Assessing the feasibility of the Effectiveness of Discontinuing Bisphosphonates trial: a pilot study.

The Effectiveness of Discontinuing Bisphosphonates (EDGE) study is a planned pragmatic clinical trial to guide "drug holiday" clinical decision making. This pilot study assessed work flow and feasibility of such a study. While participant recruitment and treatment adherence were suboptimal, administrative procedures were generally feasible and minimally disrupted clinic flow. INTRODUCTION: The comparative effectiveness of continuing or discontinuing long-term alendronate (ALN) on fractures is unknown. A large pragmatic ALN discontinuation study has potential to answer this question. METHODS: We conducted a 6-month pilot study of the planned the EDGE study among current long-term ALN users (women aged ≥65 with ≥3 years of ALN use) to determine study work flow and feasibility including evaluating the administrative aspects of trial conduct (e.g., time to contract, institutional review board (IRB) approval), assessing rates of site and participant recruitment, and evaluating post-randomization outcomes, including adherence, bisphosphonate-associated adverse events, and participant and site satisfaction. We assessed outcomes 1 and 6 months after randomization. RESULTS: Nine sites participated, including seven community-based medical practices and two academic medical centers. On average (SD), contract execution took 3.4 (2.3) months and IRB approval took 13.9 (4.1) days. Sites recruited 27 participants (13 to continue ALN and 14 to discontinue ALN). Over follow-up, 22% of participants did not adhere to their randomization assignment: 30.8% in the continuation arm and 14.3% in the discontinuation arm. No fractures or adverse events were reported. Sites reported no issues regarding work flow, and participants were highly satisfied with the study. CONCLUSIONS: Administrative procedures of the EDGE study were generally feasible, with minimal disruption to clinic flow. In this convenience sample, participant recruitment was suboptimal across most practice sites. Accounting for low treatment arm adherence, a comprehensive recruitment approach will be needed to effectively achieve the scientific goals of the EDGE study.

Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial.

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.

What liver transplant outcomes can be expected in the uninsured who become insured via the Affordable Care Act?

Our study objective is to measure the survival impact of insurance status following liver transplantation in a cohort of uninsured "charity care" patients. These patients are analogous to the population who will gain insurance via the Affordable Care Act. We hypothesize there will be reduced survival in charity care compared to other insurance strata. We conducted a retrospective study of 898 liver transplants from 2000 to 2010. Insurance cohorts were classified as private (n = 640), public (n = 233) and charity care (n = 23). The 1, 3 and 5-year survival was 92%, 88% and 83% in private insurance, 89%, 80% and 73% in public insurance and 83%, 72% and 51% in charity care. Compared to private insurance, multivariable regression analyses demonstrated charity care (HR 3.11, CI 1.41-6.86) and public insurance (HR 1.58, CI 1.06-2.34) had a higher 5-year mortality hazard ratio. In contrast, other measures of socioeconomic status were not significantly associated with increased mortality. The charity care cohort demonstrated the highest incidence of acute rejection and missed clinic appointments. These data suggest factors other than demographic and socioeconomic may be associated with increased mortality. Further investigations are necessary to determine causative predictors of increased mortality in liver transplant patients without private insurance.

Experimental pain sensitivity differs as a function of clinical pain severity in symptomatic knee osteoarthritis.

OBJECTIVE: Pain in knee osteoarthritis (OA) has historically been attributed to peripheral pathophysiology; however, the poor correspondence between objective measures of disease severity and clinical symptoms suggests that non-local factors, such as altered central processing of painful stimuli, also contribute to clinical pain in knee OA. Consistent with this notion, recent evidence demonstrates that patients with knee OA exhibit increased sensitivity to painful stimuli at body sites unaffected by clinical pain. DESIGN: In order to further investigate the contribution of altered pain processing to knee OA pain, the current study tested the hypothesis that symptomatic knee OA is associated with enhanced sensitivity to experimental pain stimuli at the knee and at remote body sites unaffected by clinical pain. We further anticipated that pain sensitivity would differ as a function of the OA symptom severity. Older adults with and without symptomatic knee OA completed a series of experimental pain assessments. A median split of the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) was used to stratify participants into low vs high OA symptom severity. RESULTS: Compared to controls and the low symptom group, individuals in the high symptom group were more sensitive to suprathreshold heat stimuli, blunt pressure, punctuate mechanical, and cold stimuli. Individuals in the low symptomatic OA group subgroup exhibited experimental pain responses similar to the pain-free group on most measures. No group differences in endogenous pain inhibition emerged. CONCLUSIONS: These findings suggest that altered central processing of pain is particularly characteristic of individuals with moderate to severe symptomatic knee OA.

