A safety estimand for late phase clinical trials where the analysis period varies over the subjects.

BACKGROUND/AIMS: Evaluating safety is as important as evaluating efficacy in a clinical trial, yet the tradition for safety analysis is rudimentary. This article explores more complex methodologies for safety evaluation, with the aim of improving the interpretability, as well as generalizability, of the results. METHODS: For studies where the analysis periods vary over the subjects, using the International Council for Harmonisation estimand framework, we construct a formal estimand that could be used in the setting of safety surveillance that answers the clinical question of 'What is the magnitude of the increase in risk of experiencing an adverse event if the treatment is taken, as prescribed, for a specific period of time?'. Estimation methodologies for this estimand are also discussed. RESULTS: The proposed estimand is similar to that found in the efficacy analyses of time to event data (e.g. in outcome studies), with the key difference of utilization of hypothetical intercurrent event strategy for the intercurrent event of treatment discontinuation. This is motivated by what we perceive to be a key difference for the safety objective compared to efficacy objectives, namely a desire for sensitivity (i.e. greater possibility of detecting a negative impact of the drug, if such exists) as opposed to the need to prove a positive effect of the drug in a conservative manner. CONCLUSION: It is valuable, and possible, to use the International Council for Harmonisation estimand framework not only for efficacy but also for safety evaluation, with the estimand driven by an interpretable, and relevant, clinical question.

Evaluation of the effect of sodium zirconium cyclosilicate on arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with hyperkalaemia: protocol for the multicentre, randomised, controlled DIALIZE-Outcomes study.

INTRODUCTION: Patients with kidney failure receiving chronic haemodialysis have elevated risk of arrhythmias potentially increasing the likelihood of sudden cardiac death, stroke and hospitalisation. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an efficacious and well-tolerated treatment for predialysis hyperkalaemia in patients undergoing haemodialysis. The DIALIZE-Outcomes study evaluates the effect of SZC on sudden cardiac death and arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with recurrent hyperkalaemia. METHODS AND ANALYSIS: International, multicentre, randomised, double-blind, placebo-controlled study conducted at 357 study sites across 25 countries. Adults (≥18 years) receiving chronic haemodialysis three times per week with recurrent predialysis serum potassium (K+) ≥5.5 mmol/L post long interdialytic interval (LIDI) are eligible. Patients (~2800) will be randomised 1:1 to SZC or placebo, starting at 5 g orally once daily on non-dialysis days and titrated weekly in 5 g increments (maximum 15 g) to target predialysis serum K+ 4.0-5.0 mmol/L post LIDI. The primary objective is to evaluate efficacy of SZC versus placebo in reducing occurrence of the primary composite endpoint of sudden cardiac death, stroke or arrhythmia-related hospitalisation, intervention or emergency department visit. Secondary endpoints include efficacy of SZC versus placebo in maintaining normokalaemia (serum K+ 4.0-5.5 mmol/L post LIDI) at the 12-month visit, preventing severe hyperkalaemia (serum K+ ≥6.5 mmol/L post LIDI) at the 12-month visit and reducing the incidence of individual cardiovascular outcomes. Safety of SZC will be evaluated. The study is event driven, with participants remaining in the study until 770 primary endpoint events have occurred. Average time in the study is expected to be ~25 months. ETHICS AND DISSEMINATION: Approval was obtained from the relevant institutional review board/independent ethics committee from each participating site (approving bodies in supplementary information). The results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2020-005561-14 and clinicaltrials.gov identifier NCT04847232.

A Phase 1, open-label, crossover study evaluating the effect of a single dose of sodium zirconium cyclosilicate on the pharmacokinetics of tacrolimus and cyclosporin.

