Fatigue independently predicts different work disability dimensions in etanercept-treated rheumatoid arthritis and ankylosing spondylitis patients.

BACKGROUND: Work disability remains a significant problem in ankylosing spondylitis (AS) and rheumatoid arthritis (RA), despite biological therapy. This study aimed to test the hypothesis that the prevalent symptom of fatigue longitudinally predicts work disability among RA and AS patients commencing etanercept. METHODS: Two observational studies, comprising RA and AS etanercept commencers, respectively, were analysed. Both provided data on work disability over 1 year and a comprehensive set of putative predictors, including fatigue. A series of repeated measures models were conducted, including baseline variables, visit (6/12 months), and the interaction between visit and each of the explanatory variables. RESULTS: A total of 1003 AS and 1747 RA patients were assessed. For AS, fatigue was significantly associated with presenteeism (linear mixed model coefficient 3.75, 95% confidence interval (CI) 2.14 to 5.36) and activity impairment (2.62, 1.26 to 3.98), but not with work productivity loss (1.81, -0.40 to 4.02) or absenteeism (generalised linear mixed model odds ratio (OR) 1.18, 95% CI 0.92 to 1.51). In RA, fatigue was associated with presenteeism (coefficient 3.44, 95% CI 2.17 to 4.70), activity impairment (1.52, 0.79 to 2.26), work productivity loss (4.16, 2.47 to 5.85), and absenteeism (OR 1.23, 95% CI 1.02 to 1.49). The lack of significant interactions between fatigue and visit supported a consistent effect of baseline fatigue over time. CONCLUSIONS: Among patients beginning etanercept therapy, fatigue has a significant and independent effect on absenteeism, presenteeism, productivity loss, and activity impairment for RA patients and a significant but dimension-selective effect on work disability among AS patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00544557 . Registered on 16 October 2007. ClinicalTrials.gov, NCT00488475 . Registered on 20 June 2006.

Factors influencing treatment escalation from long-acting muscarinic antagonist monotherapy to triple therapy in patients with COPD: a retrospective THIN-database analysis.

Purpose: Inappropriate use of an inhaled corticosteroid (ICS) for COPD has clinical and economic disadvantages. This retrospective analysis of The UK Health Improvement Network (THIN) database identified factors influencing treatment escalation (step-up) from a long-acting muscarinic antagonist (LAMA) to triple therapy (LAMA + long-acting ß-agonist-ICS). Secondary objectives included time to step up from first LAMA prescription, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grouping (2011/2013, 2017), and Medical Research Council (MRC) grade prior to treatment escalation. Materials and methods: Data were included from 14,866 people ≥35 years old with a COPD diagnosis (June 1, 2010-May 10, 2015) and initiated on LAMA monotherapy. The most commonly used LAMA at baseline was tiotropium (92%). Results: Multivariate analysis (10,492 patients) revealed that COPD exacerbations, lower forced expiratory volume in 1 second (FEV1), "asthma", MRC grade, proactive and reactive COPD primary care, elective secondary-care contact, cough, and number of short-acting bronchodilator prescriptions were positively associated with treatment escalation (P<0.05). Being older, a current/ex-smoker, or having increased sputum symptom codes were negatively associated with treatment escalation (P<0.05). Median MRC score was 2 at baseline and 3 prior to treatment escalation. Using the last MRC reading and exacerbation history in the year prior to escalation, GOLD 2017 groupings were A 27.4%, B 37.3%, C 15.3%, and D 20%. In patients with available FEV1 measures, exacerbations, and MRC code (n=1,064), GOLD 2011/2013 groupings were A 20.4%, B 19.2%, C 24.8%, and D 35.6%. Conclusion: While the presence of COPD exacerbations seems to be the main driver for treatment escalation, according to the 2017 GOLD strategy many patients appear to be overtreated, as they would not be recommended for treatment escalation. Reviewing patients' treatment in the light of the new GOLD strategy has the potential to reduce inappropriate use of triple therapy.

Protecting patient privacy when sharing patient-level data from clinical trials.

