Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

Importance: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. Objective: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors. Design, Setting, and Participants: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. Exposure: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. Main Outcomes and Measures: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. Results: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). Conclusions and Relevance: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.

Central vs site outcome adjudication in the IRIS trial.

BACKGROUND: Central adjudication of outcome events is the standard in clinical trial research. We examine the benefit of central adjudication in the Insulin Resistance Intervention after Stroke (IRIS) trial and show how the benefit is influenced by outcome definition and features of the adjudicated events. METHODS: IRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke. We compared the hazard ratios for study outcomes classified by site and central adjudication. We repeated the analysis for an updated stroke definition. RESULTS: The hazard ratios for the primary outcome were identical (0.76) and statistically significant regardless of adjudicator. The hazard ratios for stroke alone were nearly identical with site and central adjudication, but only reached significance with site adjudication (HR, 0.80; p = 0.049 vs. HR, 0.82; p = 0.09). Using the updated stroke definition, all hazard ratios were lower than with the original IRIS definition and statistically significant regardless of adjudication method. Agreement was higher when stroke type was certain, subtype was large vessel or cardioembolic, signs or symptoms lasted > 24 h, imaging showed a stroke, and when NIHSS was ≥3. DISCUSSION: Central stroke adjudication caused the hazard ratio for a main secondary outcome in IRIS (stroke alone) to be higher and lose statistical significant compared with site review. The estimate of treatment effects were larger with the updated stroke definition. There may be benefit of central adjudication for events with specific features, such as shorter symptom duration or normal brain imaging.

Scoring System to Optimize Pioglitazone Therapy After Stroke Based on Fracture Risk.

Background and Purpose- The insulin sensitizer, pioglitazone, reduces cardiovascular risk in patients after an ischemic stroke or transient ischemic attack but increases bone fracture risk. We conducted a secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke) to assess the effect of pretreatment risk for fracture on the net benefits of pioglitazone therapy. Methods- IRIS was a randomized placebo-controlled trial of pioglitazone that enrolled patients with insulin resistance but without diabetes mellitus within 180 days of an ischemic stroke or transient ischemic attack. Participants were recruited at 179 international centers from February 2005 to January 2013 and followed for a median of 4.8 years. Fracture risk models were developed from patient characteristics at entry. Within fracture risk strata, we quantified the effects of pioglitazone compared with placebo by estimating the relative risks and absolute 5-year risk differences for fracture and stroke or myocardial infarction. Results- The fracture risk model included points for age, race-ethnicity, sex, body mass index, disability, and medications. The relative increment in fracture risk with pioglitazone was similar in the lower (

Impact of apolipoprotein E genotypes on vitamin E and memantine treatment outcomes in Alzheimer's disease.

INTRODUCTION: Because apolipoprotein E (APOE) genotypes are known risk factors for Alzheimer's disease (AD), they have been measured in clinical trial participants to determine their effect on treatment outcome. METHODS: We determined APOE genotypes in a subset of subjects (N = 415) who participated in a randomized controlled trial of vitamin E and memantine in 613 veterans with mild-to-moderate AD. RESULTS: Similar to the primary study, substudy participants receiving vitamin E also had slower functional decline than those receiving placebo. Overall, there was no difference in the rate of functional decline between APOE ε4 allele carriers and noncarriers. A significant interaction was observed between treatment and the APOE genotype on AD progression: ε4 carriers declined faster than noncarriers in the vitamin E plus memantine treatment arm. DISCUSSION: APOE genotypes may modulate AD treatment response and should be included in the design of future randomized controlled trials.

Neuropsychiatric Symptoms and Caregiver Burden in Individuals With Alzheimer's Disease: The TEAM-AD VA Cooperative Study.

OBJECTIVES: To assess the prevalence of neuropsychiatric symptoms (NPS) in mild-to-moderate Alzheimer disease (AD) and their association with caregiver burden. METHODS: Secondary analyses of baseline data from the Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD) (N=613). Neuropsychiatric Inventory were used to measure severity of NPS and caregiver activity survey to measure caregiver burden. RESULTS: A total of 87% of patients displayed at least 1 NPS; 70% displayed clinically meaningful NPS. The most common symptoms were apathy (47%), irritability (44%), agitation (42%), and depression (40%). Those with moderate AD had more severe NPS than those with mild AD ( P = .03). Neuropsychiatric symptoms were significantly associated with caregiver time after adjusting for age, education, cognitive function, and comorbidity ( P-value < .0001) with every point increase in NPS associated with a 10-minute increase in caregiver time. CONCLUSION: Neuropsychiatric symptoms were prevalent in both mild and moderate AD, even in patients receiving treatment with an acetylcholinesterase inhibitors, and were more severe in moderate AD and associated with greater caregiver time.

