Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Objective: To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease. Methods: The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed. Results: Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports. Conclusion: Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease. Clinical trial registration: ClinicalTrials.gov, identifier NCT02180217.

Combination of pasireotide and octreotide: effects on GH and IGF-I secretion and glucose metabolism in healthy volunteers.

PURPOSE: To assess the pharmacokinetics, pharmacodynamics and tolerability of different doses of octreotide and pasireotide (subcutaneous [sc] and long-acting release [LAR]) when co-administered in healthy volunteers. METHODS: This was an exploratory, Phase I, single-centre study. Healthy adults were enrolled in a staggered approach into seven cohorts to receive octreotide and pasireotide (sc and LAR formulations), alone or in combination. Plasma drug concentrations, growth hormone (GH), insulin-like growth factor I (IGF-I), and plasma glucose were assessed at baseline, immediately after sc treatment, and 21 and 28 days after LAR treatment. RESULTS: Of 88 enrolled subjects, 52 and 82 participated in sc and LAR dosing phases, respectively. There were no relevant pharmacokinetic interactions between octreotide and pasireotide. In combination, pasireotide sc (150 µg) and octreotide sc (100/300 µg) resulted in numerically greater reductions in insulin levels and a higher incidence of AEs than either single agent; the rapid (within 1 h) increase in plasma glucose after pasireotide was delayed with combination treatment. Octreotide sc and pasireotide sc, alone or in combination, reduced IGF-I levels and led to undetectable GH levels in most subjects. During the LAR phase, addition of a low dose of pasireotide (5 mg) to a standard dose of octreotide (20 mg) resulted in an ~2-fold reduction in median IGF-I versus octreotide 20 mg 21 days post-dose; this effect was numerically greater than seen for pasireotide 20 mg alone. Peak plasma glucose was substantially lower after LAR than sc dosing. Interestingly, glucose levels were also numerically lower in the pasireotide 5 mg plus octreotide 20 mg group than for 20 mg of octreotide or pasireotide alone. AEs were less frequent after LAR than sc dosing. CONCLUSIONS: Combined low doses of pasireotide LAR (5 mg) and octreotide LAR (10-30 mg) provided greater suppression of IGF-I than either single agent and did not increase blood glucose or incidence of AEs versus either agent alone.

Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study.

PURPOSE: Pasireotide is an effective treatment for acromegaly and Cushing's disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs. METHODS: Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing's disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms. RESULTS: Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was - 0.28% (95% CI - 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized. CONCLUSION: Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.

Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies.

PURPOSE: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety. METHODS: Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries. RESULTS: Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61-2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia. CONCLUSIONS: The results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.

Efficacy of anti-fungal but not anti-bacterial prophylaxis in intensive primary AML therapy: a real-world, retrospective comparative single-centre study.

QUESTIONS UNDER STUDY: The optimal strategy of anti-infectious prophylaxis in patients with acute leukaemia undergoing intensive chemotherapy remains a matter of debate. We assessed the impact of primary prophylaxis with posaconazole and levofloxacin on the incidence of invasive fungal infections (IFI) and bacteraemia. METHODS: A retrospective single-centre study including two groups of adult patients with AML receiving intensive chemotherapy. Group one without anti-infective prophylaxis (September 2008 - February 2010), and group two with anti-infective prophyalaxis (March 2010 - April 2011). The primary end-point was IFI according to the EORTC/MSG 2008 definitions and bacteraemia. RESULTS: Baseline characteristics were similar in the non-prophylaxis (n = 43 patients; 99 chemotherapy cycles) and the prophylaxis (n = 45; 104 chemotherapy cycles) group. IFI were significantly reduced in the prophylaxis group (55.3% vs. 88.9%; p = 0.0032) and there was a trend of the projected IFI-free survival at 100 days to be increased (50.1% vs. 25%; p = 0.0526). One-hundred day overall survival (84.4% and 88.4%, p = 0.35) and 2-year overall survival (64.4% and 58.1%; p = 0.64) were unaffected. No difference in the occurrence of bacteraemia was observed (32.3% vs. 34.6%; p = 0.8). A total of two (3.6%) patients in the non-prophylaxis and three (6.7%) in the prophylaxis group died due to IFI, and two (3.6%) in the non-prophylaxis and none in the prophylaxis group patients had to stop leukaemia treatment due to IFI. CONCLUSIONS: The anti-infective prophylaxis with posaconazole and levofloxacin resulted in a significant reduction of 'possible' IFI with a number-needed to treat to prevent one IFI of only 3 but did not result in a reduction of the incidence of bacteraemia.

Bilaterally positive biopsy cores are associated with non-organ-confined disease in prostate cancer patients eligible for active surveillance.