BACKGROUND: Greater transparency and, in particular, sharing of patient-level data for further scientific research is an increasingly important topic for the pharmaceutical industry and other organisations who sponsor and conduct clinical trials as well as generally in the interests of patients participating in studies. A concern remains, however, over how to appropriately prepare and share clinical trial data with third party researchers, whilst maintaining patient confidentiality. Clinical trial datasets contain very detailed information on each participant. Risk to patient privacy can be mitigated by data reduction techniques. However, retention of data utility is important in order to allow meaningful scientific research. In addition, for clinical trial data, an excessive application of such techniques may pose a public health risk if misleading results are produced. After considering existing guidance, this article makes recommendations with the aim of promoting an approach that balances data utility and privacy risk and is applicable across clinical trial data holders. DISCUSSION: Our key recommendations are as follows: 1. Data anonymisation/de-identification: Data holders are responsible for generating de-identified datasets which are intended to offer increased protection for patient privacy through masking or generalisation of direct and some indirect identifiers. 2. Controlled access to data, including use of a data sharing agreement: A legally binding data sharing agreement should be in place, including agreements not to download or further share data and not to attempt to seek to identify patients. Appropriate levels of security should be used for transferring data or providing access; one solution is use of a secure 'locked box' system which provides additional safeguards. This article provides recommendations on best practices to de-identify/anonymise clinical trial data for sharing with third-party researchers, as well as controlled access to data and data sharing agreements. The recommendations are applicable to all clinical trial data holders. Further work will be needed to identify and evaluate competing possibilities as regulations, attitudes to risk and technologies evolve.

A 2-year multicentre, open-label, randomized, controlled study of growth hormone (Genotropin®) treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN) Study.

OBJECTIVE: In Europe, growth hormone (GH) treatment for children born small for gestational age (SGA) can only be initiated after 4 years of age. However, younger age at treatment initiation is a predictor of favourable response. To assess the effect of GH treatment on early growth and cognitive functioning in very young (<30 months), short-stature children born SGA. DESIGN: A 2-year, randomized controlled, multicentre study (NCT00627523; EGN study), in which patients received either GH treatment or no treatment for 24 months. PATIENTS: Children aged 19-29 months diagnosed as SGA at birth, and for whom sufficient early growth data were available, were eligible. Patients were randomized (1:1) to GH treatment (Genotropin®, Pfizer Inc.) at a dose of 0·035 mg/kg/day by subcutaneous injection, or no treatment. MEASUREMENTS: The primary objective was to assess the change from baseline in height standard deviation score (SDS) after 24 months of GH treatment. RESULTS: Change from baseline in height SDS was significantly greater in the GH treatment vs control group at both month 12 (1·03 vs 0·14) and month 24 (1·63 vs 0·43; both P < 0·001). Growth velocity SDS was significantly higher in the GH treatment vs control group at 12 months (P < 0·001), but not at 24 months. There was no significant difference in mental or psychomotor development indices between the two groups. CONCLUSIONS: GH treatment for 24 months in very young short-stature children born SGA resulted in a significant increase in height SDS compared with no treatment.

Intravenous sildenafil for postoperative pulmonary hypertension in children with congenital heart disease.

PURPOSE: To evaluate the efficacy and safety of intravenous sildenafil for immediate postoperative pulmonary hypertension (PH) in pediatric patients undergoing congenital heart surgery. METHODS: A double-blind, multicenter, placebo-controlled, dose-ranging, parallel-group trial was conducted. Patients were randomized to one of three doses of intravenous sildenafil, or placebo, for a minimum of 24 h. RESULTS: The study was heavily underpowered. Whereas enrollment of 228 patients (57 per treatment arm) was required to achieve the sample size estimate to detect difference between arms, the sponsor terminated the study after 15 months owing to slow patient accrual. Seventeen patients (median age 5 months) experiencing postoperative PH were randomized and treated, five with placebo and four each with low-, medium-, and high-dose sildenafil. In the first 24 h, 40% of placebo and 17% of sildenafil patients required additional therapy (p = 0.330). Median time to extubation (3 versus 8 days, p = 0.023) and intensive care unit stay (6 versus 15 days, p = 0.008) were shorter for sildenafil patients. Mean ± standard deviation systolic pulmonary artery pressure was reduced with sildenafil (46 ± 11 to 35 ± 6 mmHg, p = 0.027 versus placebo). No adverse events or systemic hypotension were attributed to sildenafil. CONCLUSION: Intravenous sildenafil reduced pulmonary artery pressure and shortened time to extubation and intensive care unit stay in children with postoperative PH.

Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension.

