Tolvaptan for Children and Adolescents with Autosomal Dominant Polycystic Kidney Disease: Randomized Controlled Trial.

BACKGROUND: Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD. METHODS: This was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR ≥60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n≥60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc. RESULTS: Among the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P<0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable. CONCLUSIONS: Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.

Complex Material Properties of Gel-Amin: A Transparent and Ionically Conductive Hydrogel for Neural Tissue Engineering.

The field of tissue engineering has benefited greatly from the broad development of natural and synthetic polymers. Extensive work in neural engineering has demonstrated the value of conductive materials to improve spontaneous neuron activity as well as lowering the necessary field parameters for exogenous electrical stimulation. Further, cell fate is directly coupled to the mechanical properties of the cell culture substrate. Increasing the conductivity of hydrogel materials often necessitates the addition of dopant materials that facilitate electron mobility. However, very little electron transfer is observed in native cell signaling and most of these materials are opaque, severely limiting microscopy applications commonly employed to assess cell culture morphology and function. To overcome these shortcomings, the inclusion of an ionic liquid, choline acrylate, into the backbone of a modified collagen polymer increases the bulk conductivity 5-fold at a 1:1 ratio while maintaining optical transmission of visible light. Here, we explore how the inclusion of choline acrylate influences bulk material properties including the mechanical, swelling, and optical properties of our hydrogels, referred to as Gel-Amin hydrogels, as a material for tissue culture. Despite an increase in swelling over traditional GelMA materials, the conductive hydrogels support whole dorsal root ganglia encapsulation and outgrowth. Our results indicate that our Gel-Amin system holds potential for neural engineering applications and lowering the required charge injection for the application of exogenous electrical stimulation. This is this first time an ionic liquid-hydrogel system has been used to culture and support primary neurons in vitro.

Efficacy and safety of brexpiprazole in patients with schizophrenia presenting with severe symptoms: Post-hoc analysis of short- and long-term studies.

BACKGROUND: The treatment of patients with severe schizophrenia symptoms can be complicated and expensive. AIMS: The purpose of this study was to evaluate the short- and long-term effects of brexpiprazole in patients with schizophrenia presenting with severe symptoms. METHODS: Data were pooled from three six-week, randomized, double-blind, placebo-controlled studies and two 52-week, open-label extension studies. In the short-term studies, 1405 patients received placebo or brexpiprazole 2-4 mg/day; 412 brexpiprazole-treated patients rolled over into the long-term studies and received brexpiprazole 1-4 mg/day. More severe symptoms were defined as a Positive and Negative Syndrome Scale Total score >95 (median score at baseline). Outcomes included change in Positive and Negative Syndrome Scale Total and Personal and Social Performance scale scores. RESULTS: Brexpiprazole improved Positive and Negative Syndrome Scale Total score over 6 weeks among more severely ill patients, with a least squares mean difference versus placebo of -6.76 (95% confidence limits: -9.80, -3.72; p<0.0001; Cohen's d: 0.43). Brexpiprazole also improved Personal and Social Performance scale score over 6 weeks in more severely ill patients (least squares mean difference: 4.38; limits: 2.14, 6.62; p=0.0001; Cohen's d: 0.38). Improvement of functioning was greatest in the 'Self-care' domain, followed by 'Personal and social relationships'. Among less severely ill patients, brexpiprazole was superior to placebo on Positive and Negative Syndrome Scale Total and Personal and Social Performance scale at Week 6. Improvements were maintained over 58 weeks. No new safety or tolerability concerns were observed. CONCLUSIONS: Brexpiprazole is an efficacious and well-tolerated treatment for schizophrenia in patients with more severe, and less severe, symptoms.

Effect of Brexpiprazole on Agitation and Hostility in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies.

BACKGROUND: Managing agitation and hostility represents a significant treatment challenge in schizophrenia. The aim of this analysis was to evaluate the short- and long-term efficacy of brexpiprazole for reducing agitation and hostility in schizophrenia. METHODS: This was a post hoc analysis of data from two 6-week, randomized, double-blind, placebo-controlled studies (ClinicalTrials.gov identifiers, NCT01396421 and NCT01393613) and a 52-week, open-label, extension study (NCT01397786). In the short-term studies, 1094 patients received placebo, 2 mg/d of brexpiprazole, or 4 mg/d of brexpiprazole; 346 brexpiprazole-treated patients rolled over into the long-term study and received 1 to 4 mg/d of brexpiprazole. Agitation was assessed using the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC), and hostility was assessed using the PANSS hostility item (P7). RESULTS: Brexpiprazole improved PANSS-EC score over 6 weeks, with least squares mean differences versus placebo of -0.69 (95% confidence limits, -1.28, -0.11) for 2 mg/d (P = 0.020) and -1.11 (-1.70, -0.53) for 4 mg/d (P = 0.0002). In the subgroup with hostility at baseline (P7 score ≥3; 50.8% of the randomized sample), least squares mean differences versus placebo at week 6 on the PANSS-EC were -0.63 (-1.54, 0.28) for 2 mg/d (P = 0.18) and -1.03 (-1.92, -0.14) for 4 mg/d (P = 0.024), and on P7 (adjusted for positive symptoms) were -0.27 (-0.53, -0.01) for 2 mg/d (P = 0.038) and -0.34 (-0.59, -0.09) for 4 mg/d (P = 0.0080). The improvements were maintained over 58 weeks. Adverse events were generally comparable between treatment groups over 6 weeks; the incidence of akathisia among patients with hostility was 5.9% with placebo, 5.2% with 2 mg/d, and 8.6% with 4 mg/d. CONCLUSIONS: Brexpiprazole has the potential to be an efficacious and well-tolerated treatment for agitation and hostility among patients with schizophrenia.

