Design and analysis of three‐arm trials with negative binomially distributed endpoints

A three‐arm clinical trial design with an experimental treatment, an active control, and a placebo control, commonly referred to as the gold standard design, enables testing of non‐inferiority or superiority of the experimental treatment compared with the active control. In this paper, we propose methods for designing and analyzing three‐arm trials with negative binomially distributed endpoints. In particular, we develop a Wald‐type test with a restricted maximum‐likelihood variance estimator for testing non‐inferiority or superiority. For this test, sample size and power formulas as well as optimal sample size allocations will be derived. The performance of the proposed test will be assessed in an extensive simulation study with regard to type I error rate, power, sample size, and sample size allocation. For the purpose of comparison, Wald‐type statistics with a sample variance estimator and an unrestricted maximum‐likelihood estimator are included in the simulation study. We found that the proposed Wald‐type test with a restricted variance estimator performed well across the considered scenarios and is therefore recommended for application in clinical trials. The methods proposed are motivated and illustrated by a recent clinical trial in multiple sclerosis. The R package ThreeArmedTrials , which implements the methods discussed in this paper, is available on CRAN. Copyright © 2015 John Wiley & Sons, Ltd.     

Comprehensive clinical assessment of home‐based older persons within New Zealand: an epidemiological profile of a national cross‐section

Objective : Since 2012, all community care recipients in New Zealand have undergone a standardised needs assessment using the Home Care International Residential Assessment Instrument (interRAI‐HC). This study describes the national interRAI‐HC population, assesses its data quality and evaluates its ability to be matched. Methods : The interRAI‐HC instrument elicits information on 236 questions over 20 domains; conducted by 1,800+ trained health professionals. Assessments between 1 July 2012 and 30 June 2014 are reported here. Stratified by age, demographic characteristics were compared to 2013 Census estimates and selected health profiles described. Deterministic matching to the Ministry of Health's mortality database was undertaken. Results : Overall, 51,232 interRAI‐HC assessments were conducted, with 47,714 (93.1%) research consent from 47,236 unique individuals; including 2,675 Māori and 1,609 Pacific people. Apart from height and weight, data validity and reliability were high. A 99.8% match to mortality data was achieved. Conclusions : The interRAI‐HC research database is large and ethnically diverse, with high consent rates. Its generally good psychometric properties and ability to be matched enhances its research utility. Implications : This national database provides a remarkable opportunity for researchers to better understand older persons’ health and health care, so as to better sustain older people in their own homes.     

Risk-Taking Propensity,Affect, and Alcohol Craving in Adolescents’ Daily Lives

Background: Alcohol craving is common among adolescents, stronger among those with more alcohol-related problems, and predicts drinking levels in their daily lives. Yet, the conditions that predict momentary changes in craving in real time among adolescents remain unclear. Objectives: This study examined the interactive effects of momentary risk-taking propensity and affect on adolescents’ alcohol craving by leveraging ecological momentary assessment (EMA) methods. Methods: Participants were 29 adolescents ages 15–19?years (55% female; 69% White; 10% Black; 17% Hispanic); 45% met criteria for alcohol dependence. Following a laboratory session that captured self-report and behavioral assessments, including the well-established Balloon Analog Risk Task (BART), participants completed multiple daily assessments of alcohol craving, positive and negative affect, and risk propensity for approximately one week. Momentary risk propensity was captured in real-world settings via an EMA behavioral task (“Balloon Game”). Results: Mixed-effects models with EMA reports (Level 1) nested within participants (Level 2) revealed the majority (74%) of variability in “Balloon Game” performance was due to within-person, momentary, fluctuations. Greater momentary positive affect predicted increased alcohol craving, but only when participants exhibited heightened risk-taking propensity. Negative affect did not influence the relation between momentary risk-taking and craving. Conclusions/Importance: Momentary fluctuations in positive affect predicted acute increases in craving but only in moments when adolescents demonstrated higher levels of risk-taking propensity, as captured with an EMA-delivered behavioral task. Momentary risk-taking assessments offer new avenues to substantiate dominant theories on the driving mechanisms of craving and alcohol use among adolescents.     

‘Surfing the Silk Road’: A study of users’ experiences

IntroductionThe online drug marketplace called ‘Silk Road’ has operated anonymously on the ‘Deep Web’ since 2011. It is accessible through computer encrypting software (Tor) and is supported by online transactions using peer to peer anonymous and untraceable crypto-currency (Bit Coins). The study aimed to describe user motives and realities of accessing, navigating and purchasing on the ‘Silk Road’ marketplace.MethodsSystematic online observations, monitoring of discussion threads on the site during four months of fieldwork and analysis of anonymous online interviews (n = 20) with a convenience sample of adult ‘Silk Road’ users was conducted.ResultsThe majority of participants were male, in professional employment or in tertiary education. Drug trajectories ranged from 18 months to 25 years, with favourite drugs including MDMA, 2C-B, mephedrone, nitrous oxide, ketamine, cannabis and cocaine. Few reported prior experience of online drug sourcing. Reasons for utilizing ‘Silk Road’ included curiosity, concerns for street drug quality and personal safety, variety of products, anonymous transactioning, and ease of product delivery. Vendor selection appeared to be based on trust, speed of transaction, stealth modes and quality of product. Forums on the site provided user advice, trip reports, product and transaction reviews. Some users reported solitary drug use for psychonautic and introspective purposes. A minority reported customs seizures, and in general a displacement away from traditional drug sourcing (street and closed markets) was described. Several reported intentions to commence vending on the site.ConclusionThe study provides an insight into ‘Silk Road’ purchasing motives and processes, the interplay between traditional and ‘Silk Road’ drug markets, the ‘Silk Road’ online community and its communication networks.     