Chemical recovery and browning of Nova Scotia surface waters in response to declining acid deposition.

Declining emissions of sulfur and nitrogen have curtailed acid deposition across large areas of North America and Europe. This has allowed many lakes to recover from acidification, with decreases in sulfate, increases in pH, and increases in alkalinity. But reduced acid deposition has not always coincided with chemical lake recovery. Surface waters in Nova Scotia did not exhibit clear evidence of recovery as recently as 2007, due in part to increasing organic acidity and slow replenishment of base cations. In an updated assessment with data collected as recently as 2019, we analyze water chemistry representing 81 lakes and rivers and two precipitation monitoring stations over up to 41 years. We find that Nova Scotia surface waters are now exhibiting signs of chemical recovery. We estimated the linear decrease in precipitation sulfate and nitrate yield at up to 0.31 and 0.18 kg ha-1 year-2, respectively, and the linear increase in precipitation pH at up to 0.014 year-1. Sulfate decreased in 60 of 62 lakes and 14 of 17 rivers (-0.0051 to -0.23 mg L-1 year-1), while pH increased in 55 of 64 lakes and 11 of 17 rivers (0.0015-0.072 year-1). Apparent colour increased in 54 of 62 lakes and 13 of 17 rivers (0.0026-3.9 Pt-Co year-1). We identified increasing aluminum trends in 46 of 61 lakes, and we show using size-exclusion chromatography that binding to organic and iron-based colloids may help to explain these trends. To the extent that increases in apparent colour are explained by chromophoric dissolved organic matter (DOM), they imply greater binding capacity for metals in surface waters, and greater capacity for DOM to stabilize metal (oxyhydr)oxide colloids.

Changes in pediatric waist circumference percentiles despite reported pediatric weight stabilization in the United States.

BACKGROUND: Obesity is a global health concern but the United States has reported a leveling in obesity rates in the pediatric population. OBJECTIVE: To provide updated waist circumference (WC) percentile values, identify differences across time and discuss differences within the context of reported weight stabilization in a nationally representative sample of American children. METHODS: Percentiles for WC in self-identified African Americans (AA), European Americans (EA) and Mexican Americans (MA) were obtained from 2009-2014 National Health and Nutrition Examination Survey data (NHANES2014). Descriptive trends across time in 10th, 25th, 50th, 75th and 90th percentile WC distributions were identified by comparing NHANES2012 with previously reported NHANESIII (1988-1994). RESULTS: WC increased in a monotonic fashion in AA, EA and MA boys and girls. When compared with NHANESIII data, a clear left shift of percentile categories was observed such that values that used to be in the 90th percentile are now in the 85th percentile. Differences in WC were observed in EA and MA boys during a reported period of weight stabilization. CONCLUSION AND RELEVANCE: WC has changed in the US pediatric population across time, even during times of reported weight stabilization, particularly among children of diverse racial/ethnic backgrounds.

Vitamin D and incident urinary incontinence in older adults.

