Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials.

BACKGROUND: Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough. METHODS: COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2). FINDINGS: From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9-0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1-1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2). INTERPRETATION: Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough. FUNDING: Merck Sharp & Dohme.

Discovery of a Novel DCAF1 Ligand Using a Drug-Target Interaction Prediction Model: Generalizing Machine Learning to New Drug Targets.

DCAF1 functions as a substrate recruitment subunit for the RING-type CRL4DCAF1 and the HECT family EDVPDCAF1 E3 ubiquitin ligases. The WDR domain of DCAF1 serves as a binding platform for substrate proteins and is also targeted by HIV and SIV lentiviral adaptors to induce the ubiquitination and proteasomal degradation of antiviral host factors. It is therefore attractive both as a potential therapeutic target for the development of chemical inhibitors and as an E3 ligase that could be recruited by novel PROTACs for targeted protein degradation. In this study, we used a proteome-scale drug-target interaction prediction model, MatchMaker, combined with cheminformatics filtering and docking to identify ligands for the DCAF1 WDR domain. Biophysical screening and X-ray crystallographic studies of the predicted binders confirmed a selective ligand occupying the central cavity of the WDR domain. This study shows that artificial intelligence-enabled virtual screening methods can successfully be applied in the absence of previously known ligands.

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

Skeletal muscle of torpid Richardson's ground squirrels (Urocitellus richardsonii) exhibits a less active form of citrate synthase associated with lowered lysine succinylation.

Hibernation is a metabolic/physiological strategy employed by many mammals to cope with periods when energy usage is greater than its input. Animals undergoing hibernation need to greatly reduce their metabolic rate and reshape their catabolic processes to survive on stored triglycerides. Citrate synthase (CS) is one of only two irreversible steps in the citric acid cycle (CAC) and forms an important regulatory checkpoint that gates the entry of acetyl-CoA formed in glycolysis or fatty acid catabolism into this critical central metabolic hub. This study investigated the regulation of citrate synthase in the muscle tissue of a small mammalian hibernator through comparison of functional and structural properties. The results demonstrated a significant decrease in the Vmax of purified torpid CS compared to the control euthermic enzyme (1.2-1.7 fold greater in the control) that was evident over a wide range of temperatures (8, 22 and 37 °C) that are encountered by the enzyme in hibernation. This was also reflected in the specific activity of the enzyme in crude muscle protein extracts. Analyzing the purified CS through immunoblotting demonstrated that the enzyme contained noticeably less lysine succinylation in the torpid state (about 50% of euthermic levels) and this was correlated with an increase in total levels of SIRT5, the enzyme responsible for mediating desuccinylation in the mitochondria (2.2 fold increase). Taken together, the results of this study support the idea that CS is inhibited during hibernation in the ground squirrel skeletal muscle and that this alteration could be mediated by decreases in succinylation.

Functional and post-translational characterization of pyruvate dehydrogenase demonstrates repression of activity in the liver but not skeletal muscle of the Richardson's ground squirrel (Urocitellus richardsonii) during hibernation.

Hibernation consists of a series of physiological and biochemical alterations in an animal that allows for reduced body temperatures down to near ambient levels and substantial fuel conservation allowing it to survive on stored fat supplies accumulated during the summer. The Richardson's ground squirrel is one such hibernator that undergoes such changes for as long as 9 months of the year. This study examines the role of regulation of the pyruvate dehydrogenase complex (PDC) during hibernation in the skeletal muscle and liver of the Richardson's ground squirrel. The current study demonstrates a great reduction in the activity of PDC in the hibernating liver, but not in the skeletal muscle. This was matched by a significant increase in the phosphorylation on a regulatory serine residue (S300) of the pyruvate dehydrogenase (PDH) E1α subunit. Examining the expression patterns of the relevant kinases for PDH and the associated phosphatase demonstrated some unexpected results. Specifically, an increase in PDKs 1 and 2 and a decrease in PDK4 was noted in the skeletal muscle tissue in response to hibernation and no alterations in the expression patterns of any of these enzymes were noted in the liver. This suggests that alternative modes of regulation of the kinases may be at play in hibernation to bring about the observed effects. Taken together this study demonstrates that PDH regulatory responses differ markedly between tissues and emphasize the importance of inhibition of the complex in the liver during hibernation.

Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy regimens: a subgroup analysis from a randomized clinical trial of response in subjects by cancer type.

BACKGROUND: Results from a phase III, randomized, double-blind, active comparator-controlled, parallel-group trial evaluating fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) found that a single-day, triple-antiemetic fosaprepitant regimen resulted in a significantly higher proportion of patients achieving a complete response (CR; no vomiting or rescue medication use) in the delayed phase (25-120 h after chemotherapy initiation), compared with a 3-day control regimen ( ClinicalTrials.gov , NCT01594749). As the risk for CINV is dependent on chemotherapy regimen and generally guided by tumor type, this post hoc analysis evaluated the efficacy and safety of this regimen by cancer subpopulations (gastrointestinal [GI] or colorectal, lung, breast, and gynecologic cancers). METHODS: Subjects with confirmed cancer who were naive to highly and moderately emetogenic chemotherapy (HEC and MEC) and were scheduled to receive intravenous (IV) anthracycline-cyclophosphamide (AC)-based MEC on the first day of chemotherapy were randomly assigned to receive oral ondansetron and oral dexamethasone plus either a single IV dose of fosaprepitant 150 mg (fosaprepitant regimen) or placebo (control regimen). The primary efficacy end point was the proportion of subjects achieving CR in the delayed phase. CR rates in the overall and acute phases (0-120 h and 0-24 h after MEC initiation, respectively) were assessed as secondary end points. Safety and tolerability were also assessed. RESULTS: CR rates in the delayed phase favored the fosaprepitant regimen over the control regimen across the GI/colorectal, lung, breast, and gynecologic cancer subgroups (range, 6.2-22%); similar findings were observed for CR in the overall phase. CR in the acute phase was high for all groups (≥87%). The fosaprepitant regimen was well tolerated in all cancer subgroups. CONCLUSIONS: This post hoc analysis indicated that a single-day fosaprepitant regimen was effective in preventing CINV in patients receiving MEC, regardless of cancer type. TRIAL REGISTRATION: ClinicalTrials.gov NCT01594749 , registered May 9, 2012.

Variation of radiation dose with distance from radiotherapy linac bunker maze entrances.

Instantaneous dose rate (IDR) measurements were made at the entrances of a number of linac bunkers for a range of beam energies and gantry angles in a large radiotherapy department. The results demonstrate that the IDR does not decrease with distance from the maze entrances according to the inverse square law (ISL), which is commonly used in the design of such bunkers. No simple relationship exists, but a useful guiding principle was found that the IDR at 1 m back from the maze entrance is approximately 50% of that at the entrance itself. This was found to hold with a standard error within 5% across the full extent of the maze entrance by measuring in a grid pattern. The ISL should therefore be used with caution in the design of radiotherapy bunker mazes as it may not provide accurate estimates of the dose in surrounding areas. The results of the grid pattern measurements also indicate that the centre of the maze entrance is the best position to affix passive dosemeters for the purpose of environmental monitoring. This may not always be practical (e.g. if the bunker does not have a door), but factors have been found to correct readings taken elsewhere to the central reading. For instance, if the dosemeter is placed on the wall, the measured dose rate will be equal to 94% ± 8% of the value at the centre of the bunker.

Purification of carbamoyl phosphate synthetase 1 (CPS1) from wood frog (Rana sylvatica) liver and its regulation in response to ice-nucleation and subsequent whole-body freezing.

