An Innovative Phase I Trial Design Allowing for the Identification of Multiple Potential Maximum Tolerated Doses with Combination Therapy of Targeted Agents

Treatment for cancer often involves combination therapies used both in medical practice and clinical trials. Korn and Simon listed three reasons for the utility of combinations: 1) biochemical synergism, 2) differential susceptibility of tumor cells to different agents, and 3) higher achievable dose intensity by exploiting non-overlapping toxicities to the host. Even if the toxicity profile of each agent of a given combination is known, the toxicity profile of the agents used in combination must be established. Thus, caution is required when designing and evaluating trials with combination therapies. Traditional clinical design is based on the consideration of a single drug. However, a trial of drugs in combination requires a dose-selection procedure that is vastly different than that needed for a single-drug trial. When two drugs are combined in a phase I trial, an important trial objective is to determine the maximum tolerated dose (MTD). The MTD is defined as the dose level below the dose at which two of six patients experience drug-related dose-limiting toxicity (DLT). In phase I trials that combine two agents, more than one MTD generally exists, although all are rarely determined. For example, there may be an MTD that includes high doses of drug A with lower doses of drug B, another one for high doses of drug B with lower doses of drug A, and yet another for intermediate doses of both drugs administered together. With classic phase I trial designs, only one MTD is identified. Our new trial design allows identification of more than one MTD efficiently, within the context of a single protocol. The two drugs combined in our phase I trial are temsirolimus and bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) pathway which is fundamental for tumor growth and metastasis. One mechanism of tumor resistance to antiangiogenic therapy is upregulation of hypoxia inducible factor 1α (HIF-1α) which mediates responses to hypoxic conditions. Temsirolimus has resulted in reduced levels of HIF-1α making this an ideal combination therapy. Dr. Donald Berry developed a trial design schema for evaluating low, intermediate and high dose levels of two drugs given in combination as illustrated in a recently published paper in Biometrics entitled “A Parallel Phase I/II Clinical Trial Design for Combination Therapies.” His trial design utilized cytotoxic chemotherapy. We adapted this design schema by incorporating greater numbers of dose levels for each drug. Additional dose levels are being examined because it has been the experience of phase I trials that targeted agents, when given in combination, are often effective at dosing levels lower than the FDA-approved dose of said drugs. A total of thirteen dose levels including representative high, intermediate and low dose levels of temsirolimus with representative high, intermediate, and low dose levels of bevacizumab will be evaluated. We hypothesize that our new trial design will facilitate identification of more than one MTD, if they exist, efficiently and within the context of a single protocol. Doses gleaned from this approach could potentially allow for a more personalized approach in dose selection from among the MTDs obtained that can be based upon a patient’s specific co-morbid conditions or anticipated toxicities.

Progressive regression of left ventricular hypertrophy two years after bariatric surgery.

BACKGROUND: Obesity is a systemic disorder associated with an increase in left ventricular mass and premature death and disability from cardiovascular disease. Although bariatric surgery reverses many of the hormonal and hemodynamic derangements, the long-term collective effects on body composition and left ventricular mass have not been considered before. We hypothesized that the decrease in fat mass and lean mass after weight loss surgery is associated with a decrease in left ventricular mass. METHODS: Fifteen severely obese women (mean body mass index [BMI]: 46.7+/-1.7 kg/m(2)) with medically controlled hypertension underwent bariatric surgery. Left ventricular mass and plasma markers of systemic metabolism, together with body mass index (BMI), waist and hip circumferences, body composition (fat mass and lean mass), and resting energy expenditure were measured at 0, 3, 9, 12, and 24 months. RESULTS: Left ventricular mass continued to decrease linearly over the entire period of observation, while rates of weight loss, loss of lean mass, loss of fat mass, and resting energy expenditure all plateaued at 9 [corrected] months (P <.001 for all). Parameters of systemic metabolism normalized by 9 months, and showed no further change at 24 months after surgery. CONCLUSIONS: Even though parameters of obesity, including BMI and body composition, plateau, the benefits of bariatric surgery on systemic metabolism and left ventricular mass are sustained. We propose that the progressive decrease of left ventricular mass after weight loss surgery is regulated by neurohumoral factors, and may contribute to improved long-term survival.

Explanations for unsuccessful weight loss among bariatric surgery candidates.

