Estimates of Information Growth in Longitudinal Clinical Trials

In group sequential clinical trials, it is necessary to estimate the amount of information present at interim analysis times relative to the amount of information that would be present at the final analysis. If only one measurement is made per individual, this is often the ratio of sample sizes available at the interim and final analyses. However, as discussed by Wu and Lan (1992), when the statistic of interest is a change over time, as with longitudinal data, such an approach overstates the information. In this paper, we discuss other problems that can result in overestimating the information, such as heteroscedasticity and correlated observations. We demonstrate that when using an inefficient estimator on unbalanced data, the true information growth can be nonmonotonic across interim analyses

Exploring the Benefits of Adaptive Sequential Designs in Time-to-Event Endpoint Settings

Sequential analysis is frequently employed to address ethical and financial issues in clinical trials. Sequential analysis may be performed using standard group sequential designs, or, more recently, with adaptive designs that use estimates of treatment effect to modify the maximal statistical information to be collected. In the general setting in which statistical information and clinical trial costs are functions of the number of subjects used, it has yet to be established whether there is any major efficiency advantage to adaptive designs over traditional group sequential designs. In survival analysis, however, statistical information (and hence efficiency) is most closely related to the observed number of events, while trial costs still depend on the number of patients accrued. As the number of subjects may dominate the cost of a trial, an adaptive design that specifies a reduced maximal possible sample size when an extreme treatment effect has been observed may allow early termination of accrual and therefore a more costefficient trial. We investigate and compare the tradeoffs between efficiency (as measured by average number of observed events required), power, and cost (a function of the number of subjects accrued and length of observation) for standard group sequential methods and an adaptive design that allows for early termination of accrual. We find that when certain trial design parameters are constrained, an adaptive approach to terminating subject accrual may improve upon the cost efficiency of a group sequential clinical trial investigating time-to-event endpoints. However, when the spectrum of group sequential designs considered is broadened, the advantage of the adaptive designs is less clear

Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in mucopolysaccharidosis types I and II.

Mucopolysaccharidosis I and II are lysosomal storage disorders that, despite treatment with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT), continue to cause significant skeletal abnormalities leading to pain, stiffness, physical dysfunction, and short stature. Tumor necrosis factor - alpha (TNF-α) is elevated in individuals with MPS I and II and associated with pain and physical dysfunction. Therefore, we evaluated the safety and effects of the TNF-α inhibitor adalimumab in patients with MPS I and II in a 32-week, randomized, double blind, placebo-controlled, crossover study of adalimumab at a dose of 20 mg (weight 15-<30 kg) or 40 mg (weight ≥ 30 kg) administered subcutaneously every other week or saline placebo for 16 weeks. Participants were evaluated at baseline, week 16, and week 32 with the Children's Health Questionnaire - Parent Form 50 (CHQ-PF50), the Pediatric Pain Questionnaire (PPQ), range-of-motion (ROM) measurements, anthropometry, six-minute walk test (6MWT), hand dynamometer, and laboratory evaluations for safety. The primary outcome was safety and primary efficacy outcome was bodily pain (BP) measured by the CHQ-PF50. Two subjects, one with MPS I and one with MPS II, completed the study. Adalimumab was well tolerated and there were no serious adverse events. Standardized BP scores for age and gender were higher (i.e. less pain) at the end of the treatment versus placebo phase for both subjects. Subject #1 became unblinded during treatment due to skin erythema. Behavior measured by both CHQ-PF50 and parental report improved during treatment compared to placebo in both subjects. ROM improved by > 5° in seven of eight joints in Subject #1 and five of eight joints in Subject #2 (range 7.0° to 52.8°). There was no change in the PPQ, 6MWT, or hand dynamometer. Data from this small pilot study suggest that treatment with adalimumab is safe, tolerable, and may improve ROM, physical function, and possibly pain, in children with MPS I or II. However, additional clinical trials are needed before this therapy should be recommended as part of clinical care

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes.

PurposeAbnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.MethodsIn addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.ResultsOver treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.ConclusionIntrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome

Revisiting the spectrum of bladder health: Relationships between lower urinary tract symptoms and multiple measures of well-being

Background: Little research to date has investigated the spectrum of bladder health in women, including both bladder function and well-being. Therefore, we expanded our previous baseline analysis of bladder health in the Boston Area Community Health (BACH) Survey to incorporate several additional measures of bladder-related well-being collected at the 5-year follow-up interview, including one developed specifically for women. Methods: At follow-up, participants reported their frequency of 15 lower urinary tract symptoms (LUTS), degree of life impact from and thought related to urinary symptoms or pelvic/bladder pain/discomfort, and perception of their bladder condition. Prevalence ratios were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. The BACH Survey was approved by the New England Research Institutes Institutional Review Board and all participants provided written informed consent. Results: Generally similar findings were observed in the 5-year cross-sectional analysis as at baseline, irrespective of how we categorized LUTS or measured bladder-related well-being. Approximately one in five women (16.2%-18.0% of 2527 eligible women) reported no LUTS and no diminished bladder-related well-being, the majority (55.8%-65.7%) reported some LUTS and/or diminished well-being, and a further one in five (16.9%-26.6%) reported the maximum frequency, number, or degree of LUTS and/or diminished well-being. Measures of storage function (urinating again after <2 hours, perceived frequency, nocturia, incontinence, and urgency) and pain were independently associated with bladder-related well-being. Conclusions: Our similar distribution of bladder health and consistent associations between LUTS and bladder-related well-being across multiple measures of well-being, including a female-specific measure, lend confidence to the concept of a bladder health spectrum and reinforce the bothersome nature of storage dysfunction and pain

The spectrum of bladder health: The relationship between lower urinary tract symptoms and interference with activities

Background: Little research to date has focused on lower urinary tract symptom (LUTS) prevention and bladder health promotion in women. To address this gap, the Prevention of LUTS Research Consortium developed the following working bladder health definition: "A complete state of physical, mental, and social well-being related to bladder function [that] permits daily activities [and] allows optimal well-being." To begin to inform and quantify this definition, we used data from the Boston Area Community Health Survey, drawing upon its rare collection of information on LUTS and LUTS-specific interference with activities. Methods: At baseline, participants reported their frequency of 15 LUTS and interference with 7 activities. Prevalence ratios (PRs) were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. Results: Of the 3169 eligible participants, 17.5% reported no LUTS or interference, whereas the remaining 82.5% reported some frequency of LUTS/interference: 15.1% rarely; 21.7% a few times; 22.6% fairly often/usually; and 22.9% almost always. LUTS independently associated with interference were urgency incontinence, any incontinence, urgency, nocturia, perceived frequency, and urinating again after <2 hours (PRs = 1.2-1.5, all p < 0.05). Conclusions: Our findings suggest that bladder health exists on a continuum, with approximately one in five women considered to have optimal bladder health (no LUTS/interference), the majority to have intermediate health (LUTS/interference rarely to usually), and a further one in five to have worse or poor health (LUTS/interference almost always). These findings underscore the need for LUTS prevention and bladder health promotion