μg paricalcitol (n=95); 88 patients on placebo, 92 on 1 μg paricalcitol, and 92 on2 μg paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: –3% (from 61 to 60 mg/mmol;95% CI –16 to 13) in the placebo group; –16% (from 62 to 51 mg/mmol; –24 to –9) in the combined paricalcitol groups, with a between-group difference versus placebo of –15% (95% CI –28 to 1; p=0.071); –14% (from 63 to 54 mg/mmol; –24 to –1) in the 1 μg paricalcitol group, with a between-group difference versus placebo of –11%(95% CI –27 to 8; p=0.23); and –20% (from 61 to 49 mg/mmol; –30 to –8) in the 2 μg paricalcitol group, with a between-group difference versus placebo of –18% (95% CI –32 to 0; p=0.053). Patients on 2 μg paricalcitol showed a nearly, sustained reduction in UACR, ranging from –18% to –28% (p=0.014 vs placebo). Incidence of hypercalcaemia,adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo., Interpretation: Addition of 2 μg/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes., Funding: Abbott. more...

Objective: This study examined the efficacy and tolerability of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, for the treatment of patients with generalized anxiety disorder (GAD)., Method: Patients were ≥ 18 years old and recruited from 5 European countries, the United States, and South Africa. The study had a 9-week, multicenter, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group design. A total of 513 patients (mean age = 43.8 years; 67.8% female) with a DSM-IV-defined GAD diagnosis received treatment with duloxetine 60 mg/day (N = 168), duloxetine 120 mg/day (N = 170), or placebo (N = 175). The primary efficacy measure was the Hamilton Rating Scale for Anxiety (HAM-A) total score. Secondary measures included the Sheehan Disability Scale, HAM-A psychic and somatic anxiety factor scores, and HAM-A response, remission, and sustained improvement rates. The study was conducted from July 2004 to September 2005., Results: Both groups of duloxetine-treated patients demonstrated significantly greater improvements in anxiety symptom severity compared with placebo-treated patients as measured by HAM-A total score and HAM-A psychic and somatic anxiety factor scores (p values ranged from ≤ .01 to ≤ .001). Duloxetine-treated patients had greater functional improvements in Sheehan Disability Scale global and specific domain scores (p ≤ .001) than placebo-treated patients. Both duloxetine doses also resulted in significantly greater HAM-A response, remission, and sustained improvement rates compared with placebo (p values ranged from ≤ .01 to ≤ .001). The rate of study discontinuation due to adverse events was 11.3% for duloxetine 60 mg and 15.3% for duloxetine 120 mg versus 2.3% for placebo (p ≤ .001)., Conclusion: The results of this study demonstrate that duloxetine 60 mg/day and 120 mg/day were efficacious and well tolerated and thus may provide primary care physicians with a useful pharmacologic intervention for GAD., Clinical Trials Registration: ClinicalTrials.gov identifier NCT00122824. more...

Background: To compare the safety and tolerability of duloxetine with paroxetine and placebo in patients with major depressive disorder (MDD)., Method: Data from four 8-week randomized, double-blind, placebo- and paroxetine-controlled studies of duloxetine for MDD (DSM-IV criteria) were pooled to compare the safety and tolerability of duloxetine 40 to 120 mg/day with paroxetine 20 mg q.d. Two of the 4 trials included a 26-week extension., Results: The pooled database included 1466 patients (duloxetine, N = 736; paroxetine, N = 359; placebo, N = 371). No deaths occurred in the acute phase trials. Discontinuation rates for adverse events did not differ significantly for duloxetine, 8.0%, and paroxetine, 6.1%. Nausea was the most frequent treatment-emergent adverse event for duloxetine (duloxetine, 14.4%; paroxetine, 12.0%; placebo, 3.8%). Blood pressure and corrected QT (QTc) interval changes were modest and did not differ significantly for the 3 groups. Mean heart rate increased slightly in the duloxetine group, 1.0 beat/minute, and did differ significantly (p < .001) from that in the paroxetine group, but the change is of doubtful importance. Mean changes in laboratory analytes remained within the reference range. Emergent sexual dysfunction was significantly greater among duloxetine- and paroxetine-treated patients than placebo-treated patients (p = .007 vs. duloxetine and p < .001 vs. paroxetine); however, it was significantly lower in duloxetine-treated patients than in paroxetine-treated patients (46.4% vs. 61.4%; p = .015). During the extension phase, weight gain (≥ 7% of initial body weight) was greater in both active-treatment groups than in the placebo group (duloxetine, 10.8%; paroxetine, 13.8%; placebo, 3.1%), but the active-treatment groups did not differ., Conclusions: Duloxetine is safe and well tolerated in patients with MDD, with safety and tolerability comparable to that of paroxetine. more...