BACKGROUND: Our objective was to analyze subjective explanations for unsuccessful weight loss among bariatric surgery candidates. METHODS: This was a retrospective analysis of 909 bariatric surgery candidates (78.2% female, average body mass index [BMI] 47.3) at a university center from 2001 to April 2007 who answered an open-ended question about why they were unable to lose weight. We generated a coding scheme for answers to the question and established inter-rater reliability of the coding process. Associations with demographic parameters and initial BMI were tested. RESULTS: The most common categories of answers were nonspecific explanations related to diet (25.3%), physical activity (21.0%), or motivation (19.7%), followed by diet-related motivation (12.7%) and medical conditions or medications affecting physical activity (12.7%). Categories related to time, financial cost, social support, physical environment, and knowledge occurred in less than 4% each. Men were more likely than women to cite a medical condition or medication affecting physical activity (19.2% vs 10.8%, P = 0.002, odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.28-2.99) but less likely to cite diet-related motivation (7.1% vs 14.2%, P = 0.008, OR = 0.46, 95% CI = 0.26-0.82). CONCLUSIONS: Our findings suggest that addressing diet, physical activity, and motivation in a comprehensive approach would meet the stated needs of obese patients. Raising patient awareness of under-recognized barriers to weight loss, such as the physical environment and lack of social support, should also be considered. Lastly, anticipating gender-specific attributions may facilitate tailoring of interventions.

Body weight, insulin resistance, and serum adipokine levels 2 years after 2 types of bariatric surgery.

OBJECTIVE: Bariatric surgery reverses obesity-related comorbidities, including type 2 diabetes mellitus. Several studies have already described differences in anthropometrics and body composition in patients undergoing Roux-en-Y gastric bypass compared with laparoscopic adjustable gastric banding, but the role of adipokines in the outcomes after the different types of surgery is not known. Differences in weight loss and reversal of insulin resistance exist between the 2 groups and correlate with changes in adipokines. METHODS: Fifteen severely obese women (mean body mass index [BMI]: 46.7 kg/m(2)) underwent 2 types of laparoscopic weight loss surgery (Roux-en-Y gastric bypass=10, adjustable gastric banding=5). Weight, waist and hip circumference, body composition, plasma metabolic markers, and lipids were measured at set intervals during a 24-month period after surgery. RESULTS: At 24 months, patients who underwent Roux-en-Y were overweight (BMI 29.7 kg/m(2)), whereas patients who underwent gastric banding remained obese (BMI 36.3 kg/m(2)). Patients who underwent Roux-en-Y lost significantly more fat mass than patients who underwent gastric banding (mean difference 16.8 kg, P<.05). Likewise, leptin levels were lower in the patients who underwent Roux-en-Y (P=.003), and levels correlated with weight loss, loss of fat mass, insulin levels, and Homeostasis Model of Assessment 2. Adiponectin correlated with insulin levels and Homeostasis Model of Assessment 2 (r=-0.653, P=.04 and r=-0.674, P=.032, respectively) in the patients who underwent Roux-en-Y at 24 months. CONCLUSION: After 2 years, weight loss and normalization of metabolic parameters were less pronounced in patients who underwent gastric banding compared with patients who underwent Roux-en-Y gastric bypass. Our findings require confirmation in a prospective randomized trial.

A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence.

BACKGROUND: Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence. METHODS: Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed. RESULTS: The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends (p < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence. CONCLUSIONS: Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.

The effect of body mass index on therapeutic response to bacterial vaginosis in pregnancy.

Our objective was to determine the effect of body mass index (BMI) on response to bacterial vaginosis (BV) treatment. A secondary analysis was conducted of two multicenter trials of therapy for BV and TRICHOMONAS VAGINALIS. Gravida were screened for BV between 8 and 22 weeks and randomized between 16 and 23 weeks to metronidazole or placebo. Of 1497 gravida with asymptomatic BV and preconceptional BMI, 738 were randomized to metronidazole; BMI was divided into categories: < 25, 25 to 29.9, and > or = 30. Rates of BV persistence at follow-up were compared using the Mantel-Haenszel chi square. Multiple logistic regression was used to evaluate the effect of BMI on BV persistence at follow-up, adjusting for potential confounders. No association was identified between BMI and BV rate at follow-up ( P = 0.21). BMI was associated with maternal age, smoking, marital status, and black race. Compared with women with BMI of < 25, adjusted odds ratio (OR) of BV at follow-up were BMI 25 to 29.9: OR, 0.66, 95% CI 0.43 to 1.02; BMI > or = 30: OR, 0.83, 95% CI 0.54 to 1.26. We concluded that the persistence of BV after treatment was not related to BMI.