BACKGROUND/OBJECTIVES: The aim of this study is to determine whether vitamin D status is associated with incident urinary incontinence (UI) among community-dwelling older adults. SUBJECTS/METHODS: The University of Alabama at Birmingham Study of Aging is a prospective cohort study of community-dwelling Medicare enrollees. Standardized assessment of UI was conducted using the validated Incontinence Severity Index. The analysis of 25-hydroxyvitamin D [25(OH)D] levels was performed on stored baseline sera. UI was assessed every 6-12 months for up to 42 months. The analyses included multivariable logistic regression and Cox proportional hazard models. RESULTS: Of 350 participants (175 male, 147 black, mean age 73.6±5.8), 54% (189/350) were vitamin D deficient (25(OH)D <20 ng/ml) and 25% (87/350) were vitamin D insufficient (25(OH)D: 20 ng/ml to <30 ng/ml). Among the 187 subjects with no UI at baseline, 57% (107/187) were vitamin D deficient and 24% (45/187) were vitamin D insufficient. A total of 175 of the 187 subjects had follow-up evaluation for incident UI over 42 months, and incident UI occurred in 37% (65/175). After adjustment, cumulative incident UI at 42 months was associated with baseline vitamin D insufficiency (P=0.03) and demonstrated a trend association with deficiency (P=0.07). There was no association between baseline vitamin D status and the time to incident UI. CONCLUSIONS: These preliminary results support an association between vitamin D and incident UI in community-dwelling older adults. Future studies may target specific at-risk groups, such as men with BPH or women with pelvic floor disorders for evaluation of the impact of vitamin D supplementation on urinary symptoms.

The p44S10 locus, encoding a subunit of the proteasome regulatory particle, is amplified during progression of cutaneous malignant melanoma.

Gene amplification is frequently present in human tumors, although specific target genes relevant to many amplified loci remain unidentified. An expression cloning assay enabled identification of a candidate oncogene derived from human chromosome 3p14.1. The cDNA retrieved from morphologically transformed cells contained the full-length protein coding region and detected an abundant transcript in the same cells. Sequence analysis revealed identity with the wild-type sequence of p44S10, a highly conserved subunit of the 26S proteasome that exhibits similarity to the Arabidopsis fus6/cop11 family of signaling molecules. p44S10 gene copy number and mRNA expression were increased in association with segmental 1.8 - 11-fold chromosomal gains in cutaneous malignant melanoma cell lines (5/13; 40%) and tumors (2/40; 5%), and in breast cancer MCF-7 cells. Likewise, malignant progression of human radial growth phase WM35 melanoma cells was associated with amplification and increased expression of endogenous p44S10, and increased expression of p44S10 was sufficient to induce proliferation of WM35 cells in vivo. The results demonstrate segmental copy number gains within chromosome 3p in cutaneous malignant melanoma and suggest that deregulation of a proteasome regulatory particle subunit may contribute to the malignant phenotype.

Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy.

PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL. CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.

Nutritional status of urban homebound older adults.

The purposes of this study were to assess comprehensively the nutritional status of frail older adults living in an urban area and to identify factors associated with nutritional insufficiency. Subjects were 49 adults aged > or = 65 y followed by the Jefferson County Home Health Department. Twenty-nine percent of the women and 63% of the men had a body mass index (BMI; in kg/m2) < 24. Nineteen percent had serum albumin concentrations < 35 g/L (3.5 g/dL). More than one-half of the subjects reported symptoms of oral health problems. The key dependent variables were serum albumin concentration and BMI. In univariate analyses, a lower BMI correlated with oral symptoms, male sex, increased age, and less education. Lower serum albumin concentrations were associated with advanced age, increased dependence in Activities of Daily Living (ADL), oral symptoms, and presence of a caregiver. A stepwise multiple-regression model for BMI and serum albumin showed that predictors of low BMI were increased age, less education, difficulty in chewing, and absence of dentures. Variables in the model for lower serum albumin concentrations were sex, increased age, increased dependence in ADLs, and wearing of dentures. In a secondary analysis that controlled for age, education level, functional status, and sex, oral symptoms remained associated with lower BMI but not with lower serum albumin concentrations. This study found a high prevalence of undernutrition in urban homebound older adults and suggests that oral health disability may affect nutritional status in this population.

Energy expenditure and free-living physical activity in black and white women: comparison before and after weight loss.