Background: Sodium zirconium cyclosilicate (SZC) is an oral, highly selective potassium binder approved for the treatment of hyperkalaemia in adults. SZC may change the absorption of co-administered drugs that exhibit pH-dependent bioavailability. This study evaluated whether the pharmacokinetic (PK) profiles of tacrolimus and cyclosporin were altered by concomitant SZC administration in healthy participants. Methods: This was an open-label, randomised sequence, two-cohort crossover, single-centre study. Healthy adults were assigned to one of two cohorts: Cohort 1 (tacrolimus) received a single dose of tacrolimus 5 mg and tacrolimus 5 mg + SZC 15 g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100 mg and cyclosporin 100 mg + SZC 15 g in a random order. Primary PK endpoints were maximum observed blood concentration (Cmax) and area under the concentration-time curve (AUC) from time zero to infinity (AUCinf). Differences in mean Cmax and AUCinf were analysed using a mixed effects model. Results: Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus + SZC versus tacrolimus alone: Cmax geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44-77.24], AUCinf 62.91% (55.64-71.13). Cyclosporin exposure was similar with cyclosporin + SZC compared with cyclosporin alone: Cmax GMR 102.9% (90% CI 96.11-110.10), AUCinf 97.23% (92.93-101.70). Conclusions: Tacrolimus exposure was lower when co-administered with SZC 15 g and should be administered ≥2 h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.

Potassium reduction with sodium zirconium cyclosilicate in patients with heart failure.

AIMS: Several patients with heart failure and reduced ejection fraction (HFrEF) do not receive renin-angiotensin-aldosterone system (RAAS) inhibitors at the recommended dose or at all, frequently due to actual or feared hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is an orally administered non-absorbed intestinal potassium binder proven to lower serum potassium concentrations. METHODS AND RESULTS: PRIORITIZE-HF was an international, multicentre, parallel-group, randomized, double-blind, placebo-controlled study to evaluate the benefits and risks of using SZC to intensify RAAS inhibitor therapy. Patients with symptomatic HFrEF were eligible and randomly assigned to receive SZC 5 g or placebo once daily for 12 weeks. Doses of study medication and RAAS inhibitors were titrated during the treatment period. The primary endpoint was the proportion of patients at 12 weeks in the following categories: (i) any RAAS inhibitor at less than target dose, and no MRA; (ii) any RAAS inhibitor at target dose and no MRA; (ii) MRA at less than target dose; and (iv) MRA at target dose. Due to challenges in participant management related to the COVID-19 pandemic, the study was prematurely terminated with 182 randomized patients. There was no statistically significant difference in the distribution of patients by RAAS inhibitor treatment categories at 3 months (P = 0.43). The proportion of patients at target MRA dose was numerically higher in the SZC group (56.4%) compared with the placebo group (47.0%). Overall, SZC was well tolerated. CONCLUSIONS: PRIORITIZE-HF was terminated prematurely due to COVID-19 and did not demonstrate a statistically significant increase in the intensity of RAAS inhibitor therapies with the potassium-reducing agent SZC compared with placebo.

Potassium responses to sodium zirconium cyclosilicate in hyperkalemic hemodialysis patients: post-hoc analysis of DIALIZE.

BACKGROUND: Sodium zirconium cyclosilicate (SZC) is an effective and well-tolerated treatment for hyperkalemia in maintenance hemodialysis patients. In post-hoc analyses of the phase 3b DIALIZE study, we examined the spectrum of potassium responses to SZC. METHODS: Post-hoc analyses with SZC and placebo included: the number of long interdialytic interval (LIDI) visits during the 4-week evaluation period where patients attained pre-dialysis serum potassium (sK+) concentrations of 4.0-5.0 and 4.0-5.5 mmol/L; potassium gradient (the difference between pre-dialysis sK+ and dialysate potassium) at days 36, 43, 50, and 57, and change from baseline to the end of treatment (EOT) using categories of potassium gradient (1 to < 2, 2 to < 3, 3 to < 4, and ≥ 4 mmol/L). RESULTS: A greater proportion of patients achieved the ranges of pre-dialysis sK+ concentration with SZC versus placebo for ≥1, ≥ 2, ≥ 3, and 4 LIDI visits over 4 weeks; 23.7 and 48.5% of patients in the SZC group achieved pre-dialysis sK+ concentrations of 4.0-5.0 and 4.0-5.5 mmol/L, respectively, at all 4 LIDI visits. Baseline mean potassium gradient was similar with SZC and placebo. At day 57, mean (standard deviation) potassium gradient was 2.78 (0.08) mmol/L with SZC and 3.52 (0.08) mmol/L with placebo; mean difference (95% confidence interval) was - 0.74 mmol/L (- 0.97 to - 0.52). A greater reduction in potassium gradient category from baseline towards lower-risk categories at EOT was observed with SZC versus placebo. CONCLUSIONS: These analyses expand our knowledge of the spectrum of potassium responses with SZC in hyperkalemic hemodialysis patients. TRIAL REGISTRATION: NCT03303521 .