The effect of body mass index on therapeutic response to bacterial vaginosis in pregnancy.

Our objective was to determine the effect of body mass index (BMI) on response to bacterial vaginosis (BV) treatment. A secondary analysis was conducted of two multicenter trials of therapy for BV and TRICHOMONAS VAGINALIS. Gravida were screened for BV between 8 and 22 weeks and randomized between 16 and 23 weeks to metronidazole or placebo. Of 1497 gravida with asymptomatic BV and preconceptional BMI, 738 were randomized to metronidazole; BMI was divided into categories: < 25, 25 to 29.9, and > or = 30. Rates of BV persistence at follow-up were compared using the Mantel-Haenszel chi square. Multiple logistic regression was used to evaluate the effect of BMI on BV persistence at follow-up, adjusting for potential confounders. No association was identified between BMI and BV rate at follow-up ( P = 0.21). BMI was associated with maternal age, smoking, marital status, and black race. Compared with women with BMI of < 25, adjusted odds ratio (OR) of BV at follow-up were BMI 25 to 29.9: OR, 0.66, 95% CI 0.43 to 1.02; BMI > or = 30: OR, 0.83, 95% CI 0.54 to 1.26. We concluded that the persistence of BV after treatment was not related to BMI.

Determining acquisition and cessation antecedents to adolescent cigarette smoking for development of intervention strategies

Our national focus and emphasis on the promotion of healthy behavior choices regarding tobacco and other drugs continues to target adolescents. Multiple studies have shown that adolescence is the optimum period for the prevention of substance use initiation as life-long patterns of health behaviors are established during this critical developmental stage. Tobacco use is associated with an increase in morbid and mortal health conditions of which prevalence increases throughout the lifespan. Attention to the antecedents of preventable health conditions aims to modify the risks and identify health promotion factors. Modifying antecedent factors for tobacco initiation in youth and identifying protective factors for successful smoking cessation has major public health implications across the lifespan. Of foremost interest are those risk factors and resultant behaviors that predict a youth's probability of initiating cigarette use and their cessation of cigarette use. Specifically, this dissertation supports previous results identifying intervention variables on the initiation/cessation continuum model especially with the established predictors of smoking (decisional balance and susceptibility) and with more recently identified predictors of smoking (nicotine dependence and withdrawal symptoms) in current and former smokers in a sample of high school students in Austin and Houston, Texas. These results offer insight for the development of appropriate intervention program strategies for our youth. ^

The association between mental health and hypertension in the 2005 Department of Defense Population Survey

Major objectives within Healthy People 2010 include improving hypertension and mental health management of the American population. Both mental health issues and hypertension exist in the military which may decrease the health status of military personnel and diminish the ability to complete assigned missions. Some cases may be incompatible with military service even with optimum treatment. In the interest of maintaining a fit fighting force, the Department of Defense regularly conducts a survey of health related behaviors among active duty military personnel. The 2005 DoD Survey was conducted to obtain information regarding health and behavioral readiness among active duty military personnel to assess progress toward selected Healthy People 2010 objectives. ^ This study is a cross-sectional prevalence design looking at the association of hypertension treatment with mental health issues (either treatment or perceived need for treatment) within the military population sampled in the 2005 DoD Survey. There were 16,946 military personnel in the final cross-sectional sample representing 1.3 million active duty service members. The question is whether there is a significant association between the self-reported occurrence of hypertension and the self-reported occurrence of mental health issues in the 2005 DoD Survey. In addition to these variables, this survey examined the contribution of various sociodemographic, occupational, and behavioral covariates. An analysis of the demographic composition of the study variables was followed by logistic analysis, comparing outcome variables with each of the independent variables. Following univariate regression analysis, multivariate regression was performed with adjustment (for those variables with an unadjusted alpha level less than or equal to 0.25). ^ All the mental health related indicators were associated with hypertension treatment. The same relationship was maintained after multivariate adjustment. The covariates remaining as significant (p < 0.05) in the final model included gender, age, race/ethnicity and obesity. There is a need to recognize and treat co-morbid medical diagnoses among mental health patients and to improve quality of life outcomes, whether in the military population or the general population. Optimum health of the individual can be facilitated through discovery of treatable cases, to minimize disruptions of military missions, and even allow for continued military service. ^

Integrating diabetes self-management with the health goals of older adults: A qualitative exploration