The effects of exercise on cigarette cravings and brain activation in response to smoking-related images

Rationale

Smokers show heightened activation toward smoking-related stimuli and experience increased cravings which can precipitate smoking cessation relapse. Exercise can be effective for modulating cigarette cravings and attenuating reactivity to smoking cues, but the mechanism by which these effects occur remains uncertain.

Objective

The objective of the study was to assess the effect of exercise on regional brain activation in response to smoking-related images during temporary nicotine abstinence.

Methods

In a randomised crossover design, overnight abstinent smokers (n?=?20) underwent an exercise (10-min moderate-intensity stationary cycling) and passive control (seating for the same duration) treatment, following 15?h of nicotine abstinence. After each treatment, participants underwent functional magnetic resonance imaging (fMRI) brain scanning while viewing a random series of blocked smoking or neutral images. Self-reported cravings were assessed at baseline, mid-, and post-treatments.

Results

There was a significant interaction effect (treatment?×?time) for desire to smoke, F (2,32)?=?12.5, p?Conclusion The study shows differing activation towards smoking images following exercise compared to a control treatment and may point to a neuro-cognitive process following exercise that mediates effects on cigarette cravings.     

Should measurement of vitamin D and treatment of vitamin D insufficiency be routine in New Zealand?

Epidemiological studies have reported associations between lower vitamin D levels and a great variety of diseases, prompting calls for widespread treatment of individuals with low vitamin D levels. Most of New Zealand's population have vitamin D levels for at least part of the year that are considered insufficient (25-hydroxyvitamin D <50-80 nmol/L). However, evidence for benefits of vitamin D supplementation in such populations is controversial and there is some evidence of harmful effects. Until adequately powered, randomised, controlled trials of vitamin D supplementation demonstrate safe improvements in health, clinicians should not focus on detecting/treating individuals with vitamin D insufficiency, instead treating those at high risk of vitamin D deficiency (25-hydroxyvitamin D <25 nmol/L), such as the frail elderly, and those with specific clinical indications. Treatment for such individuals does not require vitamin D measurements. Requests for vitamin D measurements in Auckland have nearly quadrupled in the past decade, from 8500 in the year 2000 to 32,800 in 2010, with substantial increases in cost. Vitamin D measurement is often inaccurate and imprecise, and the vast majority of tests performed currently do not reveal vitamin D deficiency. Therefore, a move away from routine vitamin D measurements seems sensible, though they are still indicated when investigating suspected metabolic bone disease or hypocalcaemia.     

Does the Alcohol Use Disorders Identification Test–Consumption identify the same patient population as the full 10-item Alcohol Use Disorders Identification Test?

The aim of this study was to evaluate whether a computer-based 3-item version (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]) of the Alcohol Use Disorders Identification Test (AUDIT) identifies alcohol use disorder (AUD) in the same patients as the full 10-item version in 809 women and 747 men in an anesthesiology preoperative assessment clinic. According to cutoffs used (AUDIT: 5-8 points, AUDIT-C: 4-6 points), rate of disagreement (AUDIT-positive and AUDIT-C-negative or vice versa) ranged between 4% and 31% (men) and between 4% and 19% (women). In male patients, 15% were positive for both the AUDIT (≥8 points) and the AUDIT-C (≥6 points), 7% were positive for AUDIT-C only, and 4% were positive for AUDIT only. In female patients, using cutoffs of 5 more points (AUDIT) and 4 or more points (AUDIT-C), 16% were positive for both versions, 9% were positive for AUDIT-C only, and 2% were positive for AUDIT only. The AUDIT and AUDIT-C seem to identify AUD in differing patients.     

Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

AIMS

Among the main disadvantages of currently available Δ⁹-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.

METHODS

This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.

RESULTS

Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t_1/2 was 72–80 min, t_max was 39–56 min and C_max 2.92–4.69 ng ml⁻¹. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min^–1, 95% CI 2.7, 6.5). Namisol® was well tolerated.

CONCLUSIONS

Oral Namisol® showed promising PK and PD characteristics. Variability and t_max of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.     

4th Global CRO Council for Bioanalysis: coadministered drugs stability, EMA/US FDA guidelines, 483s and carryover

The Global CRO Council for Bioanalysis (GCC) was formed in September 2010. Since then, the representatives of the member companies come together periodically to openly discuss bioanalysis and the regulatory challenges unique to the outsourcing industry. The 4th GCC Closed Forum brought together experts from bioanalytical CROs to share and discuss recent issues in regulated bioanalysis, such as the impact of coadministered drugs on stability, some differences between European Medicines Agency and US FDA bioanalytical guidance documents and lessons learned following recent Untitled Letters. Recent 483s and agency findings, as well as issues on method carryover, were also part of the topics discussed.