Carbamoyl phosphate synthetase I (CPS1) represents an important regulatory enzyme of the urea cycle that mediates the ATP-driven reaction ligating ammonium, carbonate, and phosphate to form carbamoyl phosphate. The freeze-tolerant wood frog (Rana sylvatica or Lithobates sylvaticus) accumulates high concentrations of urea during bouts of freezing to detoxify any ammonia generated and to contribute as a cryoprotectant thereby helping to avoid freeze damage to cells. Purification of CPS1 to homogeneity from wood frog liver was performed in control and frozen wood frogs by a three-step chromatographic process. The affinity of CPS1 for its three substrates was tested in the purified control and freeze-exposed enzyme under a variety of conditions including the presence and absence of the natural cryoprotectants urea and glucose. The results demonstrated that affinity for ammonium was higher in the freeze-exposed CPS1 (1.26-fold) and that with the addition of 400 mM glucose it displayed higher affinity for ATP (1.30-fold) and the obligate activator N-acetylglutamate (1.24-fold). Denaturation studies demonstrated the freeze-exposed enzyme was less thermally stable than the control with an unfolding temperature approximately 1.5 °C lower (52.9 °C for frozen and 54.4 °C for control). The control form of CPS1 had a significantly higher degree of glutarylated lysine residues (1.42-fold increase) relative to the frozen. The results suggest that CPS1 activation and maintenance of urea cycle activity despite the hypometabolic conditions associated with freezing are important aspects in the metabolic survival strategies of the wood frog.

Update on the clinical development of gefapixant, a P2X3 receptor antagonist for the treatment of refractory chronic cough.

Chronic cough, or cough lasting >8 weeks, is often associated with underlying medical conditions (ie, asthma, gastroesophageal reflux disease, nonasthmatic eosinophilic bronchitis, and upper-airway cough syndrome). In some patients with chronic cough, treatment of these underlying conditions does not resolve the cough (refractory chronic cough [RCC]), or none of these conditions are present (unexplained chronic cough [UCC]). Despite appropriate medical evaluation, patients with RCC or UCC frequently experience cough persisting for many years, as there are currently no targeted pharmacological approaches approved for the treatment of these conditions. However, the adenosine triphosphate (ATP)-gated P2X3 receptor, a key modulator of the activation of sensory neurons central to the cough reflex, has recently garnered attention as a potential therapeutic target for the treatment of chronic cough. Gefapixant, a first-in-class, non-narcotic, selective antagonist of the P2X3 receptor, recently demonstrated efficacy and was generally well tolerated in phase 2 clinical trials in patients with RCC, validating the utility of targeting this receptor in patients with chronic cough. On the basis of these data, 2 global phase 3 trials, with combined anticipated enrolment exceeding 2000 patients and with treatment durations of up to 1 year, have been initiated. Together, these trials will further evaluate efficacy and safety of gefapixant in the control of cough in patients with RCC or UCC.

Glucose-6-phosphate dehydrogenase is posttranslationally regulated in the larvae of the freeze-tolerant gall fly, Eurosta solidaginis, in response to freezing.

The freeze-tolerant larvae of the goldenrod gall fly (Eurosta solidaginis) undergo substantial alterations to their molecular physiology during the winter including the production of elevated quantities of glycerol and sorbitol, which function as cryoprotectants to survive whole body freezing. Production of these cryoprotectants depends on cytosolic pools of nicotinamide adenine dinucleotide phosphate H (NADPH), a major source being the pentose phosphate pathway (PPP). Glucose-6-phosphate dehydrogenase (G6PDH) mediates the rate-limiting and committed step of the PPP and therefore its molecular properties were explored in larvae sampled from control versus frozen states. G6PDH was purified from control (5°C) and frozen (-15°C) E. solidaginis larvae by a single-step chromatography method utilizing 2',5'-ADP agarose and analyzed to determine its enzymatic parameters. Studies revealed a decrease in Km for G6P in the frozen animals (to 50% of control values) suggesting an increased flux through the PPP. Immunoblotting of the purified enzyme showed differences in the relative extent of several posttranslational modifications, notably ubiquitination (95% decrease in frozen larvae), cysteine nitrosylation (61% decrease), threonine (4.1 fold increase), and serine phosphorylation (59% decrease). Together these data suggested that the increased flux through the PPP needed to generate NADPH for cryoprotectants synthesis is regulated, at least in part, through posttranslational alterations of G6PDH.