Clustering of Directions Improves Goodness of Fit in Kinematic Data Collected in the Transverse Plane During Robot-Assisted Rehabilitation of Stroke Patients.

The kinematic character of hand trajectory in reaching tasks varies by movement direction. Often, direction is not included as a factor in the analysis of data collected during multi-directional reach tasks; consequently, this directionally insensitive model (DI) may be prone to type-II error due to unexplained variance. On the other hand, directionally specific models (DS) that account separately for each movement direction, may reduce statistical power by increasing the amount of data groupings. We propose a clustered-by-similarity (CS) in which movement directions with similar kinematic features are grouped together, maximizing model fit by decreasing unexplained variance while also decreasing uninformative sub-groupings. We tested model quality in measuring change over time in 10 kinematic features extracted from 72 chronic stroke patients participating in the VA-ROBOTICS trial, performing a targeted reaching task over 16 movement directions (8 targets, back- and forth from center) in the horizontal plane. Across 49 participants surviving a quality control sieve, 4.3 ± 1.1 (min: 3; max: 7) clusters were found among the 16 movement directions; clusters varied between participants. Among 49 participants, and averaged across 10 features, the better-fitting model for predicting change in features was found to be CS assessed by the Akaike Information criterion (61.6 ± 7.3%), versus DS (31.0 ± 7.8%) and DI (7.1 ± 7.1%). Confirmatory analysis via Extra Sum of Squares F-test showed the DS and CS models out-performed the DI model in head-to-head (pairwise) comparison in >85% of all specimens. Thus, we find overwhelming evidence that it is necessary to adjust for direction in the models of multi-directional movements, and that clustering kinematic data by feature similarly may yield the optimal configuration for this co-variate.

Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial.

INTRODUCTION: Patients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function. METHODS: In the Insulin Resistance Intervention after Stroke (IRIS) trial, patients with a recent ischaemic stroke or transient ischaemic attack (TIA) were randomised to pioglitazone (target 45 mg daily) or placebo. All patients were insulin resistant based on a Homeostasis Model Assessment-Insulin Resistance score >3.0. For this preplanned analysis of cognitive function, we examined the Modified Mini-Mental State Examination (3MS) score (maximum score, 100) during follow-up. Patients were tested at baseline and annually for up to 5 years. Longitudinal mixed model methods were used to compare changes in the 3MS over time. RESULTS: Of the 3876 IRIS participants, 3398 had a 3MS score at baseline and at least once during follow-up and were included in the analysis. Median 3MS score at baseline was 97 (IQR 93-99). The average overall least squared mean 3MS score increased by 0.27 in the pioglitazone group and by 0.29 in the placebo group (mean difference between treatment groups -0.02; 95% CI -0.33 to 0.28, p=0.88). CONCLUSIONS: Among insulin-resistant patients with a recent ischaemic stroke or TIA, pioglitazone did not affect cognitive function, as measured by the 3MS, over 5 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT00091949; Results.

Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction.

Importance: There is growing recognition that patients may respond differently to therapy and that the average treatment effect from a clinical trial may not apply equally to all candidates for a therapy. Objective: To determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk. Design, Setting, and Participants: A secondary analysis was conducted of the Insulin Resistance Intervention After Stroke trial, a double-blind, placebo-controlled trial of pioglitazone for secondary prevention. Patients were enrolled from 179 research sites in 7 countries from February 7, 2005, to January 15, 2013, and were followed up for a mean of 4.1 years through the study's end on July 28, 2015. Eligible participants had a qualifying ischemic stroke or transient ischemic attack within 180 days of entry and insulin resistance without type 1 or type 2 diabetes. Interventions: Pioglitazone or matching placebo. Main Outcomes and Measures: A Cox proportional hazards regression model was created using baseline features to stratify patients above or below the median risk for stroke or MI within 5 years. Within each stratum, the efficacy of pioglitazone for preventing stroke or MI was calculated. Safety outcomes were death, heart failure, weight gain, and bone fracture. Results: Among 3876 participants (1338 women and 2538 men; mean [SD] age, 63 [11] years), the 5-year risk for stroke or MI was 6.0% in the pioglitazone group among patients at lower baseline risk compared with 7.9% in the placebo group (absolute risk difference, -1.9% [95% CI, -4.4% to 0.6%]). Among patients at higher risk, the risk was 14.7% in the pioglitazone group vs 19.6% for placebo (absolute risk difference, -4.9% [95% CI, -8.6% to 1.2%]). Hazard ratios were similar for patients below or above the median risk (0.77 vs 0.75; P = .92). Pioglitazone increased weight less among patients at higher risk but increased the risk for fracture more. Conclusions and Relevance: After an ischemic stroke or transient ischemic attack, patients at higher risk for stroke or MI derive a greater absolute benefit from pioglitazone compared with patients at lower risk. However, the risk for fracture is also higher. Trial Registration: clinicaltrials.gov Identifier: NCT00091949.