Tolvaptan use in children and adolescents with autosomal dominant polycystic kidney disease: rationale and design of a two-part, randomized, double-blind, placebo-controlled trial.

This report describes the rationale and design of a study assessing tolvaptan in children with autosomal dominant polycystic kidney disease (ADPKD). Phase A is a 1-year, randomized, double-blind, placebo-controlled, multicenter trial. Phase B is a 2-year, open-label extension. The target population is at least 60 children aged 12-17 years, diagnosed by family history and/or genetic criteria and the presence of ≥ 10 renal cysts, each ≥ 0.5 cm on magnetic resonance imaging. Subjects will be allocated into 4 groups: females 15-17 years; females 12-14 years; males 15-17 years; and males 12-14 years. Up to 40 subjects aged 4-11 years may also enroll, provided they meet the entry criteria. Weight-adjusted tolvaptan doses, titrated once to achieve a tolerated maintenance dose, and matching placebo will be administered twice-daily. Assessments include spot urine osmolality and specific gravity (co-primary endpoints), height-adjusted total kidney volume, estimated glomerular filtration rate, pharmacodynamic parameters (urine volume, fluid intake and fluid balance, serum sodium, serum creatinine, free water clearance), pharmacokinetic parameters, safety (aquaretic adverse events, changes from baseline in creatinine, vital signs, laboratory values including liver function tests), and generic pediatric quality of life assessments.Conclusion: This will be the first clinical study to evaluate tolvaptan in pediatric ADPKD. What is Known: • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing the development of cysts that impede kidney function over time and eventually induce renal failure • There are few data on the effects of tolvaptan, the only treatment approved for adults to slow disease progression, in pediatric ADPKD patients with early-stage disease What is New: • A phase 3, placebo-controlled study is evaluating tolvaptan over 3 years in children and adolescents with ADPKD • This study is designed to account for challenges of tolvaptan dosing and outcome assessment specific to the pediatric population.

Successful switching of patients with acute schizophrenia from another antipsychotic to brexpiprazole: comparison of clinicians' choice of cross-titration schedules in a post hoc analysis of a randomized, double-blind, maintenance treatment study.

OBJECTIVE: To compare the tolerability and efficacy of different antipsychotic cross-titration schedules, using data from a brexpiprazole study (Equator; NCT01668797). METHODS: Patients with schizophrenia were cross-titrated from other antipsychotics to brexpiprazole monotherapy in a 1-4 week open-label conversion phase, then entered a single-blind brexpiprazole treatment phase. Patients were stratified into four "conversion groups," according to the amount of time spent in the conversion phase. Discontinuation rates, treatment-emergent adverse events (TEAEs), and efficacy (Positive and Negative Syndrome Scale [PANSS]) were compared between conversion groups. RESULTS: Of the 404 patients treated with brexpiprazole, the majority (72.0%) spent 22-33 days in the conversion phase. Discontinuation rates due to lack of efficacy or adverse events were low in all conversion groups. Of the 292 patients who successfully switched and completed 8 weeks of brexpiprazole treatment, most were converted to brexpiprazole over 22-33 days (80.1%), and fewer were converted over 1-7 days (2.4%), 8-14 days (6.5%), or 15-21 days (11.0%). The incidence of TEAEs over 8 weeks was lower among those converted over 22-33 days (44.4%) than in other conversion groups (62.5-84.2%), although low patient numbers with shorter conversion times limit the generalizability of this finding. Each conversion group showed comparable improvement in PANSS total score from baseline. CONCLUSION: The majority of patients were cross-titrated to brexpiprazole over a period of 22-33 days, by investigators' choice. Additional data on shorter conversions may help clinicians to choose a switching paradigm that best meets their patients' needs.

A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Maintenance Treatment in Adults with Schizophrenia.