PURPOSE: To investigate the association between the laterality of diagnostic prostate cancer-positive biopsy cores and definitive tumor stage on final pathology (organ-confined versus non-organ-confined). PATIENTS AND METHODS: This is a retrospective analysis of 165 men after radical prostatectomy fulfilling our active surveillance criteria at the time of surgery. Nominal variables were compared using Fisher's exact test, continuous variables using Mann-Whitney test. Odds ratios including 95% Wald and probabilities including 95% Wilson confidence intervals are provided. RESULTS: 5 (3%) patients had non-organ-confined disease: 2 out of 144 (1%) patients with unilateral and 3 out of 17 (18%) patients with bilateral cancer-positive biopsy cores (p = 0.009). The estimated odds ratio for non-organ-confined disease was 14.67 (95% confidence interval 1.55-189.23) for patients with bilateral compared to patients with unilateral cancer-positive biopsy cores. The sensitivity, specificity and accuracy of bilaterally positive biopsies as an additional criterion to identify non-organ-confined disease are 60, 91 and 90%, respectively. CONCLUSION: In our cohort, patients with bilaterally positive biopsy cores were significantly more likely to harbor a non-organ-confined tumor than patients with unilaterally positive cores. Due to their high specificity, bilaterally positive biopsies may represent a reasonable exclusion criterion for active surveillance if our results are corroborated in further studies.

Evaluating faecal egg count reduction using a specifically designed package "eggCounts" in R and a user friendly web interface.

The seemingly straightforward task of analysing faecal egg counts resulting from laboratory procedures such as the McMaster technique has, in reality, a number of complexities. These include Poisson errors in the counting technique which result from eggs being randomly distributed in well mixed faecal samples. In addition, counts between animals in a single experimental or observational group are nearly always over-dispersed. We describe the R package "eggCounts" that we have developed that incorporates both sampling error and over-dispersion between animals to calculate the true egg counts in samples of faeces, the probability distribution of the true counts and summary statistics such as the 95% uncertainty intervals. Based on a hierarchical Bayesian framework, the software will also rigorously estimate the percentage reduction of faecal egg counts and the 95% uncertainty intervals of data generated by a faecal egg count reduction test. We have also developed a user friendly web interface that can be used by those with limited knowledge of the R statistical computing environment. We illustrate the package with three simulated data sets of faecal egg count reduction experiments.

The Paediatric Palliative Screening Scale: Further validity testing.

BACKGROUND: Paediatric palliative care is still often introduced late in the illness trajectory of children with life-limiting diseases. Translating palliative care into practice continues to be a challenge. AIM: To validate the Paediatric Palliative Screening Scale further by defining attributes that predict the need for palliative care in children between 1 and 18 years. DESIGN: Proportional-odds logistic regression analysis was performed to investigate the relationship between the attributes of the Paediatric Palliative Screening Scale and the experts' assessment of case vignettes with various combinations of different attribute characteristics. Estimates from regression analysis were transformed to empirical weightings of the Paediatric Palliative Screening Scale attribute characteristics. SETTING/PARTICIPANTS: Online questionnaires with case vignettes were sent to 33 paediatric palliative care experts from Europe, the United States, Canada, Australia and New Zealand. RESULTS: The highest weightings among the five previously defined attributes were estimated life expectancy <12 months (40% of maximum score) and preferences of the child/parents received (24%). Trajectory of disease and impact on daily activities of the child, expected outcome of treatment directed at the disease and burden of treatment, and symptom or problem burden were weighted less. CONCLUSIONS: According to this second step of psychometric testing of the Paediatric Palliative Screening Scale, the strongest and most urgent necessity indicators for a palliative care approach are life expectancy and child/family preferences. These results are somewhat discrepant with results from the previous validation of the instrument as well as previous research findings.

Assessment of mitral valve area during percutaneous mitral valve repair using the MitraClip system: comparison of different echocardiographic methods.

BACKGROUND: Quantification of the mitral valve area (MVA) is important to guide percutaneous mitral valve repair using the MitraClip system. However, little is known about how to best assess MVA in this specific situation. METHODS AND RESULTS: Immediately before and after MitraClip implantation, comprehensive 3-dimensional (3D) transesophageal echocardiography data were acquired for MVA assessment by the pressure half-time method and by two 3D quantification methods (mitral valve quantification software and 3D quantification software). In addition, transmitral gradients by continuous-wave Doppler (dPmeanCW) were measured to indirectly assess MVA. Data are given as median (interquartile range). Thirty-three patients (39% women) with a median age of 77.1 years (12.4 years) were studied. Before intervention, the median MVAs by the pressure half-time method, mitral valve quantification software, and 3D quantification software were 4.4 cm(2) (2.0 cm(2)), 4.7 cm(2) (2.4 cm(2)), and 6.2 cm(2) (2.4 cm(2)), respectively (P<0.001). After intervention, MVA was reduced to 1.9 cm(2) (0.7 cm(2)), 2.1 cm(2) (1.1 cm(2)), and 2.8 cm(2) (1.1 cm(2)), respectively (P=0.001). The median values for dPmeanCW before and after intervention were 1.0 mm Hg (1.0 mm Hg) and 3.0 mm Hg (3.0 mm Hg; P<0.001), respectively. At discharge, the median dPmeanCW was 4.0 mm Hg (3.0 mm Hg). In multivariate regression analyses including body surface area, the 3 different MVA methods, and dPmeanCW, a post-dPmeanCW ≥5 mm Hg was the best independent predictor of an elevated transmitral gradient at discharge. CONCLUSIONS: Transmitral gradients by continuous-wave Doppler are quick, feasible in all patients, and superior to direct peri-interventional assessment of MVA. A postinterventional transmitral gradient by continuous-wave Doppler of ≥5 mm Hg best predicted elevated transmitral gradients at discharge.