Colonoscopy vs. Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM): Rationale for Study Design.

RATIONALE: Colorectal cancer (CRC) is preventable through screening, with colonoscopy and fecal occult blood testing comprising the two most commonly used screening tests. Given the differences in complexity, risk, and cost, it is important to understand these tests' comparative effectiveness. STUDY DESIGN: The CONFIRM Study is a large, pragmatic, multicenter, randomized, parallel group trial to compare screening with colonoscopy vs. the annual fecal immunochemical test (FIT) in 50,000 average risk individuals. CONFIRM examines whether screening colonoscopy will be superior to a FIT-based screening program in the prevention of CRC mortality measured over 10 years. Eligible individuals 50-75 years of age and due for CRC screening are recruited from 46 Veterans Affairs (VA) medical centers. Participants are randomized to either colonoscopy or annual FIT. Results of colonoscopy are managed as per usual care and study participants are assessed for complications. Participants testing FIT positive are referred for colonoscopy. Participants are surveyed annually to determine if they have undergone colonoscopy or been diagnosed with CRC. The primary endpoint is CRC mortality. The secondary endpoints are (1) CRC incidence (2) complications of screening colonoscopy, and (3) the association between colonoscopists' characteristics and neoplasia detection, complications and post-colonoscopy CRC. CONFIRM leverages several key characteristics of the VA's integrated healthcare system, including a shared medical record with national databases, electronic CRC screening reminders, and a robust national research infrastructure with experience in conducting large-scale clinical trials. When completed, CONFIRM will be the largest intervention trial conducted within the VA (ClinicalTrials.gov identifier: NCT01239082).

Smoking cessation and outcome after ischemic stroke or TIA.

OBJECTIVE: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. METHODS: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. RESULTS: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48-0.90). CONCLUSION: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.

Brief Report: Preventing HIV-1 Infection in Women Using Oral Preexposure Prophylaxis: A Meta-analysis of Current Evidence.

The World Health Organization has issued an early release revision to its antiretroviral guidelines in which PrEP (pre-exposure prophylaxis in the form of daily oral, fixed dose combination tenofovir disoproxil fumarate/emtricitabine) is recommended as a prevention option to all people at substantial risk of acquiring HIV. However, lack of effectiveness in 2 major women-only PrEP trials, VOICE and FEM-PrEP, continues to be a cause for concern about achieving effectiveness for women in Southern Africa. We conducted a series of meta-analyses of oral effectiveness of tenofovir disoproxil fumarate/emtricitabine in women including all 5 randomized placebo-controlled trials that included women. An adherence-based meta-analysis model showed that with high levels of adherence (75%), oral PrEP is estimated to be effective (relative risk = 0.39, 95% confidence interval: 0.25 to 0.60). Provided that these results apply to women in Southern Africa, future prevention trial designs in that region should account for potentially reduced HIV incidence when PrEP is available.

Bayesian accrual prediction for interim review of clinical studies: open source R package and smartphone application.

BACKGROUND: Subject recruitment for medical research is challenging. Slow patient accrual leads to increased costs and delays in treatment advances. Researchers need reliable tools to manage and predict the accrual rate. The previously developed Bayesian method integrates researchers' experience on former trials and data from an ongoing study, providing a reliable prediction of accrual rate for clinical studies. METHODS: In this paper, we present a user-friendly graphical user interface program developed in R. A closed-form solution for the total subjects that can be recruited within a fixed time is derived. We also present a built-in Android system using Java for web browsers and mobile devices. RESULTS: Using the accrual software, we re-evaluated the Veteran Affairs Cooperative Studies Program 558- ROBOTICS study. The application of the software in monitoring and management of recruitment is illustrated for different stages of the trial. CONCLUSIONS: This developed accrual software provides a more convenient platform for estimation and prediction of the accrual process.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). CONCLUSIONS: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Predictors and brain connectivity changes associated with arm motor function improvement from intensive practice in chronic stroke.

Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery.  Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL:  http://www.clinicaltrials.gov. Unique identifiers:  CT00372411 & NCT00333983.

Measuring informed consent capacity in an Alzheimer's disease clinical trial.

INTRODUCTION: Accurately and efficiently determining a participant's capacity to consent to research is critically important to protect the rights of patients with Alzheimer's disease (AD). METHODS: Understanding of the informed consent document was assessed in 613 community-dwelling patients with mild-to-moderate AD enrolled in a randomized, placebo-controlled trial. Associations were examined between clinically determined capacity to consent and (1) patient demographics and clinical characteristics and (2) the Informed Consent Questionnaire (ICQ), an objective measurement of a participant's factual understanding and perceived understanding. RESULTS: A total of 453 (74%) participants were determined to have capacity to consent by clinical judgment. ICQ perceived understanding, race, measures of cognitive function, and caregiver time were all significantly associated with the determination of capacity in multivariate analyses. DISCUSSION: We found a significant association between capacity and disease severity level, caregiver time, race, and ICQ perceived understanding.

Million Veteran Program: A mega-biobank to study genetic influences on health and disease.

OBJECTIVE: To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system. STUDY DESIGN AND SETTING: Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses. RESULTS: Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented. CONCLUSIONS: By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine.

Long-term Effectiveness of Intensive Therapy in Chronic Stroke.

Background While recent clinical trials involving robot-assisted therapy have failed to show clinically significant improvement versus conventional therapy, it is possible that a broader strategy of intensive therapy-to include robot-assisted rehabilitation-may yield clinically meaningful outcomes. Objective To test the immediate and sustained effects of intensive therapy (robot-assisted therapy plus intensive conventional therapy) on outcomes in a chronic stroke population. Methods A multivariate mixed-effects model adjusted for important covariates was established to measure the effect of intensive therapy versus usual care. A total of 127 chronic stroke patients from 4 Veterans Affairs medical centers were randomized to either robot-assisted therapy (n = 49), intensive comparison therapy (n = 50), or usual care (n = 28), in the VA-ROBOTICS randomized clinical trial. Patients were at least 6 months poststroke, of moderate-to-severe upper limb impairment. The primary outcome measure was the Fugl-Meyer Assessment at 12 and 36 weeks. Results There was significant benefit of intensive therapy over usual care on the Fugl-Meyer Assessment at 12 weeks with a mean difference of 4.0 points (95% CI = 1.3-6.7); P = .005; however, by 36 weeks, the benefit was attenuated (mean difference 3.4; 95% CI = -0.02 to 6.9; P = .05). Subgroup analyses showed significant interactions between treatment and age, treatment and time since stroke. Conclusions Motor benefits from intensive therapy compared with usual care were observed at 12 and 36 weeks posttherapy; however, this difference was attenuated at 36 weeks. Subgroups analysis showed that younger age, and a shorter time since stroke were associated with greater immediate and long-term improvement of motor function.

BP and Renal Outcomes in Diabetic Kidney Disease: The Veterans Affairs Nephropathy in Diabetes Trial.

BACKGROUND AND OBJECTIVES: Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured. RESULTS: The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to ≥ 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events. CONCLUSIONS: In patients with proteinuric diabetic kidney disease, mean systolic BP ≥ 140 mmHg and mean diastolic BP ≥ 80 mmHg were associated with worse renal outcomes.

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations.

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial.

Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial.

BACKGROUND: Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack (TIA). The IRIS Trial is evaluating an approach to secondary prevention based on the established association between insulin resistance and increased risk for ischemic vascular events. Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA. DESIGN: Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment-Insulin Resistance > 3.0 without meeting criteria for diabetes. Within 6 months of the index stroke or TIA, patients were randomly assigned to pioglitazone (titrated from 15 to 45 mg/d) or matching placebo and followed for up to 5 years. The primary outcome is time to stroke or MI. Secondary outcomes include time to stroke alone, acute coronary syndrome, diabetes, cognitive decline, and all-cause mortality. Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013. Participant follow-up will continue until July 2015. SUMMARY: The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic, insulin-resistant patients with stroke or TIA. Results are expected in early 2016.