Background: Brexpiprazole is a serotonin-dopamine activity modulator with efficacy in acute schizophrenia and relapse prevention. The aim of this Phase 3, multicenter study was to assess the long-term safety, tolerability, and efficacy of treatment with brexpiprazole flexible-dose 1-4 mg/d. Methods: Patients rolled over into this 52-week open-label study (amended to 26 weeks towards the end) from 3 randomized, double-blind, placebo-controlled Phase 3 studies. De novo patients, not part of the previous studies, were also enrolled. The primary outcome variable was the frequency and severity of treatment-emergent adverse events. Efficacy was assessed as a secondary objective using the Positive and Negative Syndrome Scale and the Personal and Social Performance scale. Results: A total of 1072 patients was enrolled (952 for 52 weeks and 120 for 26 weeks), 47.4% of whom completed the study. Among patients who took at least one dose of brexpiprazole, 14.6% discontinued due to treatment-emergent adverse events, most commonly schizophrenia (8.8%) and psychotic disorder (1.5%). Treatment-emergent adverse events with an incidence of ≥5% were schizophrenia (11.6%), insomnia (8.6%), weight increased (7.8%), headache (6.4%), and agitation (5.4%). Most treatment-emergent adverse events were mild or moderate in severity. The mean increase in body weight from baseline to week 26 was 1.3 kg and to week 52 was 2.1 kg. There were no clinically relevant findings related to prolactin, lipids, and glucose, or QT prolongation. On average, patients' symptoms and functioning showed continual improvement. Conclusions: Treatment with brexpiprazole 1-4 mg/d was generally well tolerated for up to 52 weeks in patients with schizophrenia. ClinicalTrials.gov identifier: NCT01397786 (https://clinicaltrials.gov/show/NCT01397786).

Evaluation of 2009 pandemic H1N1 influenza vaccination in adults with lymphoid malignancies receiving chemotherapy or following autologous stem cell transplant.

This is a randomized trial evaluating the safety and immunogenicity of one or two doses of 2009 pandemic H1N1 influenza vaccination in adults with lymphoid malignancies. Adults with a lymphoid malignancy receiving active systemic therapy, or within a year after autologous stem cell transplant, received one dose of AS03-adjuvanted A/California/7/2009 (H1N1) vaccine, and were randomized 21 days later to a second dose or no further vaccination. The primary outcomes were seroprotection and seroconversion rates by hemagglutination inhibition 21 and 42 days after initial vaccination. Twenty-two patients received one dose, and 20 patients received a second dose. Seroconversion rates at day 21 were 30% (one dose) and 5% (two doses), and subsequently 30% for both groups at day 42. Seroprotection rates at day 21 were 40% (one dose) and 15% (two doses), and subsequently 35% (one dose) and 40% (two doses) at day 42. Differences in serologic endpoints were not statistically significant between both study arms at day 42. Patients with low levels of B-cells (CD19-positive) had low seroconversion rates on days 21 (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.59-0.93, p = 0.043) and 42 (OR 0.12, 95% CI 0.01-1.07, p = 0.058). Only three of the 14 patients who received rituximab achieved seroprotective titers by day 42. Patients with lymphoid malignancies did not achieve rates of seroconversion or seroprotection seen in healthy subjects despite a second dose and the use of an adjuvant. Notwithstanding suboptimal immunogenicity, seasonal and pandemic influenza vaccination should continue to be recommended.

Evaluation of pandemic H1N1 (2009) influenza vaccine in adults with solid tumor and hematological malignancies on active systemic treatment.

BACKGROUND: Over 85% of healthy individuals vaccinated with the pandemic H1N1 (pH1N1) vaccine achieve seroprotection. OBJECTIVES: We evaluated the safety and immunogenicity of pH1N1 vaccine in patients undergoing chemotherapy for hematological and solid tumor malignancies. STUDY DESIGN: Adult patients, receiving chemotherapy undergoing pH1N1 vaccination at our institution had blood samples drawn for CBC (baseline only) and serology prior to and ≥ 21 days post vaccination. HAI antibody testing was performed for pH1N1 (A/California/7/2009 strain) and seasonal H1 (A/Brisbane/59/07 strain). Seroprotection was defined as a pH1N1 antibody titre ≥ 1:40 and seroconversion as an antibody titre >4 × baseline. Patients completed a symptom diary card. RESULTS: Paired samples were available for 46 patients (20 solid tumor, 26 hematological), median age 56 (range 23-76) years. The seroprotective rate post-vaccination for solid tumors was 50% compared to 27% for hematological malignancy (p=0.11), respective seroconversion rates were 45% and 19% (p=0.06). In patients with solid tumors vaccination mid cycle resulted in the highest pH1N1 titres, although timing and blood count were not associated with seroconversion or seroprotection. For hematological patients, a normal leukocyte count and vaccination at the beginning of a cycle were associated with higher rates of seroconversion (p ≤ 0.05). Addition of rituximab to chemotherapy resulted in a failure to seroconvert (p=0.05). Vaccination was well tolerated by all patients. CONCLUSIONS: Although well tolerated, the seroprotection rate following pH1N1 vaccination is lower than that would be expected. Further investigation into immunization strategies in patients receiving chemotherapy is required.