Objective. This study investigates the life and health goals of older adults with diabetes, and explores the factors that influence their diabetes self-management. Methods: Qualitative in-depth interviews were conducted with 24 older adults with diabetes and other morbid conditions and/or their caregivers, when appropriate. ^ Results. Participants’ provided a consistent set of responses when describing life and health goals. Participants described goals for longevity, better physical functioning, spending time with family, or maintaining independence. Diabetes discordant conditions, but not diabetes, were seen as barriers to life goals for participants with functional impairments. Functionally independent participants described additional health goals that related to diabetes self-management as diabetes was seen often a barrier to life goals. Caregivers, co-morbid conditions, denial and retirement were among the factors that influenced initiation of diabetes self-management. ^ Conclusion. Participants endorsed health goals and diabetes self-management practices that they believed would help them accomplish their life goals. Functional capabilities and social support were key factors in the relationship between diabetes self-management and their broader goals. ^ Practice implications. When planning diabetes treatments, clinicians, patients and caregivers should discuss the relationship between diabetes self-management and health and life goals as well as the affects of functional limitations and caregiver support.^

Does diabetes mellitus contribute to the disease burden of vascular dementia?

Background. Vascular dementia (VaD) is the second most common of dementia. Multiple risk factors are associated with VaD, but the individual contribution of each to disease onset and progression is unclear. We examined the relationship between diabetes mellitus type 2 (DM) and the clinical variables of VaD.^ Methods. Data from 593 patients evaluated between June, 2003 and June, 2008 for cognitive impairment were prospectively entered into a database. We retrospectively reviewed the charts of 63 patients who fit the NINDS-AIREN criteria of VaD. The patients were divided into those with DM (VaD-DM, n=29) and those without DM (VaD, n=34). The groups were compared with regard to multiple variables.^ Results. Patients with DM had a significantly earlier onset of VaD (71.9±6.54 vs. 77.2±6.03, p<0.001), a faster rate of decline per year on the mini mental state examination (MMSE; 3.60±1.82 vs. 2.54±1.60 points, p=0.02), and a greater prevalence of neuropsychiatric symptoms (62% vs. 21%, p=0.02) at the time of diagnosis.^ Conclusions. This study shows that a history of pre-morbid DM is associated with an early onset and faster cognitive deterioration in VaD. Moreover, the presence of DM predicts the presence of neuropsychiatric symptoms in patients with VaD. A larger study is needed to verify these associations. It will be important to investigate whether better glycemic control will mitigate the potential effects of DM on VaD.^

Epidemiological trends of influenza A positive patients hospitalized at St. Luke's Episcopal Hospital, Houston, Texas September, 2009--January, 2010

This study was a descriptive analysis of 437 influenza A positive inpatients and outpatients during the five month period between September, 2009 and January, 2010. The objective of the study was to describe the epidemiological trends of the total influenza A positive population and more specifically the clinical features of patients hospitalized with influenza A at St. Luke's Episcopal Hospital in Houston, Texas from September 2009 through January 2010. Eligible cases were included if they tested positive for influenza A test using the rapid antigen test and/or rRT-PCR. Hospitalized cases were included based on the laboratory confirmation of influenza A as well as hospital admission for at least 24 hours. Data was collected from medical record abstraction and included patient demographics, clinical history and history of chronic disease. Clinical findings in the differential diagnosis that led to laboratory-confirmation of influenza A as well as course of treatment during the hospital admission were summarized. Finally, co-morbid conditions charted during the hospital visit were reviewed and evaluated for associations with influenza A complications. During the study period, forty-eight patients were included in the study of which 27 tested positive for the H1N1 subtype. Females were more likely to be hospitalized than men. The median age of all patients admitted to St. Luke's Episcopal Hospital with influenza A was 42. The distribution for admitted cases was 15 White, 15 Black, and 18 Hispanic. Patients with co-morbid disease constituted 81% of the admissions for Influenza A. The presence of an underlying medical condition remains a risk factor for both seasonal and H1N1 influenza. Although respiratory conditions such as asthma and COPD are commonly associated with complications of seasonal influenza, patients with metabolic disorders such as kidney disease and/or diabetes were admitted more frequently (58%) during the study period. The patients in the study also of a much younger age than the age that is usually associated with complications of influenza infection, i.e. no patients greater than 65 years of age were admitted with a diagnosis of influenza A. Lower infection rates among elderly populations were similarly reported in other studies of influenza during the same time period. Older patient populations may benefit from antibodies to previous H1N1 strains that have circulated during the twentieth century, whereas younger age groups lack these exposures.^