OBJECTIVE: To evaluate the safety of intravenous (IV) sildenafil, an inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase, in treating near-term and term newborns with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was an open-label, dose-escalation trial in newborns with PPHN and an oxygenation index (OI) > 15. Sildenafil was delivered by continuous IV infusion for at least 48 hours and up to 7 days. RESULTS: Five centers enrolled a total of 36 neonates with PPHN at a mean of 34 +/- 17 hours of age; 29 of these neonates were already receiving inhaled nitric oxide (iNO). A significant improvement in OI (28.7 to 19.3; P = .0002) was observed after 4 hours of sildenafil infusion in the higher dose cohorts. Thirty-five neonates survived; 1 neonate required extracorporeal membrane oxygenation (ECMO) support. In 4 neonates, sildenafil was stopped due to adverse events. Seven neonates were enrolled before developing the need for iNO. In these neonates, OI improved significantly by 4 hours after initiation of sildenafil infusion (24.6 to 14.7; P = .009); 6 neonates completed treatment without the need for iNO or ECMO. CONCLUSIONS: IV sildenafil was well tolerated, and acute and sustained improvements in oxygenation were noted in those neonates who received the higher infusion doses.

How do pharmaceutical companies approach data from sexual health studies for regulatory agencies?

We briefly outline the importance of statistical input into clinical trial research in the pharmaceutical industry and in interactions with regulatory agencies, with particular concentration on the role of the statistician in projects on sexual health during Phases 2 and 3 of clinical trials required in bringing new drugs to the market.

A multinational population survey of intravaginal ejaculation latency time.

INTRODUCTION: Intravaginal ejaculation latency time (IELT), defined as the time between the start of vaginal intromission and the start of intravaginal ejaculation, is increasingly used in clinical trials to assess the amount of selective serotonin reuptake inhibitor-induced ejaculation delay in men with premature ejaculation. Prospectively, stopwatch assessment of IELTs has superior accuracy compared with retrospective questionnaire and spontaneous reported latency. However, the IELT distribution in the general male population has not been previously assessed. AIM: To determine the stopwatch assessed-IELT distribution in large random male cohorts of different countries. METHODS: A total of 500 couples were recruited from five countries: the Netherlands, United Kingdom, Spain, Turkey, and the United States. Enrolled men were aged 18 years or older, had a stable heterosexual relationship for at least 6 months, with regular sexual intercourse. The surveyed population were not included or excluded by their ejaculatory status and comorbidities. This survey was performed on a "normal" general population. Sexual events and stopwatch-timed IELTs during a 4-week period were recorded, as well as circumcision status and condom use. MAIN OUTCOME MEASURES: The IELT, circumcision status, and condom use. RESULTS: The distribution of the IELT in all the five countries was positively skewed, with a median IELT of 5.4 minutes (range, 0.55-44.1 minutes). The median IELT decreased significantly with age, from 6.5 minutes in the 18-30 years group, to 4.3 minutes in the group older than 51 years (P<0.0001). The median IELT varied between countries, with the median value for Turkey being the lowest, i.e., 3.7 minutes (0.9-30.4 minutes), which was significantly different from each of the other countries. Comparison of circumcised (N=98) and not-circumcised (N=261) men in countries excluding Turkey resulted in median IELT values of 6.7 minutes (0.7-44.1 minutes) in circumcised compared with 6.0 minutes (0.5-37.4 minutes) in not-circumcised men (not significant). The median IELT value was not affected by condom use. CONCLUSION: The IELT distribution is positively skewed. The overall median value was 5.4 minutes but with differences between countries. For all five countries, median IELT values were independent of condom usage. In countries excluding Turkey, the median IELT values were independent of circumcision status.

Non-parametric estimators of a monotonic dose-response curve and bootstrap confidence intervals.

In this paper we consider study designs which include a placebo and an active control group as well as several dose groups of a new drug. A monotonically increasing dose-response function is assumed, and the objective is to estimate a dose with equivalent response to the active control group, including a confidence interval for this dose. We present different non-parametric methods to estimate the monotonic dose-response curve. These are derived from the isotonic regression estimator, a non-negative least squares estimator, and a bias adjusted non-negative least squares estimator using linear interpolation. The different confidence intervals are based upon an approach described by Korn, and upon two different bootstrap approaches. One of these bootstrap approaches is standard, and the second ensures that resampling is done from empiric distributions which comply with the order restrictions imposed. In our simulations we did not find any differences between the two bootstrap methods, and both clearly outperform Korn's confidence intervals. The non-negative least squares estimator yields biased results for moderate sample sizes. The bias adjustment for this estimator works well, even for small and moderate sample sizes, and surprisingly outperforms the isotonic regression method in certain situations.