Translating evidence in complex systems: a comparative review of implementation and improvement frameworks.

PURPOSE: An increasing number of implementation and improvement frameworks seek to describe and explain how change is made in healthcare. This paper aims to explore how existing frameworks conceptualize the influence of complexity in translating evidence into practice in healthcare. DATA SOURCES: A database was interrogated using a search strategy to identify publications that present frameworks and models for implementation and improvement. STUDY SELECTION: Ten popular implementation and improvement frameworks were purposively selected. DATA EXTRACTION: Comparative analysis was conducted using an analytical framework derived from SHIFT-Evidence, a framework that conceptualizes complexity in implementation and improvement initiatives. RESULTS: Collectively the frameworks accounted for key concepts of translating evidence in complex systems: understanding the uniqueness of each setting; the interdependency of practices/processes and the need to respond to unpredictable events and emergent learning. The analysis highlighted heterogeneity of the frameworks in their focus on different aspects of complexity. Differences include the extent to which problems and solutions are investigated or assumed; whether endpoints are defined as the uptake of interventions or achievement of goals; and emphasis placed on fixed-term interventions versus continual improvement. None of the individual frameworks reviewed incorporated all the implications of complexity, as described by SHIFT-Evidence. CONCLUSION: This research identifies the differences in how implementation and improvement frameworks consider complexity, suggesting that SHIFT-Evidence offers a more comprehensive overview compared with the other frameworks. The similarity of concepts across the frameworks suggests growing consensus in the literature, with SHIFT-Evidence providing a conceptual bridge between the implementation and improvement fields.

Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials.

BACKGROUND: Tildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis. METHODS: We did two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician's Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing. FINDINGS: reSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) [corrected] in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death. INTERPRETATION: In two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis. FUNDING: Merck & Co.

The Living Dead: Mitochondria and Metabolic Arrest.

Mitochondria are not just the powerhouses of the cell; these 'end of function' organelles are crucial components of cellular physiology and influence many central metabolic and signaling pathways that support complex multicellular life. Not surprisingly, these organelles play vital roles in adaptations for extreme survival strategies including hibernation and freeze tolerance, both of which are united by requirements for a strong reduction and reprioritization of metabolic processes. To facilitate metabolic rate depression, adaptations of all aspects of mitochondrial function are required, including; energetics, physiology, abundance, gene regulation, and enzymatic controls. This review discusses these factors with a focus on the stress-specific nature of mitochondrial genes and transcriptional regulators, and processes including apoptosis and chaperone protein responses. We also analyze the regulation of glutamate dehydrogenase and pyruvate dehydrogenase, central mitochondrial enzymes involved in coordinating the shifts in metabolic fuel use associated with extreme survival strategies. Finally, an emphasis is given to the novel mitochondrial research areas of microRNAs, peptides, epigenetics, and gaseous mediators and their potential roles in facilitating hypometabolism. © 2018 IUBMB Life, 70(12):1260-1266, 2018.

Optical coherence tomography indices of structural retinal pathology in schizophrenia.

BACKGROUND: Prior optical coherence tomography (OCT) studies of schizophrenia have identified thinning of retinal layers. However, findings have varied across reports, and most studies have had serious methodological limitations. To address unresolved issues, we determined whether: (1) retinal thinning in schizophrenia occurs independently of comorbid medical conditions that affect the retina; (2) thinning is independent of antipsychotic medication dose; (3) optic nerve parameters are abnormal in schizophrenia; and (4) OCT indices are related to visual and cognitive impairments common in schizophrenia. METHODS: A total of 32 people with schizophrenia and 32 matched controls participated. Spectral domain OCT generated data on retinal nerve fiber layer (RNFL), macula, and ganglion cell-inner plexiform layer (GCL-IPL) thickness, in addition to cup volume and the cup-to-disc ratio at the optic nerve head. Subjects with schizophrenia also completed measures of symptoms, visual processing, and IQ. RESULTS: The groups did not differ on RNFL, macula, or GCL-IPL thickness. However, thinning of these layers was related to the presence of diabetes or hypertension across the sample as a whole. The schizophrenia group demonstrated enlarged cup volume and an enlarged cup-to-disc ratio in both eyes, which were unrelated to medical comorbidity, but were related to increased cognitive symptoms. CONCLUSIONS: Past reports of retinal thinning may be artifacts of medical comorbidity that is over-represented in schizophrenia, or other confounds. However, optic nerve head abnormalities may hold promise as biomarkers of central nervous system abnormality, including cognitive decline, in schizophrenia.