A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia.

BACKGROUND: Patients with ESRD have minimal renal potassium excretion and, despite hemodialysis, often have persistent predialysis hyperkalemia. The DIALIZE study (NCT03303521) evaluated sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in hemodialysis patients. METHODS: In the DIALIZE study, a double-blind, placebo-controlled, phase 3b multicenter study, we randomized adults with ESRD who were managed by three-times weekly hemodialysis and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on non-dialysis days, and titrated towards maintaining normokalemia over 4 weeks, in 5 g increments to a maximum of 15 g. The primary efficacy outcome was proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0-5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval and did not require urgent rescue therapy to reduce serum potassium. RESULTS: In total, 196 patients (mean [standard deviation (SD)] age =58.1 [13.7] years old) were randomized to sodium zirconium cyclosilicate or placebo. Of 97 patients receiving sodium zirconium cyclosilicate, 41.2% met the primary end point and were deemed treatment responders compared with 1.0% of 99 patients receiving placebo (P<0.001). Rescue therapy to reduce serum potassium during the treatment period was required by 2.1% of patients taking sodium zirconium cyclosilicate versus 5.1% taking placebo. Serious adverse events occurred in 7% and 8% of patients in sodium zirconium cyclosilicate and placebo groups, respectively. The two groups displayed comparable interdialytic weight gain. There were few episodes of hypokalemia. CONCLUSIONS: Sodium zirconium cyclosilicate is an effective and well-tolerated treatment for predialysis hyperkalemia in patients with ESRD undergoing adequate hemodialysis.

Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients-a description of the DAPACARD study.

BACKGROUND: Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels. METHODS: DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET). CONCLUSION: The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.

Different reliability of instrumented gait analysis between patients with unilateral hip osteoarthritis, unilateral hip prosthesis and healthy controls.

BACKGROUND: The gait pattern varies within the population and between patient groups with different musculoskeletal diseases. It also varies over time due to various reasons. Three-dimensional gait analysis (3DGA) is frequently used to measure these changes, but the precision of this methodology may vary. METHODS: We primarily aimed to study the repeatability of hip motion measurements in patients with unilateral osteoarthritis (OA), patients with unilateral total hip arthroplasty (THA) and healthy controls. A secondary aim was to delineate any differences in hip motion during walking between these groups. Ten males and 10 females in each group were recruited. All patients underwent gait assessments using 3DGA recorded by 2 examiners. Data was analysed with comparison of variance and linear regression. RESULTS: The variability of the extension-flexion recordings was smallest in healthy controls (SD < 7.7°), increased in patients with THA (SD < 11.1°) and was most pronounced in the OA patients (SD < 12.2°). The degree of hip extension-flexion turned out to be the variable that most effectively could separate the controls from the 2 patient groups and the patient groups from each other. One to 2 years after THA the gait pattern was improved but still differed comparing a group of THA from a group of healthy controls. CONCLUSIONS: Patients with hip osteoarthritis showed the poorest repeatability between gait recordings collected by different examiners, as compared to patients operated with a THA and healthy controls. The walking pattern after THA still differed from healthy controls 1-2 years after the operation.

Validation of gait analysis with dynamic radiostereometric analysis (RSA) in patients operated with total hip arthroplasty.

