Peter D. Guarino

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.

Methodological Issues in Comparative Effectiveness Research: Clinical Trials

The US Department of Veterans Affairs (VA) Cooperative Studies Program has been conducting comparative effectiveness clinical trials for nearly 4 decades in many disease areas, including cardiovascular disease/surgery, diabetes mellitus, mental health, neurologic disorders, cancer, infectious diseases, and rheumatoid arthritis. The features that have made this program advantageous for conducting comparative effectiveness clinical trials are described along with methodological considerations for future trials based on lessons learned from its experience conducting these types of studies. Some of the lessons learned involve managing risk factors, clinical equipoise, patient preferences, evolving technology, the use of usual care as a comparator and pharmaceutical issues related to study drug blinding. These issues are not unique to the VA but can play an important role in enabling valid comparisons between treatments that may have differences in delivery or mechanisms of action and could affect the execution and feasibility of conducting a clinical trial with a comparative effectiveness aim. We also outline some future directions for comparative effectiveness clinical trials.

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).

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; Pu2009=u2009.92). 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

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

Accurately and efficiently determining a participants capacity to consent to research is critically important to protect the rights of patients with Alzheimers disease (AD).

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 45u2009mg 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.

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 Alzheimers 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.

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

Because apolipoprotein E (APOE) genotypes are known risk factors for Alzheimers disease (AD), they have been measured in clinical trial participants to determine their effect on treatment outcome.