BACKGROUND: The prevalence of obesity is higher in black than in white women. Differences in energy economy and physical activity may contribute to this difference. OBJECTIVE: The objective of this study was to compare free-living energy expenditure and physical activity in black and white women before and after weight loss. DESIGN: Participants were 18 white and 14 black women with body mass indexes (in kg/m(2)) between 27 and 30. Diet, without exercise, was used to achieve a weight loss of >/=10 kg and a body mass index <25. After 4 wk of energy balance in overweight and normal-weight states, body composition was assessed by using a 4-compartment model, sleeping and resting energy expenditures were assessed by using a chamber calorimeter, physiologic stress of exercise and exercise economy were measured by using standardized exercise tasks, and daily energy expenditure was assessed by using doubly labeled water. RESULTS: Weight loss averaged 12.8 kg. Sleeping and resting energy expenditures decreased in proportion to changes in body composition. Weight reduction significantly improved physiologic capacity for exercise in both groups of women, making it easier for them to be physically active. Black women had lower body composition-adjusted energy requirements than did white women-both before and after weight loss-during sleep (9% lower, 519 kJ/d; P < 0.001), at rest (14% lower, 879 kJ/d; P < 0.001), during exercise (6% lower; P < 0. 05), and as a daily total (9% lower, 862 kJ/d; P < 0.06). By contrast, free-living physical activity was similar between the groups. CONCLUSIONS: Weight-reduced women had metabolic rates appropriate for their body sizes. Black women had lower resting and nonresting energy requirements in both overweight and normal-weight states than did white women and did not compensate with greater physical activity, potentially predisposing them to greater weight regain.

Phase I/IIa study of concurrent paclitaxel and cisplatin with radiation therapy in locally advanced non-small cell lung cancer: analysis of early and late pulmonary morbidity.

Recent efforts to improve survival outcome in patients with locally advanced non-small cell lung cancer have focused on the use of chemoradiotherapy regimens containing vinblastine/cisplatin or etoposide/cisplatin. However, the overall treatment outcome with these regimens remains poor, emphasizing the need for new therapeutic options. Based on the activity of paclitaxel in advanced non-small cell lung cancer, its additive cytotoxicity with cisplatin, and the radiation-sensitizing effect of both agents, a phase I/IIa study was designed to examine the feasibility of paclitaxel/cisplatin concurrently with conventional thoracic irradiation in patients with locally advanced tumors. One major concern regarding combined modality therapy has been the enhancement of pulmonary toxicity. This report describes the incidence and severity of pulmonary toxicities observed in this trial according to the Radiation Therapy Oncology Group scoring criteria. A literature-based review was performed in an attempt to determine the impact of paclitaxel-based versus non-paclitaxel-based chemoradiotherapy regimens on the early and late pulmonary morbidity. Twenty-four evaluable patients died and 14 (37%) are still alive without evidence of disease. The 1- and 2-year survival rates are 62% and 40%, respectively, with a median survival of 17 months. Pulmonary toxicity >/=grade 2 was more frequently manifested as late toxicity in approximately 70% of the patients. In most, prompt symptomatic and radiologic improvement was observed with the early administration of corticosteroids. There were three late grade 5 toxicities characterized by diffuse (bilateral) rapidly progressive interstitial infiltrates. Protracted lymphocytopenia was noted in the great majority of patients, and its role in the pathogenesis of this complication remains to be determined. There were minor changes in pulmonary function parameters, except in the forced vital capacity and diffusion capacity to carbon monoxide. In a univariate analysis, no relationship was noted between paclitaxel dose level, degree of lymphocytopenia, changes in pulmonary function indices, and incidence of pulmonary toxicity. However, there was a significant dose-volume relationship (using conventional dose-volume histograms) with late pulmonary toxicity at radiation doses between 15 Gy and 30 Gy. Based on a literature review, paclitaxel-based chemotherapy regimens seem to be associated with a slightly higher risk of pulmonary toxicity; however, comparison of such toxicity between trials has many limitations that require that the conclusion reached be viewed with caution.

Natural history of arteriovenous grafts in hemodialysis patients.