We simultaneously examined 14 patients with OTS and dynamic radiostereometric analysis (RSA) to evaluate the accuracy of both skin- and a cluster-marker models. The mean differences between the OTS and RSA system in hip flexion, abduction, and rotation varied up to 9.5° for the skin-marker and up to 11.3° for the cluster-marker models, respectively. Both models tended to underestimate the amount of flexion and abduction, but a significant systematic difference between the marker and RSA evaluations could only be established for recordings of hip abduction using cluster markers (p = 0.04). The intra-class correlation coefficient (ICC) was 0.7 or higher during flexion for both models and during abduction using skin markers, but decreased to 0.5-0.6 when abduction motion was studied with cluster markers. During active hip rotation, the two marker models tended to deviate from the RSA recordings in different ways with poor correlations at the end of the motion (ICC ≤0.4). During active hip motions soft tissue displacements occasionally induced considerable differences when compared to skeletal motions. The best correlation between RSA recordings and the skin- and cluster-marker model was found for studies of hip flexion and abduction with the skin-marker model. Studies of hip abduction with use of cluster markers were associated with a constant underestimation of the motion. Recordings of skeletal motions with use of skin or cluster markers during hip rotation were associated with high mean errors amounting up to about 10° at certain positions. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1515-1522, 2017.

Upper Respiratory Infections and MRI Activity in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Although clinical reports have suggested a relationship between systemic infections and multiple sclerosis (MS) relapses, MRI evidence supporting an association is conflicting. Here we evaluated the temporal relationship between upper respiratory infections (URIs) and MRI activity in relapsing-remitting (RR) MS. METHODS: We combined individual data on URI with data on active lesions in pre-scheduled MRI examinations performed every 4 weeks for 28 weeks in 69 patients. A 4-week at-risk (AR) period started, by definition, 1 week before the onset of a URI. We recorded the relationship between the number of active lesions in each MRI with (1) the number of days of AR time in the immediately preceding 4-week period and (2) the number of days passed since the onset of a preceding URI. RESULTS: Average MRI lesions/day showed no difference between AR (0.0764) and not-AR (0.0774) periods. The number of lesions in 483 pre-scheduled MRI examinations did not correlate with the AR proportion in the prior 4-week period (rho = -0.03), and time from URI onset did not correlate with lesion number on the next MRI examination (rho = 0.003). CONCLUSION: The occurrence of a URI did not increase the risk of MRI activity evaluated in an adjacent 4-week window in RRMS.

Foot deformities, function in the lower extremities, and plantar pressure in patients with diabetes at high risk to develop foot ulcers.

OBJECTIVE: Foot deformities, neuropathy, and dysfunction in the lower extremities are known risk factors that increase plantar peak pressure (PP) and, as a result, the risk of developing foot ulcers in patients with diabetes. However, knowledge about the prevalence of these factors is still limited. The aim of the present study was to describe the prevalence of risk factors observed in patients with diabetes without foot ulcers and to explore possible connections between the risk factors and high plantar pressure. PATIENTS AND METHODS: Patients diagnosed with type 1 (n=27) or type 2 (n=47) diabetes (mean age 60.0±15.0 years) were included in this cross-sectional study. Assessments included the registration of foot deformities; test of gross function at the hip, knee, and ankle joints; a stratification of the risk of developing foot ulcers according to the Swedish National Diabetes Register; a walking test; and self-reported questionnaires including the SF-36 health survey. In-shoe PP was measured in seven regions of interests on the sole of the foot using F-Scan(®). An exploratory analysis of the association of risk factors with PP was performed. RESULTS: Neuropathy was present in 28 (38%), and 39 (53%) had callosities in the heel region. Low forefoot arch was present in 57 (77%). Gait-related parameters, such as the ability to walk on the forefoot or heel, were normal in all patients. Eighty percent had normal function at the hip and ankle joints. Gait velocity was 1.2±0.2 m/s. All patients were stratified to risk group 3. Hallux valgus and hallux rigidus were associated with an increase in the PP in the medial forefoot. A higher body mass index (BMI) was found to increase the PP at metatarsal heads 4 and 5. Pes planus was associated with a decrease in PP at metatarsal head 1. Neuropathy did not have a high association with PP. CONCLUSIONS: This study identified several potential risk factors for the onset of diabetic foot ulcers (DFU). Hallux valgus and hallux rigidus appeared to increase the PP under the medial forefoot and a high BMI appeared to increase the PP under the lateral forefoot. There is a need to construct a simple, valid, and reliable assessment routine to detect potential risk factors for the onset of DFU.