Heat waves, incidence of infectious gastroenteritis, and relapse rates of inflammatory bowel disease: a retrospective controlled observational study.

OBJECTIVES: The objective of this study was to evaluate the effect of heat waves on flares of inflammatory bowel disease (IBD) and infectious gastroenteritis (IG). METHODS: In this retrospective controlled observational study, data from 738 IBD and 786 IG patients admitted to the University Hospital of Zurich in the years 2001-2005, as well as from 506 other noninfectious chronic intestinal inflammations, which were used as control, were collected. Climate data were obtained from the Swiss Federal Office for Meteorology and Climatology. RESULTS: The presence of a heat wave increased the risk of IBD flares by 4.6% (95% confidence interval (CI): 1.6-7.4%, P=0.0035) and of IG flares by 4.7% (95% CI: 1.8-7.4%, P=0.0020) for every additional day within a heat wave period. In the control group there was no significant effect (95% CI: -6.2-2.9%, P=0.53). Screening of alternative forms for the effect of heat waves suggested that for IG the effect is strongest when lagged by 7 days (risk increase per day: 7.2%, 95% CI: 4.6-9.7%, P<0.0001), whereas for IBD no such transformation was required. Other formulations with additive effects, interactions between heat waves and time of the year, and additional adjustments for daily average temperature did not show any improvement in model fit. CONCLUSIONS: In this retrospective controlled observational study, we found a substantial increase in hospital admissions because of flares of IBD and IG during heat wave periods. Whereas the effect on IG is strongest with a delay of 7 days, the effect on IBD flares is immediate, suggesting different mechanisms.

Modeling seasonality in space-time infectious disease surveillance data.

Infectious disease data from surveillance systems are typically available as multivariate times series of disease counts in specific administrative geographical regions. Such databases are useful resources to infer temporal and spatiotemporal transmission parameters to better understand and predict disease spread. However, seasonal variation in disease notification is a common feature of surveillance data and needs to be taken into account appropriately. In this paper, we extend a time series model for spatiotemporal surveillance counts to incorporate seasonal variation in three distinct components. A simulation study confirms that the different types of seasonality are identifiable and that a predictive approach suggested for model selection performs well. Application to surveillance data on influenza in Southern Germany reveals a better model fit and improved one-step-ahead predictions if all three components allow for seasonal variation.

The contribution of simple random sampling to observed variations in faecal egg counts.

It has been over 100 years since the classical paper published by Gosset in 1907, under the pseudonym "Student", demonstrated that yeast cells suspended in a fluid and measured by a haemocytometer conformed to a Poisson process. Similarly parasite eggs in a faecal suspension also conform to a Poisson process. Despite this there are common misconceptions how to analyse or interpret observations from the McMaster or similar quantitative parasitic diagnostic techniques, widely used for evaluating parasite eggs in faeces. The McMaster technique can easily be shown from a theoretical perspective to give variable results that inevitably arise from the random distribution of parasite eggs in a well mixed faecal sample. The Poisson processes that lead to this variability are described and illustrative examples of the potentially large confidence intervals that can arise from observed faecal eggs counts that are calculated from the observations on a McMaster slide. Attempts to modify the McMaster technique, or indeed other quantitative techniques, to ensure uniform egg counts are doomed to failure and belie ignorance of Poisson processes. A simple method to immediately identify excess variation/poor sampling from replicate counts is provided.

Statistical approaches to the monitoring and surveillance of infectious diseases for veterinary public health.

This paper covers the aspect of using statistical methodology for the monitoring and surveillance of routinely collected data in veterinary public health. An account of the Farrington algorithm and Poisson cumulative sum schemes for the prospective detection of aberrations is given with special attention devoted to the occurrence of seasonality and spatial aggregation of the time series. Modelling approaches for retrospective analysis of surveillance counts are also described. To illustrate the applicability of the methodology in veterinary public health, data from the monitoring of rabies among fox in Hesse, Germany, are analysed.