Most hemodialysis patients in the United States have an arteriovenous graft as their vascular access. Grafts have a relatively short life span and are prone to recurrent stenosis and thrombosis, requiring multiple salvage procedures to maintain their patency. There is little information in the literature regarding the clinical factors that determine graft survival and complications. We evaluated prospectively the outcomes of 256 grafts placed at a single institution during a 2-year period. A salvage procedure to maintain graft patency (thrombectomy, angioplasty, or surgical revision) was required in 29% of the grafts at 3 months, 52% at 6 months, 77% at 12 months, and 96% at 24 months. Thus, primary graft survival (time from graft placement to the first intervention) was only 23% at 1 year and 4% at 2 years. Primary graft survival was significantly less among patients with hypoalbuminemia compared with patients with a normal serum albumin level (P = 0.003). Secondary graft survival (time from graft placement to permanent graft failure) was 65% at 1 year and 51% at 2 years. Neither primary nor secondary graft survival was significantly correlated with patient age, sex, diabetic status, body mass index, or graft site. A mean of 1.22 interventions per graft-year were required to maintain access patency, including 0.51 thrombectomies, 0.54 angioplasties, and 0.17 surgical revisions. In conclusion, hypoalbuminemia is a strong predictor of the requirement for an early graft intervention. Patients with hypoalbuminemia may require a heightened index of suspicion in monitoring their grafts for evidence of stenosis.

A prospective trial of telepathology for intraoperative consultation (frozen sections).

Telepathology is a maturing technology that, for a variety of reasons, has not been widely deployed. In addition, clinical validation is relatively modest compared with accepted telemedicine applications such as teleradiology. A prototype telepathology system (Tele-Path(sm)) featuring high-resolution images selected from a remote microscope site has been developed at the University of Alabama at Birmingham (UAB). To validate the diagnostic efficacy of the system, a prospective study was undertaken of parallel diagnoses by conventional microscopy and telepathology with a remotely operated microscope. Slides from 99 intraoperative consultations from 29 tissue/ organ sites in the University of Alabama Hospitals by 9 academic pathologists were used in the study. Each microscopic and telepathology diagnosis was compared with the final diagnosis rendered by a referee pathologist. Diagnoses were classified as correct, false positive, or false negative or classification error. Of the 99 frozen sections evaluated, 3 cases were deferred. Of the remaining 96 cases, 2 received incorrect diagnoses in both the microscopic and telepathology arms of the study. Three errors occurred only in the telepathology arm. There was 1 false-positive diagnosis, 1 false-negative diagnosis, and 1 classification error. Statistical analysis indicated no significant difference between telepathology and conventional microscopy. Qualitative data indicated that the pathologists were generally satisfied with the performance of the system. Telepathology using this system paradigm is sufficiently accurate for real time utilization in a complex surgical environment. Telepathology therefore may be an effective model to support the surgical services of hospitals lacking full-time pathology coverage, resulting in full-time access to anatomic pathology services.

Retinal venous oxygen saturation correlates with blood volume.

OBJECTIVES: To evaluate the sensitivity of retinal venous O2 saturation (SrvO2) for early blood loss and reinfusion. A secondary objective was to measure the correlation between SrvO2 and mixed venous O2 saturation (SvO2) during blood loss and reinfusion. METHODS: Seven anesthetized swine were bled at 0.8 mL/kg/min to 16 mL/kg. Shed blood was re-infused at the same rate and the swine were allowed to equilibrate. After equilibration, repeat hemorrhages were performed at 1.6 mL/kg/min and 2.4 mL/kg/min. SrvO2 was measured using an eye oximeter (EOX) and SvO2 was measured using a fiber-optic catheter. RESULTS: During blood loss, SrvO2 correlated with blood removed (r = -0.88, -0.97, -0.96) and SvO2 (r = 0.87, 0.98, 0.92). During reinfusion, SrvO2 correlated with blood re-infused (r = 0.63, 0.76, 0.82) and SvO2 (r = 0.80, 0.93, 0.96). SrvO2 decreased 1.22 +/- 0.60%/mL/kg of blood removed. The rate of decrease in SrvO2 per minute (deltaSrvO2) when blood was removed at 2.4 mL/kg/min was significantly greater than deltaSrvO2 when blood was removed at 0.8 mL/kg/min (p < 0.007). The rates of change in blood pressure (BP) and pulse were not significantly different at any rate of blood removal. CONCLUSIONS: In this model, retinal venous O2 saturation correlated with blood volume and central venous O2 saturation. Unlike the rate of change in BP and heart rate, deltaSrvO2 values were significantly different at different rates of blood removal. Use of an EOX to monitor for blood loss, estimate the rate of hemorrhage, and evaluate the response to therapy during resuscitation warrants further study.