The outcome spectrum of multiple sclerosis: disability, mortality, and a cluster of predictors from onset.

Interest in the long-term natural history of multiple sclerosis (MS) is being revived, as disability endpoints become increasingly important with the advent of highly efficacious long range but potentially harmful drugs. MS had an increasingly benign course, probably due to better assessment and changing diagnostic criteria. Incidence cohorts reduce inclusion bias, capturing both extreme benign and severe cases. We conducted a 50-year follow-up of an incidence cohort of Gothenburg residents with MS onset in 1950-1964 (n = 254; 212 with an initial relapsing-remitting course and 42 with a monophasic course, diagnostic criteria according to Poser). Patients were followed longitudinally until censoring, death, or study termination in 2012 and evaluated using Kaplan-Meier estimates and Cox regression analysis. Median time to secondary progression was 15 years. Median time to EDSS6 and EDSS7 was 26 and 48 years (n = 254), respectively. The cumulative risk of reaching EDSS6 was 50% at 55 years of age and 80% at 80 years of age (n = 212). A score based on a cluster of clinical features at onset predicted secondary progression, EDSS6, EDSS7, and EDSS10 (hazard ratio 1.6-2.3 per score unit for women, 0.99-1.49 for men). This score predicted the disease course during five decades indirectly, by predicting time to secondary progression. Age at onset predicted the course in men, with 3-6% yearly increase in the risk of reaching disability milestones. The present incidence cohort provided hard outcome data in untreated patients over several decades.

A decision theoretic approach to optimization of multiple testing procedures.

This paper focuses on the concept of optimizing a multiple testing procedure (MTP) with respect to a predefined utility function. The class of Bonferroni-based closed testing procedures, which includes, for example, (weighted) Holm, fallback, gatekeeping, and recycling/graphical procedures, is used in this context. Numerical algorithms for calculating expected utility for some MTPs in this class are given. The obtained optimal procedures, as well as the gain resulting from performing an optimization are then examined in a few, but informative, examples.

A novel fibrosis index comprising a non-cholesterol sterol accurately predicts HCV-related liver cirrhosis.

Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5-6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) = -12.17+ (age × 0.11) + (BMI (kg/m(2)) × 0.23) + (D7-lathosterol (µg/100 mg cholesterol)×(-0.013)) + (Platelet count (x10(9)/L) × (-0.018)) + (Prothrombin-INR × 3.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86-0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82-0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.

Comparison of plantar pressure in three types of insole given to patients with diabetes at risk of developing foot ulcers - A two-year, randomized trial.