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in paediatric subjects: An analysis by age group.

BACKGROUND: This was a subgroup analysis of age group, dexamethasone use, and very highly emetogenic chemotherapy (VHEC) use from a randomised, multicentre, double-blind, Phase 3 study of oral aprepitant in paediatric subjects. METHODS: Subjects aged 6 months to 17 years scheduled to receive chemotherapeutic agents associated with at least moderate risk for emesis were randomly assigned to receive either aprepitant plus ondansetron (aprepitant regimen) or placebo plus ondansetron (control regimen); both could be administered with or without dexamethasone. This secondary analysis evaluated subjects stratified by pre-specified age groups, dexamethasone use, and VHEC use. The primary endpoint of this analysis was the proportion of subjects who experienced complete response (CR) during the delayed phase. RESULTS: CR rates in the delayed phase were numerically higher with the aprepitant than the control regimen across all age categories, and reached significance for subjects aged 12-17 years (51% vs. 10%; P < 0.0001). In subjects receiving dexamethasone, CR was twice as high for the aprepitant versus control regimen in the 6 months to <2 year group (50% vs. 25%) and significantly higher in the 12-17 year group (40% vs. 7%, P < 0.05). CR was also significantly higher with aprepitant in the 6 months to <2 year and 12-17 year age groups who received VHEC. Similar proportions of subjects experiencing at least one adverse event were seen in both regimens across age categories. CONCLUSION: A 3 day aprepitant regimen seemed effective and safe for prevention of chemotherapy-induced nausea and vomiting in paediatric subjects across subgroups (ClinicalTrials.gov NCT01362530).

Evaluation of factors contributing to the response to fosaprepitant in a heterogeneous, moderately emetogenic chemotherapy population: an exploratory analysis of a randomized phase III trial.

PURPOSE: Fosaprepitant improved prevention of chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase III trial (PN031). This post hoc analysis explored factors that may have influenced response. METHODS: Adult subjects (N = 1000) scheduled to receive non-anthracycline and cyclophosphamide (AC) moderately emetogenic chemotherapy (MEC) on day 1 were randomly assigned 1:1 to a single-dose, 150-mg intravenous fosaprepitant regimen or a control regimen. Both regimens included dexamethasone and ondansetron on day 1, with ondansetron continuing through day 3 in the control arm only. Complete response (CR; no vomiting and no rescue medication) rates in the acute, delayed, and overall phases (0-25, 25-120, and 0-120 h, respectively) were analyzed by chemotherapy type (carboplatin-based vs non-carboplatin-based), chemotherapy duration (single-day vs multiple-day), and baseline characteristics. RESULTS: Most subjects received single-day chemotherapeutic regimens (70.6%), which were mainly carboplatin-based (67.6%). CR with fosaprepitant was consistent (76-80%) during the delayed and overall phases in carboplatin-based and non-carboplatin-based subgroups and in subgroups receiving single-day or multiple-day MEC regimens. Treatment effects favored fosaprepitant for the carboplatin-based versus the non-carboplatin-based group during the delayed phase (14.1 vs 6.5%; p = 0.06), and for the single-day versus the multiple-day subgroup during the delayed (13.2 vs 3.2%; p = 0.02) and overall phases (12.8 vs 4.0%; p = 0.06). CONCLUSIONS: This exploratory analysis confirms that single-dose fosaprepitant is effective for the prevention of CINV in subjects receiving carboplatin or non-carboplatin in both single- and multiple-day non-AC MEC chemotherapy regimens. This trial is registered at ClinicalTrials.gov , number NCT01594749.