Effects of small-peptide and whole-protein enteral feedings on serum proteins and diarrhea in critically ill patients: a randomized trial.

BACKGROUND: It has been proposed that enteral feeding formulas containing small peptides are more efficacious and better tolerated than whole-protein formulas in critically ill patients. METHODS: Intensive care unit patients were stratified with regard to treatment with antibiotics and serum albumin and randomized to treatment with a small-peptide enteral diet or an isoenergetic, isonitrogenous whole-protein diet for 10 days. To assess efficacy, we measured serum prealbumin and fibronectin, and to assess tolerance, we monitored the incidence of diarrhea. A protocol was followed to ascertain all causes of diarrhea (defined as > 200 g stool or > or = 3 liquid stools on 2 consecutive days). RESULTS: Fifty subjects completed the trial. Serum prealbumin and fibronectin increased between 21% and 36% in both groups, but the increase was significant only in the small-peptide group. The change in fibronectin between days 5 and 10 was significantly greater in the small-peptide group (p = .02). Diarrhea occurred in 10 subjects (17.8% of days) receiving small-peptide feeding and 4 subjects (7.5% of days) receiving whole-protein feeding (P = .07 for incidence and 0.03 for prevalence), but the difference was explained by the coincidental use of more diarrhea-causing medications in the former. Only one case of diarrhea could be attributed to tube feeding. CONCLUSIONS: During 10 days of feeding, the small-peptide diet produced slightly greater increases in serum rapid-synthesis proteins than did the whole-protein diet, especially between days 5 and 10. The clinical implications of this difference between the diets are unknown. Both small-peptide and whole-protein diets were well tolerated.

A two stage conditional power adaptive design adjusting for treatment by covariate interaction.

During the design and planning phase of clinical trials, researchers often assume that no covariate by treatment interaction exists. This assumption has led to many trials being underpowered to detect such interactions and perhaps inaccurate interpretation of treatment effects. We propose a two-stage adaptive design that incorporates the likely existence of a treatment by covariate interaction into the design and implementation of the clinical trial. The information in stage 1 is used to test for the presence of the covariate by treatment interaction. A statistically significant interaction influences how the second stage of the trial will be implemented, thereby aiding in the full understanding and consequently, an accurate interpretation of the treatment effect. We examine the statistical properties of the proposed design using a binary outcome under different types of covariate by treatment interactions and treatment allocation schemes. A conditional power approach is used to prevent inflation of the overall trial type I error rate while maintaining adequate statistical power conditional on the statistically significant interaction.

Stochastically curtailed phase II clinical trials.

Phase II trials often test the null hypothesis H(0): p or=p(1), where p is the true unknown proportion responding to the new treatment, p(0) is the greatest response proportion which is deemed clinically ineffective, and p(1) is the smallest response proportion which is deemed clinically effective. In order to expose the fewest number of patients to an ineffective therapy, phase II clinical trials should terminate early when the trial fails to produce sufficient evidence of therapeutic activity (i.e. if p or=p(1)), the trial should declare the drug effective in the fewest patients possible to allow for advancement to a phase III comparative trial. Several statistical designs, including Simon's minimax and optimal designs, have been developed that meet these requirements. In this paper, we propose three alternative designs that rely upon stochastic curtailment based on conditional power. We compare and contrast the properties of the three approaches: (1) stochastically curtailed (SC) binomial tests, (2) stochastically curtailed (SC) Simon's optimal design, and (3) SC Simon's minimax design to those of Simon's minimax and Simon's optimal designs. For each of these designs we compare and contrast the number of opportunities for study termination, the expected sample size of the trial under the null hypothesis (p