BACKGROUND: Special insoles and shoes designed to prevent foot ulcers caused by repetitive high pressures are recommended for patients with diabetes who have any of the following risk factors: neuropathy; peripheral vascular disease; foot deformities; previous ulcers; amputation; and skin pathologies. However, there is a need for increased knowledge regarding: a) differences in the peak pressure (PP) and pressure time integral (PTI) for different types of insoles; and b) the properties of the pressure distribution for insoles used over a period of several months. We present the results of a randomized trial to compare the plantar pressures of three commonly used insoles. OBJECTIVES: The primary objective was to compare the PP and PTI between three types of insoles. The secondary objective was to explore the long-term pattern of peak plantar pressure distribution and variations in specific regions of interest (ROI). The tertiary objective was to investigate the impacts of insole adjustments, how much the insoles were used, and the levels of patient satisfaction. METHODS: In a 2-year trial, 114 patients with type 1 (N = 31) or type 2 (N = 83) diabetes (62 men and 52 women; mean age, 57.7 ± 15.4 years; duration of diabetes, 12.3 ± 11.2 years; neuropathy, 38%), were randomized to be supplied with one of three different insoles. The ethylene vinyl acetate (EVA) insoles were used in outdoor walking shoes. The 35 EVA group (N = 39) received soft custom-made insoles composed of EVA of 35 shore A hardness, the 55 EVA group (N = 37) received custom-made insoles composed of EVA of 55 shore hardness, and the control group (N = 38) received prefabricated insoles composed of a hard core with a top layer of soft 12 shore hardness microfiber. Using F-Scan®, the in-shoe plantar pressures were measured at seven ROI (hallux, metatarsal head 1, metatarsal head 2, metatarsal head 4, metatarsal head 5, lateral aspect of the mid-foot, heel) on five occasions during the study period. The plantar-pressure variables used were PP (main outcome) and PTI. The plantar patterns of load were explored, satisfaction and usage of the insoles were rated by the participants, and insole adjustments were recorded. RESULTS: A mixed model analysis estimated lower PP values in the heel regions for the 35 EVA and 55 EVA insoles (171 ± 13 and 161 ± 13 kPa, respectively) than for the prefabricated insoles (234 ± 10 kPa) (p < 0.001). Also for some of the other six ROI indications of difference in PP or PTI could be observed. The redistribution of peak plantar pressure for all of the insoles, was stable at the mid-foot, while the proportion of load on the distal area changed during the study period According to the self-reported answers (scale, 0-100), the average usage of the insoles was rated as 79 and satisfaction was rated as 85 (N = 75). Thirty-two percent of the subjects had not received foot care. Fourteen adjustments to insoles were made during the study period, and 86 pairs of insoles were exchanged due to wear, with 49% being exchanged in the 35 EVA group. CONCLUSIONS: Custom-made insoles used in combination with stable walking shoes gave lower pressures at the heel region. The variation makes it difficult to detect a systematic difference in plantar pressure for the 6 ROI, if such a difference indeed exists. The levels of satisfaction and usage for all the insoles tested were high. The insoles maintained their pressure redistribution properties over long periods, and few adjustments were needed.

On the choice of doses for phase III clinical trials.

Many potential new medicines fail in phase III clinical trials, because of either insufficient efficacy or intolerability. Such failures may be caused by the absence of an effect and also if a suboptimal dose is being tested. It is thus important to consider how to optimise the choice of dose or doses that continue into the confirmatory phase. For many indications, it is common to test one single active dose in phase III. However, phase IIB dose-finding trials are relatively small and often lack the ability of precisely estimating the dose-response curves for efficacy and tolerability. Because of this uncertainty in dose response, it is reasonable to consider bringing more than one dose into phase III. Using simple but illustrative models, we find the optimal doses and compare the probability of success, for fixed total sample sizes, when one or two active doses are included in phase III.

The dual test: safeguarding p-value combination tests for adaptive designs.

Many modern adaptive designs apply an analysis where p-values from different stages are weighted together to an overall hypothesis test. One merit of this combination approach is that the design can be made very flexible. However, combination tests violate the sufficiency and conditionality principles. As a consequence, combination tests may lead to absurd conclusions, such as 'proving' a positive effect while the average effect is negative. We explore the possibility of modifying the test so that such illogical conclusions are no longer possible. The dual test requires both the weighted combination test and a naïve test, ignoring the adaptations, to be statistically significant. The result is that the flexibility and type I error level control of the combination test are preserved, while the naïve test adds a safeguard against unconvincing results. The dual test is, by construction, at least as conservative as the combination test. However, many design changes will not lead to any power loss. A typical situation where the combination approach can be used is two-stage sample size reestimation (SSR). For this case, we give a complete specification of all sample size modifications for which the two tests are equally powerful. We also study the overall power loss for some suggested SSR rules. Rules based on conditional power generally lead to ignorable power loss while a decision analytic approach exhibits clear discrepancies between the two tests.